Beone Medicines-h Aktie

Good day, everyone. Welcome to BeOne Medicines Q3 2026 Earnings Call webcast. [Operator Instructions] At this time, I would like to turn the call over to the company.

Hello, and welcome. Thanks for joining us today. I'm Dan Maller, Head of Investor Relations at BeOne Medicines. Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentation on the Investor Relations section of our website, ir.beonemedicines.

I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most recent periodic report filed with the SEC. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation.

Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our Investor Relations website along with our earnings release. All information in this presentation is as of the date of the presentation, and we undertake no duty to update such information unless required by law.

Now turning to today's call as outlined on Slide 3. John Oyler, our Co-Founder, Chairman and CEO, will provide a business update; Aaron Rosenberg, our CFO, will provide an update on our third quarter financial results and 2026 financial guidance; and Lai Wang, President and Global Head of R&D, will discuss our R&D and pipeline progress. We will then open the call for questions.

Joining the team for the Q&A portion of the call will be Xiaobin Wu, President and Chief Operating Officer; Matt Shaulis, our General Manager of North America; Mark Lanasa, Chief Medical Officer for Solid Tumors; and Amit Agarwal, Chief Medical Officer for Hematology. I'll now pass the call over to John. John?

Thank you, Dan, and welcome. I'm pleased to present our Q3 results today across every dimension of the business. BeOne is executing at the very highest level in our history. The results speak for themselves. Financially, we continue to deliver rapid growth and strong earnings. Aaron will take you through that shortly.

In hematology, BRUKINSA's powerful and sustained BTK inhibition continues to translate into clinical and real-world differentiation. Building on BRUKINSA, BEQALZI and tacabrutideg are expanding our leadership and extending it well into the future. In solid tumors, we're living up to our promise that 2026 would be an inflection year. Last week, we shared data for 3 of our most promising programs at ESMO. We have now shared differentiated data for 5 pivotal late-stage solid tumor programs.

We've reached a level of productivity that I think is very rare in our industry. And the model we have worked so hard to build is already delivering very tangible results and we've only just begun to scratch the surface of what's possible. Here, we see BRUKINSA's performance for the quarter. Sales totaled $1.4 billion, growing 34% year-over-year with U.S. sales exceeding $1 billion for the quarter for the first time.

The underlying fundamentals continue to be very strong. BRUKINSA is not just a leader in CLL. It's a powerful treatment option across 4 other B-cell malignancies, and we are far from done. BRUKINSA, both as a single agent and in combination, continues to generate the most Phase III data across the BTKI class. We often talk about BRUKINSA's clinical differentiation. It was designed for complete and sustained BTK inhibition, and it remains the only CLL therapy to show PFS superiority over ibrutinib in a head-to-head trial.

The results we see in the clinical trial data for BRUKINSA are increasingly reinforced in the real world, and the picture is remarkably consistent. This slide brings together 6 independent data sets in CLL, representing tens of thousands of patients across 3 endpoints: overall survival, time to discontinuation and time to next treatment. Across all of it, the answer is the same. All 21 hazard ratios favor BRUKINSA. And overall survival versus acala, the 4 large U.S. claims data sets, including Medicare, range from 16% to 25% lower risk of death versus ibrutinib, the reduction was 27% to 36%.

Taken together across U.S. and European patients, claims and health records, survival and treatment durability and versus both acala and ibrutinib, the real-world evidence consistently favors BRUKINSA. BRUKINSA has established a strong foundation in hematology, but it's only the beginning of what we believe our heme franchise can achieve. With BRUKINSA, BEQALZI and tacabrutideg, we're the only company with potentially best-in-class medicines across the 3 key mechanisms of action in B-cell malignancies.

So whether a patient wants continuous or fixed duration therapy or requires an option after progression, we will be able to meet the need with the right medicine alone or in combination. No other company is positioned to do that. This isn't hypothetical. In the pivotal trials for the regimens on this slide, they're already reading out, and the data will be coming fast and furious over the next 3 years. And behind these 3 promising medicines, the next wave of heme assets from our prolific discovery engine is entering the clinic. And this includes small molecules, multispecific antibodies and novel cell therapies.

Now turning to solid tumors. Over the past several months, we've shared differentiated data for 5 programs, our GPC3 x 4-1BB bispecific antibody, our brain-penetrant PRMT5 inhibitor, our CEA ADC, our CDK4 inhibitor and our B7-H4 ADC. Most companies have just 1 exciting asset. Some have 2. From just the first wave of our solid tumor pipeline, we have 5, all advancing towards registration-enabling development in roughly the same time. These programs target some of the most common and deadly cancers in the world, including lung, breast, liver, gastric and ovarian cancer.

Together, they affect millions of patients every year and account for millions of cancer deaths worldwide. When we started this company 16 years ago, the goal was simple: to fight cancer and to fight for life and also to dramatically change how things were done in our industry by building a company that could sustain that purpose. And today, that's no longer a vision. It's a reality. So how are we doing this? This slide reiterates something fundamentally different about BeOne.

For years, we've talked about our goal to build a lasting oncology company, one that generates higher returns for each dollar of R&D investment by leveraging our global development super highway. Today, we're seeing the results. Over the last 3 years, we brought more new oncology medicines into the clinic than any other company in our industry. We are moving them through the clinic with exceptional speed behind the power of our global development super highway.

Our CDK4 inhibitor and B7-H4 ADC programs show what this looks like in practice, both moved from first-in-human to pivotal development in just 2.5 years, allowing us to rapidly close the gap with the competition. And now we're seeing that pipeline advance into registrational trials, which puts BeOne in an exceptionally select group of oncology innovators. So if you look back at any 18-month period in oncology since 2010, very few companies have ever seen this level of late-stage productivity.

Our peers on this list are the largest, most accomplished pharma companies in the world with R&D budgets many times ours. And yet, there we are, among the top. Our scientists are generating more high-quality shots on goal. We're advancing them faster. And importantly, we're converting them into late-stage programs. And really, we're just getting started. At BeOne, we believe we've created something truly special. So I just want to thank the team again for doing this.

After these years of sustained investment and hard work, we've certainly built a model that's unique in the industry and is extremely difficult to replicate. It's built on 4 competitive advantages: rigorous and prolific internal research, our global development super highway, global commercial presence and an entrepreneurial culture driven by a deep sense of urgency because cancer patients just can't wait. These advantages create a self-reinforcing feedback loop.

Together, they enable us to drive industry-leading R&D returns at scale, turn that innovation into profitable growth and to fund a growing level of investment in next-generation medicines. Each turn of the cycle strengthens the next. That compounding effect is BeOne's greatest long-term competitive advantage and the best way to maximize long-term value is to keep investing behind it.

As Aaron will discuss later, we think it's important to retain the financial flexibility to fully fund the opportunities we see in the business. We believe this is the right approach to bring more transformative medicines to patients and to achieve our goal of building the world's leading oncology company. And with that, I'll turn it over to Aaron to discuss our financial performance. Aaron?

Thanks, John. Our third quarter results demonstrate continued strong execution across the business with broad-based revenue growth, expanding operating income and strong cash generation. Starting with our commercial performance. We delivered another strong quarter across the portfolio with product revenue growing 33% year-over-year to approximately $1.9 billion. BRUKINSA global revenues reached approximately $1.4 billion, representing 34% of sustained global leadership and growth in all regions.

U.S. BRUKINSA sales exceeded $1 billion in the quarter, representing growth of 36%. Growth was driven by continued strong demand with trends consistent with those that I discussed last quarter. These include sustained high level of new patient starts, meaningful growth from all approved indications, improved patient adherence and duration of treatment compared to relevant historical benchmarks. U.S. BRUKINSA sales did have an approximate $50 million tailwind due to order timing, inclusive of an extra shipping day in the quarter.

TEVIMBRA generated approximately $243 million, growing 28% year-over-year. We maintained our leadership position in China and saw launches in other markets increasingly contributing to growth. Since the August U.S. approval and launch of the Horizon regimen, we have seen encouraging early prescriber reception, reflecting the strength of the triplets differentiated profile in first-line HER2-positive GEA. Our Amgen in-licensed portfolio generated approximately $167 million, growing 26% year-over-year. Overall, we are pleased with the breadth of performance across the portfolio and the continued strength of the underlying commercial business.

Let's turn to the geographic composition of our business. Growth remains broad-based across every region. The U.S. generated approximately $1 billion in product revenue and remains our largest market. BEQALZI launched in the U.S. in the relapsed/refractory MCL, and we are excited for this innovative medicine to be available for patients in this setting. Given the size of the approved indication and the timing of launch, we do not expect BEQALZI to be a meaningful revenue driver this year.

China contributed approximately $527 million, growing 21% in its seasonally high third quarter. Growth was seen across our commercial portfolio with continued market leadership for both TEVIMBRA and BRUKINSA and launch contributions from BEQALZI and ZIIHERA. Note that foreign exchange contributed 7% of reported growth given year-over-year Renminbi strengthening. While our Amgen portfolio delivered 26% growth in Q3, we are beginning to see some impact from biosimilars for XGEVA that was highlighted earlier in the year. This competition, along with potential VBP inclusion risk for XGEVA and Kyprolis will likely lead to revenue pressure for these brands beyond 2026.

Europe generated approximately $234 million, growing 41%, driven by demand growth for BRUKINSA and launch uptake for TEVIMBRA. And our rest of world markets contributed approximately $80 million, representing 58% growth. Key markets such as Japan and Brazil are making contributions that are increasingly meaningful at the enterprise level. Turning to the GAAP P&L. Total revenue was $1.9 billion compared with $1.4 billion in the prior year. Gross margin was approximately 88%. This includes a noncash intangible asset impairment charge of $22 million associated with the company's decision to revert promotional rights for POBEVCY.

Operating expenses totaled approximately $1.25 billion, representing 19% growth as we continue to invest behind the advancement of our pipeline and commercial growth. Moving down the P&L. We continue to demonstrate substantial scalability in the model with income from operations growing 157% to $419 million, even as we continue to increase investment behind the tremendous opportunity of our late-stage pipeline. And finally, net income totaled $385 million. GAAP diluted earnings per ADS were $3.28 compared with $1.09 in the prior period.

Now turning to our adjusted results with a full reconciliation provided in the appendix of our results presentation. Adjusted income from operations increased to $612 million, representing growth of more than 79%. Adjusted net income increased to $539 million, while adjusted diluted earnings per ADS increased to $4.59 compared with $2.65 a year ago. Cash generation continues to build momentum with free cash flow up 34% from the prior year to $474 million.

Turning to our updated full year outlook. Given our performance through the third quarter and our expectations for the remainder of the year, we are raising and narrowing our 2026 guidance. We now expect total revenue of $6.9 billion to $7 billion compared with our prior range of $6.6 billion to $6.8 billion. We continue to see a modest net pricing benefit in the U.S. for BRUKINSA for the balance of the year. Looking ahead to 2027, we expect relatively stable net pricing.

Note that the increase in our Medicare Part D manufacturer liability will likely pivot the modest tailwind we've seen in 2026 to a flat to modest headwind next year. This is a statutory increase associated with our specified small manufacturer designation for BRUKINSA. Our gross margin outlook remains unchanged in the high 80% range. We now expect operating expenses of $4.9 billion to $5 billion, a narrowing of the prior range of $4.8 billion to $5 billion. We expect GAAP operating income of $1.2 billion to $1.3 billion, an increase of $200 million across the range. And finally, we expect non-GAAP operating income of $1.9 billion to $2 billion, also an increase of $200 million across the range.

Moving to income taxes. I'd like to provide an update on the income tax valuation allowance that I spoke about earlier this year. As background, we have historically been in a valuation allowance whereby the accumulated deferred tax assets we have a reserve against them. Given our recent history of earnings, we believe there will be sufficient positive evidence to recognize a portion of these assets. We continue to evaluate and assess the magnitude, but the current expectation is that the reversal will occur in the fourth quarter and that it will result in a material tax benefit to the income tax provision and correspondingly to our full year GAAP net income.

In reporting periods after the reversal occurs, we will reflect deferred tax assets in our financial statements, and our effective tax rate will become a more meaningful and predictable metric, although it might take several years to normalize. We plan on providing additional commentary for this in our fourth quarter call. As we look beyond 2026, I'd like to make one broader point on the trajectory of operating margins. The business is performing really well, and our underlying earnings power has continued to increase as you see in our guidance updates over the course of the year.

This profitability has translated into free cash flow and an increasingly strong balance sheet, which provides us with increased financial and strategic flexibility. Moving forward, we now have multiple differentiated assets advancing into pivotal development across some of oncology's largest indications. Given the quality of these opportunities and those will come, that will come from the next wave of our model as well as potential business development, we intend to continue investing with discipline to maximize our impact for patients and value for shareholders.

As I said last quarter, we anticipate 2027 operating expenses growth to be at least consistent with where we have been over the past several years given the size of our pipeline opportunity. As a result, while we expect operating income to continue to grow meaningfully, the pace of margin expansion is likely to be modest as compared to 2025 and 2026 as we balance near-term margin percentage gains with investments in future growth. And with that, I'll turn the presentation over to Lai.

Thank you, Aaron. We continue to make strong progress across our pipeline this quarter in both hematology and solid tumors. Today, I will highlight several important clinical and development updates, including the new solid tumor data we recently presented at ESMO. Let me start with a few highlights across the portfolio. For BRUKINSA, in treatment-naive mantle cell lymphoma, we have completed submissions in the U.S., Europe and China and the FDA has granted priority review. The MANGROVE results will also be featured in a plenary presentation at ASH.

For BEQALZI, CELESTIAL-304 remains on track to complete enrollment before year-end. For tacabrutideg, the Phase II portion of CaDAnCe-101 met its primary endpoint and following discussion with the FDA, we are planning for a potential submission in mid-2027. I will come back to taca-deg in more detail shortly. In solid tumors, we continue to accelerate our late-stage programs. For our CDK4 inhibitor, we're increasing the sample size of the Phase III KANDELA-302 study. Importantly, we're doing this to bring the study readout earlier. We have achieved first subjects enrolled for our B7-H4 ADC STARSTONE-301 Phase III study.

This marks the second start of a Phase III study in our solid tumor franchise this year. We're also advancing our GPC3 x 4-1BB bispecific into pivotal development while development of our PRMT5 inhibitor and CEA ADC continues to advance following the data presented at ESMO. Stepping back, this progress reflects our deliberate R&D strategy. We are building depth in disease areas where we believe we can establish leadership rather than developing individual assets in isolation. And we do this across small molecules, degraders, ADCs and multispecifics, matching modality to biology and increasingly building combinations from within our portfolio.

Our goal is not simply to generate more molecules. It is to create the next treatment paradigm that can meaningfully improve outcomes for patients. Now let me come back to taca-deg. The Phase II study in relapsed/refractory CLL achieved its primary ORR endpoints with encouraging duration of response, PFS and safety. We're targeting a potential FDA submission in mid-2027. Our growing confidence in CaDAnCe-304 is also allowing us to optimize the broader development program. We are increasing enrollment number in the 304 study from 500 to 600 patients to accelerate the readout while remaining on track to complete enrollment in early 2027.

Given our increased confidence in 304 outcome, we are converting CaDAnCe-302 to a Phase II study. And importantly, we'll continue to expand the program. Our Phase III study of taca-deg plus sonro in relapsed/refractory CLL is on track to begin enrollment in the first half of 2027. The right-hand panel highlights what we believe differentiates taca-deg, excellent selectivity in kinome and the protein degradation assays. Primarily a BTK degrader, taca-deg also provides a distinct secondary BTK inhibitory function that may increase the barrier to resistance and potentially extend the response duration. We will share additional data at ASH.

Turning to solid tumors. I will start with our GPC3 x 4-1BB bispecific. HCC remains an area of significant unmet medical need. In the U.S., liver cancer ranks the sixth in cancer mortality. Its incidence is similar to that of multiple myeloma and triple-negative breast cancer and higher than that of the small cell lung cancer and EGFR mutant non-small cell lung cancer. Despite this burden, there have been only 2 global Phase III HCC studies since 2021, far fewer than any of the other tumor types shown this slide.

At ESMO, BGB-B2033 monotherapy demonstrated a 36% confirmed response rate in heavily pretreated second-line plus HCC with strong durability and a favorable safety profile without CRS. This compares favorably with historical TKI response rate of approximately 5% to 10% in this study. We are moving quickly into registrational development. The potential pivotal third-line plus cohort for China and Korea is fully enrolled. Before year-end, we expect to initiate both a second-line plus single-arm study supporting a potential U.S. accelerated approval pathway and the second-line plus Phase III confirmatory trial.

We're also very encouraged by the progress of our first-line combination with TEVIMBRA and Avastin, supporting our plan to initiate a global Phase III study in first-line HCC in the first half of 2027. Let me first highlight the differentiated safety profile. The treatment-related adverse events shown here are predominantly low grade with very few grade 3 or high events among the most frequently reported adverse events. Importantly, we have not observed CRS. Now turning to efficacy. In addition to the high response rate, I really want to emphasize the durability of the responses.

Among the 27 confirmed responders, the 6 months duration of response rate was approximately 79%. The long-lasting responses we are seeing are reminiscent of the durability that has been a hallmark of immune therapies. Our second major ESMO data set was BGB-58067, our brain-penetrant PRMT5 inhibitor. We have observed objective responses across multiple MTAP-deficient tumor types. In previously treated MTAP-deficient EGFR wild-type non-small cell lung cancer, the confirmed response rate was 38.5% with median PFS of 8.1 months. We also observed intracranial responses in patients with brain metastases.

The potential opportunity extends beyond non-small cell lung cancer. MTAP deletion occurs across a number of tumor types, and our development strategy includes pancreatic cancer, GBM and potentially other tumors. In non-small cell lung cancer, we are already evaluating combination with PD-1 and chemotherapy in first-line setting. And in pancreatic cancer, we plan to begin evaluating combinations with the RAS inhibitors from our Revolution Medicines collaboration before year-end. Here again, our strategy is to take an encouraging early signal and rapidly build a broader development program around the differentiated properties of the molecule.

Looking more closely at the efficacy, I first want to highlight the durability we are seeing. Responses have been durable, and we are also seeing patients with prolonged stable disease. This is encouraging because the benefit appears to extend beyond patients who achieve an objective response. Now another important feature of 58067 is brain penetrant. Among non-small cell lung cancer patients with active brain metastasis, the confirmed intracranial response rate was 30.8%. What I found particularly interesting is the low intracranial progression rate of 16%. This is substantially lower than what has been reported for Dato-DXd and docetaxel and is more in the range of what we see with CNS penetrant target therapies such as osimertinib.

Let me turn next to BGB-C477 ADC. At ESMO, we presented initial proof-of-concept data in heavily pretreated CEA non-small cell lung cancer. The confirmed response rate was 60% with a 6-month CR rate of 73% in Phase Ia data set. We also observed a favorable safety profile, including no grade 3 or higher ILD or ocular events in the data set presented. Approximately 1/3 non-small cell lung cancer tumors are estimated to have high CEA expression. Based on these early results, we are developing C477 across the non-small cell lung cancer treatment spectrum.

A global Phase III study in second-line non-small cell lung cancer is in planning. A first-line combination cohort with PD-1 is ongoing. We're also evaluating opportunity in earlier-stage disease. Looking more closely at the efficacy, we are seeing broad activity across both squamous and non-squamous non-small cell lung cancer and across EGFR status. Within the non-squamous disease, the response rate was numerically higher in EGFR wild-type than in EGFR mutant patients. We are also encouraged by the durability. The 6-month PFS rate was 76.2%, and the median PFS has not been reached at the data cutoff.

Now let's turn to ASH. We have 45 accepted abstracts and five oral presentations across BRUKINSA, BEQALZI, and tacabrutideg, including MANGROVE in treatment-naive mantle cell lymphoma at the ASH plenary.

We believe MANGROVE supports the potential for BRUKINSA to establish new chemo-free standard of care in treatment-naive mantle cell lymphoma. In CLL, our 7-year overall survival data show life expectancy matching the general population, moving us closer to our cure zone ambition. And as John discussed, real-world evidence continues to report a survival advantage for BRUKINSA.

For BEQALZI, the frontline combination with BRUKINSA showed 100% 3-year PFS rate, while the ramp-up data highlight convenience advantages over venetoclax. And for taca-deg, longer clinical follow-up and the differentiated mechanistic data continues to support its potential as the first and best-in-class BTK degrader, including a distinct design that may address resistance mechanisms and the high selectivity among BTK degraders in the clinical relevant for blood assays. We'll have much more to discuss at our ASH investor event on December 14.

Let me close with this overview of our upcoming milestones. As you can see, we have already addressed the vast majority of this today, reflecting the significant momentum across both hematology and solid tumor portfolios. We will provide additional updates on our 2027 milestones at JPMorgan. And with that, I will turn it back to John.

Thanks, Lai. We will now open the call to Q&A. Please limit the number of questions that you have so we can ensure that we have time to hear from as many attendees as possible. Operator, please go ahead.

[Operator Instructions] We have our first question from Jessica Fye from JPMorgan. [Operator Instructions]

A couple on the pipeline. Can you just expand a little bit on what's behind the timing shift on the filing for tacabrutideg for relapsed/refractory CLL? And then for the GPC3 x 4-1BB bispecific, I guess, for Mark or Lai, I think BioNTech had some interesting liver cancer data for their PD-(L)1 x VEGF bispecific combined with the B7-H3 ADC in liver cancer. Can you talk about where you think your GPC3 x 4-1BB bispecific might have advantages over that regimen?

Thanks, Jessica. I hope you're well. I guess we can start with Amit and then move to Mark.

Thank you, John. Yes, let me provide a little bit of color on the TAG update. So first off, we are pleased to report the positive readout of the Phase II trial. As Lai mentioned in his prepared remarks, the study met its primary endpoint of ORR. And in terms of other endpoints like duration of response, progression-free survival and safety, the data is very strong and reinforces our confidence in the program. We did recently have discussions with the FDA on our potential accelerated approval submission.

And based on those discussions, the FDA requested some additional follow-up. And as a result of this, we are now planning to file for accelerated approval in mid-2027. What I'll say is this is not an unusual request from the FDA, especially for a first approval of a new molecular entity. And so again, overall, we remain confident in the program. And as Lai also provided an update, what we're doing for this CaDAnCe-304 trial, which is our head-to-head trial versus pirtobrutinib, we are increasing the size of that trial. And we think this will accelerate the timing of that interim readout and allow us to keep the enrollment time lines manageable. So really looking forward to all of these updates in 2027. With that, I'll turn it over to Mark.

Thank you, Amit, and thanks, Jess, for the question. We are very excited about the potential of our GPC3 x 4-1BB targeting bispecific and have increasing confidence that this will be a transformative molecule for patients with hepatocellular carcinoma. As you heard from Lai, at ESMO, we recently reported a monotherapy response rate in later line extensively pretreated patients of 36%. These responses were durable with a 6-month duration of response rate of 79%. Now critically, we're delivering that efficacy with a highly favorable safety profile.

Now hepatocellular carcinoma is somewhat unique among solid tumors and that cytotoxic chemotherapy is really not a part of the standard of care. And that's because these patients have compromised liver function and associated comorbidities. Therefore, while ADCs do have a meaningful response rate in this patient population, tolerability is a major challenge and therefore, durability becomes difficult. With our favorable safety profile and very favorable efficacy profile, we have already been combining, as you heard from Lai, with TEVIMBRA plus bevacizumab in a frontline patient population. We've enrolled over 70 patients. So we think that we have clear line of sight, not only in the later-line patient segment where we've shared compelling data, but also in earlier lines of therapy where our favorable safety profile will enable higher order combinations to maximize patient benefit.

Next question please.

Okay. We have our next question from Yigal Nochomovitz, and they are from Citigroup. [Operator Instructions]

John, you mentioned, of course, the Fast and Furious data coming for the next 3 years for the CLL franchise. I'm wondering if at this point, you're able to provide a little bit more granular timing with respect to the first PFS readouts for the fixed duration studies, the 2 that you're running, ZS versus VO and versus AV. Second, maybe for Lai or Mark, with regard to the PRMT5 and the RevMed combination, do you expect or not expect to see a DDI with RAS(ON) as, of course, we've seen with some competing PRMT5. And third, on the CEA, anything to read into with respect to the differential efficacy on the mutants versus the wild types?

Yes. I think maybe we can start with Lai. And Lai, if you want to pass off to your team, please go ahead.

Happy to. I will just comment on the DDI question related to PRMT5 with the RevMed assets. We have done preclinical modeling and so far data suggests there's no significant concern around the potential DDI. Certainly, this need to be validated in the clinical setting. Maybe I'll pass this on to Mark to comment on the CEA ADC.

Thank you, Lai. Thank you, Yigal. Yes. So this is something that we noted in the early emerging data. However, I would caution that the number of patients included, particularly in the EGFR mutant analysis is relatively small. We are very excited about what we're seeing in terms of the response rate across all patients with non-small cell lung cancer. And importantly, durability is strong across these patients as well. So we are currently in our dose optimization and expansion phase, and we'll be able to share larger data sets in the near future.

Amit, same comment. Yes.

Yes. Thank you for the question, Yigal. So on the 2 Phase III studies, the CELESTIAL-301 study where we're comparing ZS to VO and the CELESTIAL-304 study where we're comparing ZS to AV. Again, as you know, both of those are event-based endpoints. And so we haven't shared yet the approximate time lines, but we're hoping to do that in 2027. Overall, I would say things are going really well with the CS program. We will have updates at ASH from the 101 study. So we'll share some updates in '27.

Next question please.

Our next question comes from Sean Laaman from Morgan Stanley.

I have 2 questions. So the first one relates to the RevMed collaboration. So you're funding and conducting the Phase III RASonate 312 CRC study. What does that responsibility indicate about your long-term ambitions in precision oncology is the first question. The second one, maybe one for Aaron, is just the commentary on margins. So I think you said expect a more moderate pace in margin expansion versus this year and last year. But are you expecting margin to keep increasing from here given the significant R&D investment BeOne has going on?

Sure. I think we'll start with Lai and then move over to Aaron.

Yes. Thank you so much for the question. This is the major reason I think that RevMed want to do this collaboration with BeOne because they believe in our development super highway. So we're conducting the 312 study, which is the frontline study in the CRC, which is testing the RAS(ON) in combination with the standard of care. We are very excited about this opportunity. And hopefully, this will help RevMed to really fulfill their ambition about be the leader in the RAS space.

And certainly, this will also give us opportunity to potentially combining our pipeline assets with the molecules even further, as I think we mentioned in the press release, in addition to combining the PRMT5 with RevMed assets, we are also combining our EGFR MET trispecific with RevMed asset. As you can imagine, a combination with zoldonrasib in the CRC will be one of the lead indication for us to explore.

Thanks for the question, Sean. So first, let me just start by saying we are in an incredibly strong position financially, and we're really proud of what we've accomplished in our profile. The business is performing really well, and the setup continues to support growth, albeit with a larger base of business as we look forward. Since 2024, we have shifted, as you know, to a profit-making business with operating margins that are set to expand by more than 10% in '26 alone based on the midpoint of our current guidance. That's something we're really proud of.

And candidly, as you see in our guidance updates this year, it's at a pace ahead of where we thought we'd be at this time. Moving forward, our key message is that we're building a company to last and supported by increasing financial flexibility. We have tremendous opportunity with our pipeline and our repeatable innovation model, and we're going to invest to realize that full potential. As a result, we anticipate operating expenses to grow at a similar rate, as I said last quarter, to what we've seen over the last couple of years. And taken together, we do expect that we will be able to fund our future ambitions while driving meaningful growth in profits, although the pace of growth and profit margin percentage will be modest as compared to what you've seen in recent years. Thanks for the question. Really appreciate it.

Our next question comes from Andrew Berens from Leerink. [Operator Instructions]

Definitely, pipeline is expanding very rapidly. I guess 2 for me. One, as we go into ASH, how you are seeing the CDAC BTK agents fitting into the evolving treatment paradigms, especially with pirto seemingly moving more forward. And then another one on the PRMT5 program that we saw at ESMO. How do you think your collaboration with RevMed positions this program relative to companies that have a head start in combos like Tango and Prelude and then Bristol in lung?

Yes. Thanks for the question. Why don't we start with Amit and then move to Mark.

Yes. Thank you for that question. So in terms of the taca-deg program, I think, again, we're very excited about the program as a whole and what we're presenting at ASH. Lai alluded to this a little bit. I think one of the interesting sort of preclinical presentations that we will have at ASH is really sort of this idea of having a secondary inhibitor function. And really what we think this is going to, or how we think this is going to translate into the clinic is particularly on the durability side of things. Beyond this, I think we are very well positioned to execute on that broad development plan for taca-deg.

You heard a little bit of an update on our head-to-head study versus pirto, which is designed to show that taca-deg is clearly superior to pirto. And so as pirto moves in earlier lines, I think having this particular data set is going to be particularly important. But beyond this, we're also initiating a study of taca-deg plus sonro in the relapsed CLL space, which we believe will be the fixed duration or best fixed duration treatment for that patient group regardless of what type of treatments that they received in the frontline treatment paradigm.

And beyond this, we also see major challenges with the triplet regimen that pirto has just released with the pirto-rituximab data set because the CD20 antibody really might be adding more toxicity there than providing clinical benefit. And so overall, we're very confident in the program and really looking forward to some of these new studies with tacabrutideg.

Now maybe we turn it over to Mark.

Thank you, Amit, and thank you, Andy, for the question. We're very excited about the opportunity to combine our CNS penetrant PRMT5 inhibitor with the RevMed RAS(ON) molecules. In addition to the clinical data that has been disclosed for that combination, we also have strongly supportive preclinical evidence that we've generated in-house for that combination. And I would highlight that in the recent disclosure that we had at ESMO, there were really a large number of patients treated across a broad number of solid tumors.

So we have a substantial global footprint in our Phase I study. The amendment for the RevMed molecules has already gone through. It's posted on clinicaltrials.gov. We anticipate that enrollment will begin imminently. There's very high investigator enthusiasm. And therefore, we believe that our development super highway again can close any time gap. And as you heard from Lai, we're also not expecting a drug-drug interaction. And therefore, we think that we have all the ingredients in place with a best-in-class PRMT5 inhibitor plus the development super highway that we can meaningfully close the gap and ultimately be leaders in this space.

Okay. Our next question comes from Gregory Renza from Truist Securities. Gregory, just checking if you can hear us. If not, we will move on to the next question.

Maybe just a question to follow up on the TAG update. Good to see your increased confidence. So maybe just to talk a little bit about just confirming your confidence about an accelerated approval filing once you implement the changes that you're highlighting today. And maybe just talk a little bit about how you see that peak opportunity perhaps evolving? Do the updates and that confidence perhaps help to alter or maybe inform the longer-term positioning? And just lastly, if I may, I'm just seeing the mention of the CSU trial and just broadening in the I&I. Maybe talk a little bit about that potential expansion and how intact that is.

Thanks for the question. It's always hard to answer regulatory questions. But Amit, please share what you can.

Yes. Thank you, John, and thank you for that question, Greg. So what I would say is, again, I think right now, we're very happy with the results we've seen from the Phase II trial, and particularly when it comes to accelerated approvals, we certainly want to make sure that we respect that regulatory process. And so without getting too ahead of ourselves, we remain confident in what the data set shows and the unmet need in that particular population and look forward to continuing the engagement with the FDA.

Now ultimately, I think the accelerated approval opportunity is still a smaller opportunity in the broader context of the program. And particularly the trials that we're outlining now, whether it's the head-to-head versus pirtobrutinib or even the combination trials and future development that we have planned for taca-deg as a whole, we think that those are more meaningful opportunities. And certainly, as that head-to-head study reads out, it will open up the possibilities for a broader group of CLL patients to benefit from taca-deg. And so we certainly think that the opportunity is much more beyond the accelerated approval opportunity. And perhaps I'll ask Lai to comment on the CSU part of things.

Yes. We have took a little bit of time to really contemplating our strategy for our BTK CDAC. We do believe with this extremely long half-life, we have a potential advantage for this molecule. We are on path to initiate the CSU trial early 2027.

Our next question comes from Kalpit Patel from Wolfe Research.

This is Mitchell on for Kalpit. I wanted to ask on the breast cancer study. We noticed that the trial increased in size. Given that this is an event-driven study, can you help us understand how adding more patients get due to the readout sooner or you think the required number of events changed? Or has some of the same statistical assumptions?

Thanks. I'll pass that to Mark.

Great. Thank you for the question. So the KANDELA-302 study is progressing very well. We're actually recruiting slightly ahead of our internal projections, and we've had very strong investigator feedback to date on the study design and the early experiences in the trial. Now in that context, upsizing the study has a number of statistical benefits that are conveyed by increasing the power of the study.

And it is our belief that we will be able to enroll this somewhat larger study, approximately 10% larger study in the same period of time we were originally projecting for the originally sized study of a little over 1,000 patients, now 1,200 patients. So without changing the assumptions in terms of the overall event rates, that actually pulls in our time line somewhat because we have increased our statistical power. So again, if the period of enrollment is fixed, then we will get to that readout earlier.

We have our next question from Yaron Werber, who is from TD Cowen.

So maybe just 2 quick questions. So first of all, on tacabrutideg, the pushout to mid next year, is that have to do with looking at more durability data? And are you thinking about filing for a broad label, essentially including both BTK inhibitors, covalent, non-covalent and BCL-2? And then secondly, for the RAS(ON) frontline CRC study, I just wanted to catch in combination with chemo, is that Phase III starting by year-end this year? Or is it early next year?

Thanks so much. Hope you're well. And I guess we're going back to.

Yes. Thank you, John, and thanks for that question. So in terms of the population for the Phase II study, certainly, this was a mix of patients who had a covalent BTK inhibitor and a BCL-2 inhibitor as well as patients who had a covalent, non-covalent and BCL-2 inhibitor. And we've seen encouraging results across those populations.

To your question about the sort of shift there, it is related to the follow-up that we see. And certainly, this is something that we can expect given that new molecular entities, typically, the FDA can ask for more data in terms of both the safety as well as the durability data. And so that's where we are with that one. And then I think the other question was...

I can take the other question, which is related to the 312 study for RevMed. We are initiating the study. We're working very closely with RevMed. At this moment, we won't be able to comment on exactly the time of the first patient to be dosed.

Okay. We have our next question from Ziyi Chen who is from Goldman Sachs.

First is going to be on BRUKINSA. BRUKINSA has been the BTK leader for years now, and we have not seen a slowing down in market share gain trend. So what has been the drivers in the past few quarters behind the acceleration? And also under this context, how do you see the impact of the new pirto's updated data for the BRUIN CLL-313 in the first line with a much longer median follow-up period? So that's my first question.

And second, we are really a big fan of GPC3 x 4-1BB, excited about the data at ESMO. Given the safety profile looks very good, we're kind of curious about the plan for 4-1BB-based pipeline expansion. What will be the next big thing coming from 4-1BB-based bispecific that we could be seeing and also prove the 4-1BB-based bispecific design is expandable to broad pipeline?

Sure. I think that we'll start with Matt, jump to Amit and then go back to Lai because Mark may be getting tired today.

Thanks, John. Yes, we're very pleased with the momentum in BRUKINSA. And in terms of drivers, we continue to be a new patient start share leader across our indication settings. This is driven by very strong long-term data across CLL patient types and physician experience that's leading to preference. We've also, as you heard Aaron comment, have been very pleased to see our duration of therapy and a more mature view on that with claims and real-world evidence. That's more mature and allowed us to get a good read on what we believe is a pretty substantial duration of therapy.

And then we've also seen growth come from indications beyond CLL in our other B-cell malignancies, particularly with some strength in Waldenstrom's. Now with regard to pirto, happy to comment on that as well. We, of course, know that this was studied in a limited patient population, has limited data in elderly patients, no long-term data and really limited differentiation on safety, like infections, cytopenias and discontinuation rates.

But I think the most important factor is that these resistance mechanisms to pirto confer resistance to covalent BTK inhibitors. And as a result, physicians don't want to burn a line of therapy. And thus far, we've really seen uptake contained to the later lines of therapy. But I'll hand it over to Amit to make some further commentary on that.

Yes. Thank you, Matt. I think in terms of the frontline setting, we continue to believe BRUKINSA is the gold standard when it comes to the data that's been presented so far. When you look at especially the long-term outcomes with a 6-year PFS of 74% with a COVID adjustment of 77% and an overall survival of 84%, really, I don't think the data stacks up for pirto just yet. Obviously, the approval for pirto in the front line was based on the BRUIN CLL-313 study, where pirto was being compared to BR, which really in the U.S. is an obsolete control arm. And the initial results were presented with a very short follow-up.

Now the biggest problem with this study besides the control arm is really the demographic skew of that study. So the study enrolled really young patients. And when you look at the safety data there, it really needs to be evaluated in the light of that patient demographics. And as Matt alluded to this, when you look at the BRUIN CLL-314 data, there's very little differentiation between pirto and ibrutinib. On efficacy, there are 2 events that separate pirto and ibrutinib the last time this data was presented. So basically, we're talking about 48 versus 50 PFS events.

And on the safety side, pirto just did not show a significant difference versus ibrutinib in terms of infection, cytopenias and discontinuation rates. And even the AFib rate, when you age match it, it really is very comparable to what we've seen in SOC. And in addition to this, as Matt highlighted, when we talk to thought leaders in CLL, the idea of effectively giving pirto ahead of a covalent BTK inhibitor and potentially burning a line of treatment, if you would, really is not giving. And so we're not surprised that there is very limited uptake for in front. With that, I'll hand it to Mark.

Maybe I can jump to take this question. Thank you, Ziyi. This is a really very good question. I'd love to answer it. So I want to mention besides the great safety profile, what we have observed with GPC3 x 4-1BB, maybe this immune kind of mediate MOA is really validated by the clinical data. If you look at the spider plot, we actually have a patient who not only the response is durable, we actually have some patients began to show up the response very late. So there was 1 patient become a responder at week 36.

4-1BB isn't the strongest kind of the T cell activator. So when you combine this potentially in the first line with some other agent, which can help to control disease, which we believe this drug perhaps will perform even better. So over the years, we have built this really strong feedback loop between the preclinical to the clinical. So once we, our preclinical assessment of GPC3 x 4-1BB was validated in the clinic setting, we began to really think about how can we maximize the value of our proprietary 4-1BB platform.

So we're working on 2 things. One is really leveraging this unique binder as well as the testing system to set up a whole set of the TA4-1BB pipelines. So I can assure you there are many programs we're working on at this moment. In addition to that, we're also working on next generation. We believe there is further room to improve on the current 4-1BB T cell activator. So that is also coming. So starting from next year, you'll begin to see new molecules coming from our 4-1BB platform. This will be one of the important technology platform we will leverage to build our pipeline.

Next slide. Can we get another question, please?

Our next question comes from Michael Schmidt from Guggenheim. [Operator Instructions]

I just had a housekeeping question on guidance. It looks like the updated guidance suggests flat to down revenue in the fourth quarter sequentially. Just wondering if that is just seasonality, conservatism or if there's anything else going on towards the end of the year? And then just regarding the MANGROVE plenary at ASH, just remind us of the opportunity in that particular setting for the BRUKINSA franchise.

Sure. Thanks, Michael, for the question. We'll start with Aaron and then move on to Amit.

Great. So thanks for the question. Obviously, we're very pleased with our performance through the first 3 quarters of the year. We're doing $5.1 billion of revenue, 33% growth. And I mentioned when you account for the $50 million in timing that I noted, sequential and year-over-year growth are largely consistent where we tracked through the first 3 quarters of the year. Similarly, expenses reflect typical seasonality that you see in the industry as well as the increasing investments from our late-stage R&D programs. The guide, therefore, reflects a fairly consistent investment growth that you've seen over the past 2 years, and that will continue into 2027, as I said before.

Yes. Thank you, Aaron. So in terms of MANGROVE, again, I think this is really exciting in terms of just what this means for frontline MCL patients. As we've indicated before, MANGROVE is the first and only chemo-free regimen for these patients that has shown superiority over a chemo regimen. And the data and the fact that this has been accepted as a plenary presentation really speaks to the broader excitement that the oncology and hematology community are seeing with this particular regimen. And similarly, I think the priority review, we're hoping that this will come to the patients very soon. But I'll turn it over to Matt to talk a little bit about the commercial opportunity here.

Thanks, Amit. But just to put it into context, mantle cells about 4,000 U.S. patients a year as compared to right around 20,000 CLL patients a year. So that gives you sense of the size. As you heard from Amit, there's a really important unmet need for effective treatment options in frontline mantle cell that are supported by robust clinical evidence, particularly in the setting where MANGROVE was studied. So this opportunity with a chemo-free option in previously untreated mantle cell with the strong efficacy and safety data that we'll be bringing to the market, we think when approved, will lead to extending the overall BTK class share within the space. And then, of course, we believe that we'll take brand share within that class and really drive some growth here.

We also submitted the application in Europe and China. This is also first-line mantle cell patients in China and Europe, so 3,000 and 4,000 each that provide additional opportunity for us.

Questions. Are there further questions?

There are no further questions. I will now turn the call over to John Oyler for closing remarks. Thank you.

Thanks so much. In closing, we've never been better positioned. Our commercial business is delivering, our pipeline is deeper than ever, and our model is proving repeatable. The work ahead is significant, but so is the opportunity. I really want to thank the patients and the families that we serve, our physicians, our partners and our more than 12,000 colleagues around the world whose focus and urgency make our progress possible. Thank you all so much for joining us today, and have a wonderful week.

Good morning, everyone. I'm Sean Laaman, Head of U.S. Mid-cap Biotech Equity Research here at Morgan Stanley, and welcome to our Global Healthcare Conference.

Before we begin, for important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have from BeOne Medicines, CFO, Aaron Rosenberg; and Head of Strategy, John Scotti. Welcome, and thanks for your time, gentlemen.

Maybe just to open sort of a macro question. Can you talk broadly about how the company has changed in the past 10 years as it's become a fully integrated global oncology company with capabilities to address industry challenges?

That's great. And thanks, Sean, for having us. It's great always to be here at the Morgan Stanley conference. So it's hard to go through everything that's changed in the last 10 years. I mean, 10 years ago, the company was nascent. It was a company that had very little revenue, a couple of hundred employees and was just -- really had no significant commercial or manufacturing capabilities to speak of. So much has happened over that 10-year period with where today we are a leading global oncology company.

I think the hallmark of that capability difference is the investment across the value chain in our fully integrated business model from research with our high throughput research organization through ultimately what we believe is a key differentiating advantage for the company, our wholly owned global clinical development infrastructure, what we call our global development super highway. And then pulling that through the remainder of our value chain into manufacturing, into commercial and behind incredible brands like BRUKINSA, bringing innovative oncology medicines to as many patients around the world as we can. And now our goal is to leverage that incredible capability and do so repeatedly with the cost and time advantages that we've created through that global development superhighway for the next wave of innovation that I'm sure we'll spend a lot of time talking about today.

Awesome. Thank you. We're debating this a little bit in -- when we're just chatting just here, but let's get straight into the solid tumor portfolio before reaching into the heme side of the equation. So you've framed 2026 as a solid tumor inflection point. You've got 5 programs moving forward that are pivotal. To start with on the CDK4 inhibitor, the 43395, how do you think about the registrational strategy and the sequencing across first and later lines? And what did the ASCO data change about your conviction in a best-in-class profile versus Pfizer's drug and the established CDK4/6?

Yes. Thank you. It's a great question. I think if you step back, it's worth reminding everyone how we develop the molecule and design the molecule. The molecule was designed to be the most potent against CDK4 in the class and also the most selective. And ultimately, the therapeutic hypothesis behind that was, could you hit CDK4 the hardest while also sparing CDK6 and therefore, sparing the CDK6 mediated hematologic toxicity that you know impacts many of the real-world dose reductions and dose discontinuations that you see with the CDK4/6 class, including the 3 that are approved.

What we saw in the ASCO data was that, that preclinical profile was really translating into the clinic. So just to remind everyone at ASCO, we showed in the frontline hormone receptor positive HER2-negative setting, a response rate roughly around 70%, which compares favorably to what you see for the CDK4/6 inhibitors, which is roughly around the low 50s and a hematologic toxicity profile that is clearly differentiated. So we had at the recommended Phase III dose, 0 cases of grade 3 neutropenia, which to provide some context, if you think about a drug like IBRANCE, the rates of grade 3 neutropenia are in the mid-60% range. And even for the competitive CDK4 molecule from Pfizer, at ESMO last year, they showed rates of grade 3 neutropenia of 26.5%. And we think that's a function of our greater selectivity again for CDK4 over CDK6.

What we also showed at ASCO is how the GI profile can be ameliorated with the co-administration with food. And when you -- it turns out when you administer the drug with food, you substantially reduce the rate of GI AEs. And it really transforms the GI profile from that perspective. Of course, these are small patient numbers at this stage, but we are in the Phase III that is up and running now and enrolling very nicely. We are co-administering the drug with food. So ultimately, this is a frontline trial. The market, as you're aware of in the frontline hormone receptor-positive setting is quite large. And if that profile translates into Phase III, it will be a very commercially relevant profile GI tolerability that is no different, hopefully, than other agents with a very differentiated heme tox profile that also, by the way, enables combinations with other assets in our own internal pipeline such as CDK2 degrader, KAT6 and the ultra-potent BCL2 inhibitor for solid tumors we're developing. All these are in Phase I, each of which in some cases, has its own intrinsic heme tox. And so we feel like with our CDK4 inhibitor, we have the ability uniquely to combine with some of these other agents because we do not have a heme tox profile that the other agents have.

Sure. Maybe ask you about some of the other programs. So we can spend a bit of time on your GPC3 x 4-1BB bispecific in liver cancer. So maybe, John, if you can size the opportunity and your path forward from here on that one.

Sure. That's an asset that we're very excited about. I think the reason why we're excited about it, have again, you look at our data we presented at ASCO in an oral presentation. HCC is a very high unmet medical need indication. The 5-year survival for HCC is on the order of what you see with pancreatic cancer. There unfortunately has not been a tremendous amount of innovation in this space. And what we've developed here is a first-in-class GPC3 x 4-1BB bispecific antibody. And 4-1BB is a target that I think many folks are aware of. But what's interesting about our 4-1BB is we really feel like we've cracked the code from a scientific perspective on how to engage this axis and do so with a novel binder, novel biology. We really spent some time preclinically to design this appropriately. And ultimately, how that's translating into clinical data, we saw roughly in the late-line HCC setting, 30% response rate, which for context here, the IMbrave251 trial was presented at ASCO. That's a second-line TKI. The response rate was 5.8%. The response rate in the frontline setting with the standard of care, which is PD-1 bevacizumab is about 30%. So we're seeing response rates in the late-line setting that are roughly comparable to what you see in the frontline setting.

We also announced at earnings recently that we fully enroll a potentially registrational cohort in China in roughly around 2 months. We plan to start a Phase III global trial in the second-line setting by the end of this year. And of course, we're looking beyond the second line and trying to move to the frontline setting as early as possible.

From a market size perspective, this market is not small. It's actually a much bigger opportunity than many think. In the U.S., for example, there's about 35,000 patients across all lines, roughly equivalent incidence to CLL, just for some context. Of course, the difference here is the duration of therapy, and that's the area that we hope to improve upon with this next-generation agent. In Asia, the prevalence of HCC is quite large. There's almost 300,000 patients with HCC in Asia. So it is a very substantial opportunity for us, and it's a first-in-class asset. We're moving as fast as possible, excited about.

And can you talk about your PRMT5 inhibitor? Can you talk about how that may compare if it's known to some of the competitors out there like Tango? And can you talk about the establishment of the relationship with Revolution Medicines and how companies will both benefit from that?

Sure. Maybe I can touch first on PRMT5 and Aaron, you can transition. I think what we've developed is a molecule that is the most potent against PRMT5, but critically is brain penetrant. And we think that's critical differentiation, particularly in lung cancer, where upwards of 30% to 40% of patients develop brain metastases. It's a critical unmet need, and it's an area where we believe we will be the only brain-penetrant molecule, assuming all 3 end up making it to lung, and that's going to be a very important area of competitive differentiation.

At ESMO upcoming, we're going to present the first data set for this molecule. We're looking forward to presenting those data. They will be -- primarily, this is a Phase I data set. We're looking at targeted expansion primarily in lung cancer. Again, we prioritize lung cancer. That's not to say we're not developing into pancreatic and also GBM, which we are. But this will be a primarily lung cancer data set, and we're looking forward to sharing the data.

And then this collaboration is another great example. I talked in the opener just about the power of our global development superhighway. I think the ability to execute and have a transaction with a collaborative partner like RevMed is a great example of the power of that capability. As part of the collaboration, we have the ability through a clinical supply agreement to study our innovative medicines with the leading RAS portfolio that RevMed is bringing forth. That includes our PRMT5, that includes our EGFR x MET x MET as well as other early-stage programs. As part of the arrangement, we will conduct a clinical trial on behalf, testing our global superhighway and providing that capability for RevMed. And in exchange, we will receive commercial rights to the RevMed portfolio for China commercial.

Sure. Yes, we've spent a bit of time on CDK4, the GPC3 bispecific. When you step back and think about the opportunities on B7-H3, B7-H4, your PRMT5 and your CEA ADC, which of those opportunities excite you the most?

I think collectively, what we're trying to build here is an engine that can generate sustainable innovation over time. And what's so meaningful about this wave of 5 assets is that the CDK4 inhibitor only entered the clinic in December 2023, and it's already moved into the initiation of a Phase III trial in just 2.5 years. This is Wave 1 is the point. And all of these assets are coming from a pool of substantially more assets that entered the clinic in this time frame. And so the way we think about the portfolio is this portfolio will continue to evolve over time, and we anticipate a cadence of solid tumor assets. For example, the assets that are entering the clinic now, we'll see what those look like. And next year, hopefully, we'll have a series of new assets to discuss while these mature in their respective registrational trials.

So I know I didn't answer your question specifically. Each of them has its own opportunity. I think CEA, it's -- right now, we're going to be presenting data at ESMO in lung cancer. Obviously, that's a substantial market. PRMT5 could be lung, pancreatic, GBM. These are substantial markets. B7-H4, we're looking at studying the agent first in a Phase III in ovarian cancer maintenance. And there, the critical differentiation is not only do you need to have a PFS benefit, but that PFS benefit needs to translate to overall survival. In order to do that, you need to have a favorable safety profile in addition to a favorable efficacy profile. And that's, I think, where we feel we are best positioned. And we talked about the PRMT5 and we talked about the GPC3 [indiscernible].

Sure, sure. Thank you, John. And maybe a question for you, Aaron, a lot of modalities going on, and it almost seems that whatever modality sort of emanates in the oncology field that BeOne has one. But what I'm noticing more and more is you're getting this sort of top line acceleration, but the OpEx doesn't seem to follow suit. So you've got this sort of -- I think it's an underappreciated earnings compound story going on in the background. So how should investors think about that?

So thank you. We're very proud of how we've evolved the financial profile of the company. It's easy to forget, but just a couple of years ago, this was a company that was continuing to make investments. It was only last year that we pivoted to generating GAAP profitability. And obviously, that's translating this year into increasing leverage, as you said, and most importantly, free cash generation. Candidly, we talked about the profile this year that we're tracking ahead of schedule in terms of both revenue. We updated our guidance on revenue and profit for 2026. We also did provide perspective that with all this opportunity that we talked about with the pipeline, that we will continue to invest. Ultimately, this is exactly where our investors want us to put our capital.

So we did provide some perspective that continued margin expansion would be modest as we move forward. We provided some perspective on 2027 expenses as an example, that one might expect 2027 expenses to track at a similar growth rate to what we saw in '25 and '26, that was sort of in the mid-teen level. So you used your own language about what the profile looks like, but we are investing. We're investing for long-term growth, and we'll continue to do so to make sure that we're putting our valuable capital in what drives long-term value. We're not tracking to a specific trajectory of margins. What we're ensuring is that we have sustainability and we're investing in the potential innovations that will matter for patients down the line.

Thank you, Aaron. Getting on to more of the sort of here and the now. So BRUKINSA putting up its highest new patient starts in more than 6 years, global sales up 31% in Q2. What's reaccelerating the franchise at this stage? And how do you think about the durability of those growth rates versus a natural maturing curve?

Yes. So we spent some time on our last earnings call just talking about the drivers performance, and we're very pleased with the performance in the United States, but really globally with BRUKINSA. Ultimately, this is driven by the differentiated long-term data that we have shared with BRUKINSA, both in the clinical setting and then now what we're seeing repeatedly in real-world evidence. And we shared the study of 10,000 Medicare patients, which track both OS advantages as well as duration of treatment advantages for BRUKINSA, which is effectively the translation of that clinical setting into the real world.

Growth is really driven by demand. You mentioned that we saw in Q2 our highest level of new patient starts since launch. Behind that is not just CLL performance, but it's the breadth and totality of the 5 approved indications, which is the broadest label in the class. We do see some advantages on duration of therapy playing out. Again, that's sort of the reality playing forward in our assumptions relative to the real-world experience. So all these in total are driving really strong sustained growth. And we think, obviously, this will translate to continued durability of the franchise.

Awesome. And also at Q2, you raised guidance, $300 million -- operating income by $250 million. What's really driving your conviction in raising those performance metrics?

It's what we're seeing in the marketplace. We talked about the strength of our U.S. franchise with BRUKINSA. We see it globally, really strong performance with our European business, where we're a bit earlier in the launch trajectory, even earlier when you think about rest of world markets, important markets like Japan and Brazil. Ultimately, our conviction is driven by the differentiation of BRUKINSA and how that's translating to demand. And ultimately, that led us to increase our guide by $300 million, as you said, on the top line, and that translates to bottom line performance while we continue to still invest for growth for the long term.

Sure. And just thinking moving towards where we are in the back half of the decade, but just underwriting the growth in BRUKINSA for the back half of the decade and sort of what underwrites that?

Well, I think there's still plenty of opportunity. We're not satisfied with the share that we're capturing today. We have plenty of opportunity. We're obviously the leader from a value perspective. But even from a new patient starts, there's more opportunity to ensure that BRUKINSA is prescribed in the marketplace for the patients where it continues to be, in our view, the best BTKi based on the totality of the evidence.

We do have new indications that we believe will drive increased growth. We talked about the MANGROVE data, which is in the frontline MCL setting, the first chemo-free BTKi, which really provided from a hazard ratio perspective of 0.57, the best outcomes we've seen in a clinical trial in a frontline setting. MCL is not as large as CLL, but it's still about 1/5 that opportunity. And importantly, MCL is a space where BTKIs are relatively underpenetrated. So this is an area with a chemo-free regimen to really make a difference for patients and to drive growth for BRUKINSA. We have other studies which potentially read out in the years to come, including MAHOGANY, which is in the MZL follicular setting. And then ultimately, our broader hematology franchise in the combination with BEQALZI and then ultimately with tacabrutideg, our degrader, really to satisfy patient need across the continuum from the frontline setting through the late-line setting in CLL and beyond with our approved indications.

Sure. Looking at ex U.S., where is Europe and the rest of the world in its trajectory? And is that the most underappreciated piece of the commercial story today?

Well, I think there's a lot that we'd love to see more appreciation for. But obviously, our European business and our Rest of World business, particularly big markets that I touched on, they're just a bit earlier. They continue to perform very well. Similar to the U.S., they're tracking well in terms of their new patient start capture, but there's still more opportunity as the franchise continues to grow and evolve. So overall, I think we feel really confident in where we sit, but there's more opportunity to go in that segment.

Awesome. Changing gears a little bit on policy tariffs and corporate structure. So let's talk about the agreement you announced with the U.S. government recently. You're joining a federal pricing framework, which would price future FDA-approved products in line with other developed markets. Can you share more details on this? And how should we think about the impact of most favored nation style pricing on either your current or future launches?

Sure. So like many of our peer companies, we voluntarily agreed to participate in the GENEROUS model. This is with respect to TEVIMBRA, our PD-1 inhibitor, which provides access to MFN-like pricing in the Medicaid setting for TEVIMBRA. BRUKINSA and BEQALZI are not in scope for that agreement. Additionally, we agreed to price future launches outside of those products with pricing consistent with those found in developed markets around the world. And we also committed to an onshoring agreement, consistent with our broader supply chain strategy to bring U.S. manufacturing to support U.S. patients. We've invested $800 million in our Hopewell facility, which is very biologics focused. We recently announced a $300 million investment for drug product manufacturing and small molecules. So this is just from a totality perspective, our continued investment in our global infrastructure for access, including to support patients in the United States.

Wonderful. You just mentioned TEVIMBRA. We've seen the recent approval of ZIIHERA in GEA. How do we think about that as a tailwind for Tisle?

Yes. It's certainly a very nice incremental opportunity as we continue to globalize TEVIMBRA. We've been in the process of launching in Europe, in the United States and markets outside. And this is a great tailwind for that franchise. Obviously, the data with the HERIZON-GEA data is differentiating. We're talking about 7 months of OS advantage. We do believe that the triplet will be practice changing. It's obviously very early days in terms of the launch trajectory there. But we think this is a sizable opportunity. There's, I think using the data that Jazz has disclosed, about 8,000 patients in this setting. So we do believe that this is a great opportunity for TEVIMBRA in the United States and other markets in which it launches to continue to support the globalization of the brand.

I guess you're the only company with foundational therapy in all modalities around B-cell malignancies. So the BCL2 inhibitor, BTK inhibitor and the degrader. What's the rationale behind like owning all 3?

I think the clear rationale is to be able to combine these agents in ways that can drive patient benefit and value for patients and that other companies are unable to access because they simply do not have access to these 3 foundational medicines. I think Aaron touched on it earlier, the overarching goal here when you think about how we're developing this franchise is to have a BeOne regimen as the best regimen for patients, driving the greatest long-term benefit for patients regardless of line of therapy or treatment preference. So we have BRUKINSA as, in our view, the best-in-class BTK inhibitor. We'll talk about perhaps zanu plus sonro in the fixed duration space. That's currently in 2 Phase III trials. And then we'll also be working on and potentially talk about the degrader in the relapsed/refractory setting.

Sure, sure. On that sonro and BRUKINSA combo, just remind us what the next signposts are? And do you think the Street adequately appreciates the revenue opportunity from that combo?

So with regard to next signposts, this is in 2 Phase III trials. The regulatory endpoint for both of those trials is PFS, and these are event-driven endpoints. So the first trial is a head-to-head versus venetoclax plus obinutuzumab, which is the current standard of care for fixed duration in the U.S. It's about 20%, 25% of patients receive this regimen. And there, we're looking to improve upon some of the issues we see with venetoclax and obinutuzumab.

So as we talked about in earnings, this is a regimen that at 6 years in all-comers if you just look across trial, of course, the 6-year PFS is roughly 20% below what we see with continuous BRUKINSA. And in high-risk patients, which is more than half the patients, it's 28% below. And you have to deal with the limitations of obinutuzumab infusions. You have to deal with the ramp-up of venetoclax and the lack of feasibility to be able to expand that into the community setting.

And then also from the safety side, the CLL 17 trial taught us that even after you stop therapy with VO, you still see elevated rates of serious infections for up to 4 years after -- 3 years after stopping treatment, which is higher than continuous ibrutinib, which was the comparator in that trial and continuous ibrutinib never catches up. And the reason for that is because obinutuzumab is a blunt sort of a -- it's a blunt weapon here. It completely obliterates the entire B-cell repertoire and that prolonged depletion of the immune system lasts well beyond the fixed 1 year of treatment.

And then despite all that, when you look at these trials, CLL 14, 17, et cetera, half the patients who progressed on that regimen actually unfortunately died. And so that naturally precludes the opportunity to retreat these patients. So what we're trying to do with ZS is develop a regimen that patients who opt for a fixed duration regimen will not have to sacrifice long-term outcomes relative to what they are able to achieve with a well-studied continuous BRUKINSA, which is very convenient and a daily pill that can be taken for a long time.

I think the other option here is acalabrutinib plus venetoclax, which was recently approved in the U.S. We have a separate Phase III trial that is head-to-head of zanubrutinib plus sonrotoclax versus acalabrutinib plus venetoclax. That trial is slightly behind simply because AV wasn't on the market yet. It's slightly behind the head-to-head versus VO. But there, based on the AMPLIFY data, which -- in that trial, they enrolled a patient population that was roughly 10 years below the median age of diagnosis of CLL and excluded high-risk patients. And despite that, saw the lowest rate of 3-year PFS of any of the major regimens and the lowest rate of undetectable MRD that was actually worse statistically than chemotherapy. So we feel like that's a lower bar from that perspective for us. And we want to unambiguously demonstrate, hopefully, pending the Phase III results from that trial that we have a better BTK and BCL2 combination.

Sure. And on competition, are you seeing any impact from acalabrutinib with any combo?

It's still early days. We've talked -- Europe has historically been a bit mature in this space because ibrutinib plus venetoclax has historically been approved so we see a bit more traction in the European market. It's just a market that's more primed for BCL2 and BTKi combination. The U.S., it is still early days. The approval was in February. We haven't seen meaningful traction of yet, but we continue to be mindful of competition and are doing our part to ensure that the BRUKINSA data continues to be out and appreciated in the public domain.

Sure. Same -- similar question on pirtobrutinib, just to get your latest thoughts on that as a potential 1L entrant in CLL.

Yes. It's a great question. I think it's important for pirto also to recognize how the drug was designed and developed. This was an agent that was designed specifically to retain activity against patients who develop cysteine 481 serine mutations, which would otherwise abrogate activity to the covalent inhibitors. And it does that really well, and it's approved in that setting, and it benefits a lot of patients in that setting.

And so -- but the question was, what does the data look like in BTK-naive patients, right? And we got the answer to that question last ASH, where, for example, we saw data from the BRUIN-314 trial, which was their head-to-head trial against ibrutinib. And in that trial, 2/3 of the population was relapsed/refractory. And then SAT, that is the key secondary endpoint that they will need to hit to be able to show superiority to ibrutinib. And those results were underwhelming. I think the hazard ratio was 0.845, the p-value was 0.4. If you look at the IRC PFS data, there was only 2 events separating pirtobrutinib from ibrutinib and that trial was 48 versus 50.

And if you compare that to what we saw with zanubrutinib versus ibrutinib in ALPINE, we saw a hazard ratio of 0.69, so 31% reduction in the risk of progression that was statistically significant with a p-value of 0.01. So early separation that was sustained, and we also have much longer-term follow-up data. I think the point I was trying to make is we think we're going to be the only agent that can say we have demonstrated PFS superiority against ibrutinib in a head-to-head trial. The other piece on pirto too is the safety. And in that head-to-head trial, the safety was perhaps more surprising because the safety was actually, in many cases, numerically worse than ibrutinib. It was better than ibrutinib in AFib, but the AFib rates were roughly comparable to what we see again across trial in SEQUOIA.

So you have to ask the question, for pirtobrutinib to be used in the front line, it needs to generate outcomes that are above and beyond what have already been shown with zanubrutinib also because in order to make that decision, you have to give up the opportunity to use pirtobrutinib in the later line setting where it is already benefiting patients in a way that zanubrutinib is unable to do because we're not a non-covalent inhibitor. We don't have activity against those C481S mutation. And the conclusion really to us, when we look at the data, is there's no need to change the treatment paradigm and the treatment paradigm and the data support BRUKINSA as the best-in-class first line [indiscernible].

Sure. Going back a little bit, following the zanu and sonro combo in CELESTIAL 301, the uMRD update that you provided, how should we think about the uMRD data and the read-throughs to the PFS endpoint?

Thanks for asking. It's an important question. So we did -- for everyone's awareness, we did announce at our earnings call that we did not reach the statistical superiority for undetectable MRD in that trial. Importantly -- so a couple of things. One, this was a very high scientific bar, and I'll go through why that was the case in a second. But it doesn't change 2 things. Number one is the regulatory strategy and time lines. And number two is our confidence in the ultimate regulatory endpoint here, which is, as we mentioned earlier, PFS.

So on number one, uMRD is not a regulatory -- it's not an accepted regulatory surrogate endpoint for approval as it is in myeloma. And PFS is the clear regulatory endpoint. On number two, it's important to consider that the MRD rates in CLL are actually dependent on the types of regimens that you use to combine. So in other words, venetoclax and obinutuzumab had an MRD rate of 73% in the CLL 17 trial. Ibrutinib plus venetoclax, which was compared head-to-head versus VO in that same trial, had an MRD rate of 46%. But remarkably, the Kaplan-Meier curves were superimposable. And this is because it seems to be that there is a mechanism dependence with regard to MRD. What we've shown in our Phase I results is the highest rates of uMRD for a BTK plus BCL2 combination of north of 90%. Again, this compares to IV in the mid-40s in CLL 17 and AV, which is even lower than that in the roughly 30s range in the AMPLIFY trial. And that has translated, hopefully, we'll see into a PFS benefit. But that's ultimately where our confidence lies in the PFS.

Sure, sure. Thank you, John. On to the degrader, I just want to make sure we talk about that. And so it's heading toward a potential accelerated approval submission in 2H 2026 and you're studied head-to-head against pirto. How do you think about the potential market opportunity here and the competitive positioning?

Sure. So with respect to the guidance, we have guided to provide an update on a potential accelerated approval filing in the second half of this year. We'll have more to say when we have something to say. I think you also referenced the head-to-head trial that is currently ongoing and hopefully we'll finish enrollment in early '27 versus pirtobrutinib. Our confidence in that trial is twofold. First, it's mechanistic. This is an interesting mechanism because it is able to retain activity against a substantial number of mutations in BTK that would otherwise render pirtobrutinib inactive. And it's important also to remember that pirtobrutinib, it's an ATP competitive inhibitor that binds to the active site, which means if there's a kinase-dead mutation, if there are other active site mutations, it no longer works, right? No different from the covalent inhibitors.

What the degrader does is it targets the whole protein for proteasomal degradation, which means it retains activity against those mutations, which would otherwise render pirtobrutinib ineffective. It also retains activity critically against the scaffold function of the protein and where the kinase activity does not signal and yet -- or does not -- there's no signaling from the kinase activity, but you still see BTK pathway. So there's a mechanistic reason here. And then ultimately, there's the clinical data that we've generated.

The clinical data so far, it's cross-trial comparisons, of course, but we've shown a mid-80s response rate in fifth-line CLL patients who really don't have many other options, the vast majority of which upwards of 80% have seen BTK and BCL2. And at the recommended Phase II dose of 200 milligrams, that response rate was 94%. Our median PFS in the most recent update was 2 years. That compares to what pirtobrutinib saw in the BRUIN 321 trial in roughly the same setting, slightly less pretreated, 1 line less therapy. Roughly half of patients had seen BCL2, so less pretreated from that perspective. And their median PFS was roughly a year. So if that translates into a Phase III, the goal here is to unambiguously show in a head-to-head trial that tacabrutideg is the better option for patients in this setting.

With respect to the market opportunity, I think we could look at what pirtobrutinib is annualizing at right now, which is nearly $800 million and it's approved in that setting and it's growing quite nicely. So I think there is a real market here, and that's the opportunity that we have ahead of us.

Sure. Well, we're right on time. We've touched on a lot. We've touched on the strategy, the financial solid tumor portfolio, the outlook near term for BRUKINSA, what you've got in various combos and other things on the heme side. Is there anything that I didn't ask before we sign off?

No, I think we covered a lot of ground. We really appreciate your time and questions. We're really excited about how the current year is performing and all that lies ahead. You asked about what -- reflecting back 10 years ago to where we are today, what we're really focused on is what we're going to be 10 years from now and so much opportunity in front.

Awesome. Well, thank you, gentlemen, for your time. It's wonderful. Thank you...

Thank you so much.

Good day, everyone. Welcome to BeOne Medicines Q2 2026 Earnings Call Webcast. [Operator Instructions] At this time, I would like to turn the call over to the company.

Hello and welcome. Thank you for joining us today. I'm Dan Maller, Head of Investor Relations at BeOne Medicines. Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentation on the Investor Relations section of our website, ir.beonemedicines.com.

I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most recent periodic report filed with the SEC.

Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation. Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our Investor Relations website, along with our earnings release. All information in this presentation is as of the date of this presentation, and we undertake no duty to update such information unless required by law.

Now turning to today's call. As outlined on Slide 3, John Oyler, our Co-Founder, Chairman and CEO, will provide a business update. Aaron Rosenberg, our CFO, will provide an update on our second quarter financial results and 2026 financial guidance. And Lai Wang, President and Global Head of R&D, will discuss our R&D and pipeline progress. We will then open the call to questions. Joining the team for the Q&A portion of the call will be Dr. Wu, President and Chief Operating Officer; Matt Shaulis, General Manager of North America; Mark Lanasa, Chief Medical Officer for Solid Tumors; and Amit Agarwal, Chief Medical Officer for Hematology.

I'll now pass the call over to John. John?

Thank you, Dan, and welcome, everyone. Q2 was a very strong quarter across every dimension of our business. From a financial perspective, we achieved $1.7 billion in total revenues and $2.05 in GAAP earnings per ADS. This represents growth of 30% and 144% compared to the prior year, respectively. BRUKINSA, our foundational BTK inhibitor continues to exceed our high expectations in the marketplace. More than 6.5 years after its initial launch, BRUKINSA is seeing its highest level of sustained new patient starts showing favorable early trends in duration of therapy, and it's showing strong growth across all 5 approved indications.

On the back of these strong results, we're raising our 2026 guidance ranges for revenue and GAAP operating income by $300 million and $250 million, respectively, and Aaron will detail this later. As impressive as our financial performance was in the quarter, our pipeline progress was equally significant. This is highlighted by the FDA approval of BEQALZI as the first and only BCL2 inhibitor in mantle cell lymphoma and the success of the Phase III MANGROVE study of BRUKINSA which is so exciting that it warrants the entire next slide. We also announced a $300 million expansion of our flagship U.S. manufacturing site in Hopewell, New Jersey.

MANGROVE is yet another example of the growing body of evidence supporting BRUKINSA as the foundational BTK inhibitor. We're excited about MANGROVE for 2 key reasons: the first is because it represents the first chemo-free treatment option for patients with frontline mantle cell. And secondly, because when you see the data, we believe the efficacy will speak for itself.

We're confident that this BRUKINSA-based chemo-free regimen has the potential to become the future standard of care for the roughly 21,000 new patients diagnosed with MCL each year in the major markets. Global submissions are planned for the second half of 2026, and we're looking forward to sharing the full data at an upcoming medical meeting.

Let's now turn to BRUKINSA's commercial performance. In Q2, BRUKINSA's global revenues reached over $1.2 billion, representing growth of 31% year-over-year. BRUKINSA is the #1 BTK inhibitor both in the U.S. and globally, and it has the broadest label of any BTKi with approvals in 5 B-cell malignancies. We often talk about BRUKINSA in the context of CLL and with good reason. But it is important to remember that BRUKINSA is a very important option for patients with other B-cell malignancies, including MCL, Waldenstrom's, marginal zone and follicular lymphoma.

BRUKINSA has now treated more than 300,000 patients across 80-plus markets, but market share alone doesn't tell the full story. The reason we're winning is scientific. And that story has 3 chapters: differentiated design, differentiated clinical outcomes and differentiated real-world evidence. At BeOne, we're committed to generating and sharing the evidence needed to fully characterize our medicines for the patients and physicians that we serve.

On the left side of this slide, you can see the highlights of the breadth of Phase III data generated for BRUKINSA as a single agent. Here, you can see BRUKINSA has reported the most Phase III data of any single agent BTK. The right side illustrates the substantial body of data currently being generated in combination where you can see that BRUKINSA has the most reported and ongoing Phase III data of any BTKi agent.

This slide demonstrates the scale of BRUKINSA's development plan compared to the more curated efforts of our peers. In addition to MANGROVE, BRUKINSA has 4 more potentially market-expanding Phase III readouts in the next 3 years. A major wave of data is coming that will extend BRUKINSA's evidence base and its label well into the future.

One quick reminder of why BRUKINSA performs the way it does. From day 1, BRUKINSA was designed to deliver a complete and sustained BTK inhibition through its potency and its PK profile. Our hypothesis was simple. Continuous BTK coverage would translate into a superior, therapeutic profile. And over a decade of clinical and real-world evidence has really borne that out. And that's what the next few slides show.

Let me remind you now that BRUKINSA is the only BTK inhibitor that has demonstrated PFS superiority versus ibrutinib in a head-to-head randomized trial. In Alpine, BRUKINSA delivered a hazard ratio of 0.69, and that separation has been sustained to a median follow-up of 42.5 months. In ELEVATE-RR, Acala showed early separation from ibrutinib, but that separation was not sustained. The curves crossed, and the final hazard ratio was one. And in Bruin314, Pirto reported a hazard ratio of 0.845. Put simply, there was very little differentiation between the 2 arms, with 48 PFS events reported for Pirto versus 50 for ibrutinib. And with respect to tolerability, Pirto showed numerically more discontinuations due to AEs zenibrutinib, whereas both BRUKINSA and Acala each showed markedly fewer discontinued zenibrutinib in their respective head-to-head trials.

When comparing afibrates of next-generation BTK inhibitors across studies, it's important to understand the protocol differences that may affect patient selection and event reporting. As you can see on the left, both BRUKINSA and Acala studies in frontline CLL used highly similar eligibility criteria and AFib reported. In contrast, the Pirto studies utilized more restrictive eligibility criteria that may have resulted in a fitter study population, and they also incorporated sponsor adjudication of Afib events.

As a reminder, Afib events and rates are known to rise substantially with age. In a large study of more than 17,000 adults in U.S. primary care clinics, the absolute prevalence of Afib was nearly 4% higher among those aged 70 to 74 as compared to 65 to 69. So factoring for this level of age difference in studies really matters.

Despite the differences in inclusion criteria, which may have led to roughly half the percent of patients above the age of 75 in Bruin 313 and a 4-year lower median age in the Pirto studies and despite the differences in Afib reporting methods, Afib rates were generally similar in the active treatment arms across studies. Interestingly, if we apply the more restricted Bruin 313 and 314 eligibility criteria to the Sequoia population, 15 of the highest-risk patients would have been excluded from the BRUKINSA arm. And in fact, those 15 patients had roughly twice the rate of serious grade 3 or higher infections and more than twice the rate of deaths due to AEs compared to the overall study.

This analysis underscores the extent to which differences in protocol inclusion criteria may play a key role in the clinical narrative. Although some have suggested that Pirto may be well suited for use in older patients due to lower Afib and improved tolerability, it is the least studied BTK inhibitor in that population. It lacks relevant long-term data with only 28 months of follow-up and the narrative about being more tolerable and having less Afib are not supported by the data. The totality of evidence continues to support BRUKINSA's best-in-class profile.

One of the key lessons we've recently learned in CLL trials is that long-term follow-up matters. Many regimens can appear highly effective in the first 3 years, but that's not enough time to understand their true durability. This slide shows the reported landmark PFS at years 3 through 6 across the respective frontline CLL Phase III trials for the frontline treatment regimens. Recognizing the limitations of cross-trial comparisons, a few items jump out.

One, the landmark PFS rates for BRUKINSA are higher and continue to diverge over time compared to the other 2 continuous BTKis. In fact, in year 6, the delta between the landmark PFS rates reaches 12%, which is equivalent of 1 in 8 patients not progressing. Two, there's an even more pronounced delta between BRUKINSA's landmark PFS and that of VO. In year 6, there's a delta of 21% or roughly 1 in 5 patients. While the all-comer story is compelling, the high-risk story is even more striking. It raises important questions about the use of the current fix duration regimens in high-risk patients, which I want to point out represent the majority of CLL patients. This is not a small patient subgroup.

This slide shows how the current expiration treatments performed relative to the foundational BRUKINSA in unmutated IGHV patients. those with the highest unmet medical need. BRUKINSA remains durable, 84% landmark PFS at year 3 and 70% at year 6. In contrast, VO drops from 82% at year 3 to just 42% at year 6, a 40-point collapse. And AV amplify based on the limited data disclosed to date shows just 69% at year 3, which is, of course, lower than VO at a similar time point.

There's a few important takeaways from this slide. First, while we're big believers in the promise of fixed duration, the existing Venn-based treatments are not compelling option for higher-risk patients, where foundational BRUKINSA has generated the best-in-class data. Second, long-term follow-up is critical in CLL. As you can see on this slide, many regimens look promising at 3 years, but by 6 years, the outcomes can diverge meaningfully, especially in high-risk patients. And that's why we've consistently prioritized long-term follow-up in our studies and why we believe 6-year data provide a more complete picture of treatment durability. It's also why we're concerned when reached on regimens based on only 3 years of data or less are made.

We've been very surprised that some studies have not continued to report longer-term follow-up data because years 3 to 6 are critical to evaluate the true long-term benefit of any CLL therapy. Patient outcomes are at stake. The durability advantage that we're seeing in the clinical data for foundational BRUKINSA is increasingly being reinforced in the real world. And it's both consistent, and it's compelling.

At ASCO 2026, we published an analysis of over 10,500 Medicare free service patients with previously untreated CLL. This is the largest real-world data set ever assembled in this setting. In this patient population, BRUKINSA reported statistically significant 24% and 36% reduction in the risk of death compared to those treated with Acala and ibrutinib, respectively, 24% and 36%.

As you can imagine, this data set generated significant interest from physicians at ASCO, given both its size and the importance of these findings to the real-world U.S. Medicare population. The study has since been published in a peer-reviewed journal. And importantly, this is now one of several large real-world analysis, showing a consistent advantage for BRUKINSA, including a recent study of claims data from 17,000 frontline CLL patients, which also reported improved survival and treatment durability for BRUKINSA versus Acala.

Stepping back, BeOne is the only company in the world with foundational medicines across the 3 mechanisms of action for B-cell malignancies. BRUKINSA, our foundational BTK inhibitor, BEQALZI, our recently approved next-generation, potentially best-in-class BCL2 inhibitor and Tacabrutideg, our potentially first and best-in-class BTK degrader. Only BeOne is equipped to provide the best-in-class therapies as monotherapy or in combination for every CLL patient and other lymphomas, regardless of their stage of disease, risk status or treatment preference.

I've spoken about how 2026 is an inflection year for our solid tumor pipeline. And we presented data this quarter that supports our confidence in moving our CDK4 inhibitor, our B7-H4 ADC and our GPC3 4-1BB bispecific antibody into registrational trials. Looking forward to ESMO, we'll be sharing similar proof-of-concept data sets for 2 more potentially best-in-class medicines, our PRMT5 inhibitor and our CEA ADC.

It's an incredibly exciting time for our company, for our portfolio and for our pipeline. And with that, I'll hand it over to Aaron for the financial results.

Thanks, John. Our second quarter financial results reflect strong execution and a durable and healthy underlying business as we invest with discipline to support growth over the long term.

Starting with our commercial performance. we delivered another strong quarter across the portfolio with continued broad-based growth. Total revenue for the quarter was $1.7 billion, representing 30% growth compared to the prior year. U.S. BRUKINSA sales totaled $893 million, representing growth of 31%, which exceeded expectations due to several underlying factors. Despite the competitive environment, in Q2, we saw the highest level of sustained new patient starts since BRUKINSA's launch. Prescribers increasingly selected BRUKINSA for their patients given the totality of evidence for efficacy and durability and supported by the clinical data and their real-world experience.

We also continue to see meaningful growth from indications beyond CLL, which speaks to the breadth of the BRUKINSA label and the diversification of the franchise. And while duration of therapy remains immature for BRUKINSA, the data suggests favorable duration relative to historical benchmarks. This makes sense given the unprecedented long-term data seen with Sequoia as well as recently published real-world studies that reinforce statistically significant advantages for BRUKINSA in time to discontinuation relative to both acalabrutinib and ibrutinib. And finally, patient adherence has also improved, potentially linked to the launch of the tablet formulation late last year, which reduced both pill size and burden. High adherence rates are important for patient outcomes, and we are pleased to see this progress.

These factors are not unique to the U.S., and we expect they will support durable long-term global demand growth for BRUKINSA. Beyond BRUKINSA, TEVIMBRA generated $229 million in global sales, representing 18% growth versus the prior period. TEVIMBRA maintained its market leadership in China in the face of steep competition. Our global launches are also gaining traction and this is ahead of the potential catalysts associated with the approval of TEVIMBRA in combination with Xihura and chemotherapy for patients with first-line HER2-positive GEA. Our Amgen in-licensed portfolio also delivered $157 million in revenue, growing 25% year-over-year.

Next, I'd like to highlight the broad-based nature of growth across geographies. The U.S. remained our largest market, contributing approximately $899 million in revenue during the quarter and growing 31% year-over-year. China contributed approximately $500 million in revenue and grew 17% year-over-year, demonstrated continued strength across our commercial portfolio while maintaining market leadership for both TEVIMBRA and BRUKINSA. Note that foreign exchange contributed 7% of reported growth given year-over-year renminbi strengthening.

Europe continues to be an important growth driver for the company, generating approximately $208 million in revenue and growing 37% year-over-year. We also continue to see strong momentum across our rest of world markets, where revenue more than doubled to approximately $73 million.

Key markets such as Japan and Brazil are making contributions that are increasingly meaningful at the enterprise level.

Turning to the GAAP P&L. Gross profit was $1.5 billion with gross margin of just under 90%, benefiting from mix as well as productivity improvements for both BRUKINSA and TEVIMBRA. Operating expenses totaled $1.2 billion, representing 13% growth, reflecting advancement of key clinical programs and continued investment to support commercial growth. We continue to demonstrate the scalability of our model in the quarter with income from operations growing to $325 million. And finally, net income totaled $237 million. This includes the previously disclosed tax audit settlement, which had an approximate $60 million impact.

GAAP diluted earnings per ADS were $2.05 compared with $0.84 in the prior period.

Now turning to our adjusted results with a full reconciliation provided in the appendix of our results presentation. Adjusted income from operations increased to $503 million representing growth of more than 80% year-over-year. Adjusted net income increased to $444 million, while adjusted diluted earnings per ADS increased to $3.84 and compared with $2.25 a year ago. Cash generation continues to build momentum with free cash flow doubling from the prior year period to $435 million.

Turning to our updated full year outlook, which reflects the strong first half performance and confidence in the trajectory of our business. We are raising our revenue outlook by $300 million to a range of $6.6 billion to $6.8 billion. This increase reflects the continued strength we are seeing across the portfolio, led by BRUKINSA's performance in the U.S., ongoing global expansion and continued contributions from the broader commercial portfolio.

We continue to expect gross margin to remain in the high 80% range. We are investing in both commercial execution and pipeline advancement with a modest increase in operating expenses to an updated range of $4.8 billion to $5 billion. Including those investments, the strength of the business translates to the bottom line, with the guidance raised in 2026 operating income by $250 million across the range.

We now expect GAAP operating income of $1 billion to $1.1 billion and non-GAAP operating income of $1.7 billion to $1.8 billion. Other underlying assumptions remain unchanged. Overall, this updated outlook reflects the strong performance we've delivered year-to-date and our confidence in continued execution for the remainder of the year.

As we have now rounded the first half of the year and while staying away from providing detailed guidance, I'd like to provide some perspectives as you update your models and begin thinking beyond this year. Our 2026 outlook provides confidence in the durability of our commercial business, including the prospects for continued BRUKINSA growth despite the competitive environment. And as you see in our implied operating expense guidance for the second half of the year, we are investing to realize the full potential of our pipeline that we believe will drive sustainable long-term value for shareholders and the potential to address multiple unmet need for patients.

We remain committed to our dual objectives of growth with measured margin expansion in the near term. Operating expenses will continue to be prioritized against our high hurdle rates but can be expected to grow at a year-over-year rate in 2027, similar to what we've seen over the recent 2 years, given the positive progression of key pipeline assets. We look forward to providing our next financial update in November with Q3 results.

And with that, I'll now pass the presentation over to Lai.

Thank you, Aaron. Hello, everyone. Thank you for joining us today. Across our portfolio, we'll continue to deliver meaningful progress. Starting with hematology, John already highlighted the positive readout from the MANGROVE study in treatment mantle cell lymphoma. BRUKINSA plus rituximab has the potential to redefine frontline treatment and become the first chemo-free regimen for these patients. For BEQALZI, we achieved our first FDA approval in relapsed refractory mantel cell lymphoma.

Moving on to the CELESTIAL 301 study update. The regimen did not reach statistical superiority in the uMRD analysis versus the VO regimen. The IDMC recommended the study continue toward its primary regulatory endpoint of progression-free survival. While the uMRD comparison was an interesting scientific question, uMRD superiority represented a very high bar given the historical high uMRD rates associated with VO regimen. Importantly, uMRD rates do not consistently predict PFS outcomes when comparing different MOAs, such as BTK inhibitor versus anti-CD20 antibody. For example, in CR 17, despite 26% lower uMRD rates than VO, the ibrutinib venetoclax regimen demonstrated comparable PFS outcomes as VO. As a result, if a BTK inhibitor plus BCL2 inceptor combination achieved similar uMRD rates as VO, it should translate into better PFS than VO.

Given the higher uMRD rates and exceptional durability observed with the regimen in Study 101, we remain highly confident in achieving the PFS end point.

Next, our BTK degrader Tacabrutideg, continues to advance through potentially registrational Phase II studies, while our Phase III CaDAnCe-304 study against the Pirto remains on track. Together, this program support our ambition to lead the next generation of therapy in B-cell malignancies.

In solid tumors, TEVIMBRA reached another important milestone with FDA acceptance and the party review of our HER2-positive GA application. We also made regulatory progress in China with the CDE accepting submissions for both TEVIMBRA and ZIIHERA. Beyond TEVIMBRA, we'll continue to advance a diversified and increasingly innovative pipeline. Our CDK4 inhibitor has begun Phase III development in breast cancer. Our GPC3 4-1BB bispecific recently completed enrollment in a potentially China registration-enabling HCC cohort.

We also remain on track to initiate a Phase III study in second-line HCC before year-end. In addition, our PRMT5 inhibitor received FDA orphan drug designation for pancreatic cancer, and we initiated clinical development of our PD-1 VEGF CTLA-4 trispecific. The milestones from the last quarter are a reflection of more than strong execution. They demonstrated the power of focused on this strategy.

We concentrate our investments in disease areas where we can establish leadership, building disease franchises rather than stand-alone products. Supporting that strategy is a growing technology from degraders and novel payloADCs to cell therapies and the T cell engagers. Because we're not tied to any single modality, we can pair the right biology with the right therapeutic approach. The result is a pipeline designed not just to be brought, but to be sustainable.

As our innovation engine matures, we are creating gaps within disease area with multiple assets and mechanisms working together. That gaps opens the door to combinations from within our own portfolio, driving differentiation and maximizing the value of our innovation investments.

As we discussed on the previous slide, our innovation engine is generating a growing number of high-quality opportunity across the portfolio. Historically, our solid tumor pipeline was heavily weighted toward immuno-oncology. The CDK4 inhibitor marked the beginning of a new chapter, one defined by more diversified mechanisms broader modalities and a sharper focus on specific tumor types.

Today, that evolution is clearly visible. We now have 5 solid tumor programs that have achieved clinical proof of concept and are advancing towards pivotal development. Remarkably, each is on track to progress from first increment studies to pivotal stage in approximately 2.5 years. Our CDK4 inhibitor is already enrolled in Phase III. The B7-H4 ADC is expected to enter a pivotal study in ovarian cancer by year-end. For GPC3 4-1BB, we completed enrollment of the China registration intent expansion cohort with approximately 100 patients in just 2.5 months. You heard it right, it's only 2.5 months, underscoring our ability to execute at an exceptional speed.

Based on this momentum, we also expect to initiate a Phase III study in second-line CC by year-end. In parallel, our CEA ADC and PRMT5 inhibitor have achieved a proof of concept and are advancing towards registration-enabling development. Taken together, these programs demonstrated a repeatable model built on differentiated science, disciplined portfolio strategy and a strong clinical execution. As multiple internal discovered assets advance into late-stage development, we are creating a growing number of value inflection points.

Now let's take a closer look at some of the assets we highlighted at ASCO, starting with our CDK4 inhibitor. The data continue to be highly encouraging and are consistent with our scientific. At ASCO, we reported a potentially best-in-class profile, combining promising efficacy with differentiated hematological safety. That is the Phase III dose. BGB-43395 achieved an objective response rate of around 70% in combination with letrozole in first-line HER-positive, HER2-negative breast cancer. Safety remains a key point of differentiation. At the 400 milligram, the overall neutropenia rate was just 21% with no grade 3 or higher events. This compares favorably with both and approved CDK4/6 captures where severe neutropenia remains a meaningful clinical challenge.

Together, these findings provide strong support for our ongoing Phase III program, which is enrolling rapidly. They also create opportunities for novel combinations across our portfolio, including with our CDK2 degrader BCL2 inhibitor and the KAT6 inhibitor.

Turning to our GPC3 x 4-1BB program. BGB-B2033 continues to demonstrate what could be a breakthrough profile in HCC, combining strong monotherapy activity with a highly favorable safety profile. At ASCO, we reported objective response rate of over 30% in second line plus HCC comparable to current first-line combination regimens and well above what was reported with available TKIs in the post-IO setting. Safety remains a key differentiator, enabled by our unique BB approach. This profile supports development in earlier lines, where approximately 70 patients have already been enrolled in combination with TEVIMBRA and. Development momentum also remains strong. We completed enrollment in a potentially China registration enabling expansion cohort in post-IO, post-TKI HCC. In parallel, we are engaging with global regulatory authorities to explore accelerated approval pathways in second-line plus HCC based on the compelling efficacy and the safety profile observed to date.

Turning to our B7-H4 ADC, BG-C9074. At ASCO, we presented data that supports its potential to become a leading program in ovarian cancer. The key differentiator is safety at 6 mg per kilo treatment-related grade 3 or higher adverse events were approximately 26%, less than half the rates reported for other ADCs in development for first-line ovarian cancer without biomarker selection. This profile is particularly attractive in the maintenance setting, where long-term tolerability is critical. We also reported encouraging efficacy including activity that appears independent of B7-H4 expression, supporting our all-comer development strategy.

Based on this data, we plan to initiate a Phase III study in first-line maintenance ovarian cancer before the end of 2026, while continuing to expand the opportunity to endometrial cancer and TNBC. Taken together, C9074 combines competitive efficacy with potentially best-in-class tolerability, positioning it as a leading B7-H4 ADC.

We're excited for ESMO where we have 12 abstracts accepted, including one rapid oral presentation and 9 posters. Highlights include our GPC3 x 4-1BB bispecific Phase I dose optimization data, the first exposure of Phase I proof of concept data for our PRMT5 inhibitor with a focus on non-small cell lung cancer and the initial evidence of clinical meaningful brain activity.

An initial concept data for CEA ADC that underscore its compelling first-in-class potential in non-small cell lung cancer. Together, this presentation highlights the strength and the breadth of our innovation engine.

We have covered most of the milestones already. I will just call out a few items on this slide. We remain on track for a potential accelerated approval submission of Taca in relapsed refractory CLL by the end of this year, further expanding our sales franchise in B-cell malignancies. In addition, we plan to start Tacasonro fixed-duration combination Phase III development in relapsed refractory CLL in 2027.

In solid tumors, we expect to initiate pivotal studies for both our GPC3 x 4-1BB bispecific in second line plus HCC and our B7-H4 ADC in first-line maintenance ovarian cancer before year-end. Looking further ahead, both our PRMT5 inhibitor and the CEA ADC are positioned to enter Phase III development in 2027.

I will now turn it back to John.

Thanks so much, Li, and we'll now open the call to Q&A. Please limit the number of questions to ensure we have time to hear from as many attendees as possible. Operator, please go ahead.

[Operator Instructions] Your first question comes from the line of Yanan Zhu with Wells Fargo.

Great. And congrats on the raise quarter. So could you provide more color on the growth of BRUKINSA sales. And specifically, I was wondering if you can quantify how much of the growth is coming from indications outside versus CRL itself. And within CLL, do you see any impact from the Acala launch? And how do you think the dynamics could evolve in the next couple of quarters from that perspective? And also very quickly on CELESTIAL-301, any color on the HR of the 2 arms. It sounds like it could be similar at this stage, but any color would be helpful.

Thanks. So I think we kind of got 3 sub questions in there. Maybe I will start and give a quick answer related to your question on Acala plus then, then we can jump to Aaron and he can answer your general BRUKINSA question, and we can come to CELESTIAL with Amit. So let me just start. I think right now, we're not seeing much impact from the AV AMPLIFY in the U.S. it's early. It's hard to say how it will evolve. And if Amit has extra detail on that, he can add it when he jumps to CELESTIAL. So with that, Aaron, do you want to talk more broadly about where growth is coming from?

Thank you. So we really saw BRUKINSA growth and really for the rest of our portfolio, driven by strong growth in demand across all of our regions. We spent some time talking about our U.S. business. And at the last quarter, we talked about the strength that we saw coming out of April and May. And obviously, that's continued into our second quarter performance. I highlighted in my prepared remarks, 3 core areas. The first, we are achieving our highest level of new patient starts since launch. So we're really pleased to see the uptake in the marketplace. This is driven by strength in CLL as well as our non-CLL indication. So we really do see that durable growth across all indications.

You talked a bit about sort of context. I mean if you look at just prevalence across the 5 approved indications, there's about 1/3 of the total prevalence in those non-CLL indications. And we're punching a little bit above our weight in those areas because we actually have really strong share in those indications.

The other piece that we had talked about was duration of therapy, and that continues to be highly constructive, yet immature. This is reinforced by real-world data, we talked about the study in 10,000 Medicare patients that were recently published. And this was really noteworthy, with BRUKINSA showing meaningful long-term benefits on discontinuation of therapy versus acalabrutinib and ibrutinib. In fact, BRUKINSA did not meet the median time to discontinuation in this data cut. And what we're really pleased about is how this relates directly to patient outcomes and experience. And this is what you see in our overall demand growth.

As a result of data such as this, we have updated our internal planning assumptions to reflect longer duration of therapy. And overall, the business is just performing exceptionally well. So Amit, will you take the next question?

Yes. Thank you, Aaron. I think the question was about Amplify. And I think John mentioned this in his remarks, but long-term outcomes are very important in CLL. As we have seen, there is a huge difference between what happens with patients between years 3 and 6. And for AV, we only have the 3-year data. We don't have long-term data, and what we've seen from that data is the lowest rate of uMRD as well as landmark PFS even among the wind-based regimens. So while it is hard to say what will happen with this data set in 6 years, we do have other data sets that look better than AV at the 3-year mark with a longer follow-up, including Veno and Veni. And when we look at these data, they really highlight some of the challenges that are seen with the current venn-based fixed duration regimens.

Now in particular, when we look at that unmutated IGHV, per patient population, which represents a majority of the frontline CLL patients, there's a clear distinction between the results from BRUKINSA and other ven-based combinations. For example, at 6 years, BRUKINSA has shows 70% PFS, whereas the fixed duration ven-based regimens show PFS in the low 40s. We're talking about a 30% difference in the PFS. This really matters.

Now when we couple this with the fact that there are safety issues and some of the VEM-based regimens have serious infection rates of 20% to 30%, including fatal infections and the fact that almost half of the progression events our not even allowing patients an opportunity for retreatment, it is clear that these patients are really not being served well with -based regimens. And the fact that BRUKINSA is the treatment of choice makes a lot of sense.

Now maybe I'll quickly address this. So that's your question around the hazard ratio. So as Lai mentioned in his prepared remarks, this was an IDMC event where the IDMC reviewed the data for the uMRD and BeOne remains unblinded to the data. So we do not have the details of the hazard ratio. But having said that, again, we remain very confident in the PFS endpoint and our ability to show superiority for ZS overview and for the primary regulatory endpoint, which is PFS. With that, I'll turn it back to John.

Yes. Thank you so much, Amit. And can we have another question, please, operator?

Your next question comes from the line of Reni Benjamin with Citizens.

Congratulations on an outstanding quarter. As my question mainly has to do with the MANGROVE study. Can you maybe provide some early physician feedback regarding the results you've disclosed? Any sort of thoughts on the study, not including rituximab maintenance arm and kind of how they're viewing the data? And how do the physicians kind of interpret this relative to the ECHO regimen, which has already been approved?

Thank you so much for the question. Again, we haven't disclosed that much data on this yet, but I think, Amit, this is back in your wheelhouse.

Yes. Thank you, John, and thank you for the question, Reni. So really, I think we're all very excited about the MANGROVE results. And really what MANGROVE has let us do is it's another great example of how BRUKINSA's differentiated profile leads to really meaningful advantage for patients. So from a design perspective, one of the important differences for MANGROVE compared to some of the other studies is that MANGROVE was designed to test a chemo-free regimen in that frontline MCL setting and show, for the first time, that it actually is better than the standard of care chemo-free -- chemotherapy regimens.

The other BTK inhibitors, as you mentioned, ECHO being one example, have really added the BTK inhibitor to that chemotherapy regimen. And so they are more add-on rather than replacement designs. And MANGROVE for the first time, showed that a chemo-free regimen of ZR was superior to BR with a hazard ratio of 0.57 in favor of the ZR arm. And these results themselves are really unprecedented in terms of thinking about that chemo-free regimen.

We've talked about the OS data being immature. But I think when you see that data, it will really sort of tell an important story there. And when we shared these results with physicians, KOLs, experts who treat MCL, they're really excited about this data. I think they really understand the impact that this can have. The fact that the chemo-free regimen really is going to allow for patients to avoid some of the toxicities that are seen with chemotherapy, avoid the rituximab infusion. Actually, there is a high level of interest in understanding what the rituximab maintenance-free regimen would also look like. And so overall, we've received very positive feedback from the community so far.

Yes. Thanks, Amit. I just want to reiterate that the response I've had is wonderful. So thank you so much, operator. Could we have the next question, please?

Your next question comes from the line of Michael Schmidt with Guggenheim.

I had one on the BTK degrader program, sticking with hematology. Maybe comment a bit about how you're tracking towards completing the first registration study in relapse refractory CLL? What is the efficacy buy in this setting, especially in the context of a single arm study? And longer term, how do you see the degrader program position relative to other programs, specifically the Norex Roche program?

Thanks, Michael. Nice to hear your voice. I think that Amit is very popular this morning. So please can you jump into that?

Yes. Thank you, John. So as Lai mentioned in his remarks, we remain on track and if the dealer support this, we're looking forward to that AA submission in Q4 of this year. Now I'll remind folks that the FDA has previously granted Fast track designation for tacabrutideg for adult patients with relapsed/refractory CLL, who received at least 2 prior lines of therapy, including a BTK and BCL2 inhibitor. And in the context of what we've seen so far from our Phase I data, across different patient populations, we've seen very encouraging, both response rates as well as the durability of those responses. And we think that this is a profile which is compelling. And when we think about previous accelerated approvals, we think that the profile really supports accelerated approval in that context.

Now in addition to this, we also have important Phase III studies, which are executing very well. Particularly, I would call out a head-to-head comparison of tacabrutideg versus pirtobrutinib, the non-covalent BTK inhibitor. The study is enrolling very well, and we are very excited to share those results when they are available. And in addition to this, Lai mentioned the tacabrutideg + sonrotoclax relapsed/refractory study that we also plan to initiate early next year. So overall, I think this really reflects our growing confidence in the program and our ability to execute on a sort of profile, which is going to allow tacabrutideg to become a foundational asset in CLL along with the rest of our portfolio.

Thanks, Amit. And operator, we're ready for another question.

Your next question comes from the line of Etzer Darout with Barclays.

Great. Congrats on the updates, today. Maybe another one on MANGROVE, if you can maybe talk about when we could see an additional data cut here and any sort of potential presentations we may see around that? And then secondly, and maybe one for Lai around the pipeline. Just curious around the KAT6 design elements and the potential to combine maybe with the CDK4 selective program or other programs in our pipeline, just given sort of some of the other efficacies we've seen with that and the intriguing profile that, that could have. But again, does the safety being limited, just curious around sort of your design elements there to maybe overcome some of those limitations would be great.

Thanks so much for the question. Let's start with Amit and jump to Li.

Yes. I think the question about MANGROVE was really just when are we presenting the data. And I think as you mentioned, John, we are very excited to present this at an upcoming congress. So we'll hopefully share with details very soon. Lai?

Yes. In terms for the KAT6, this molecule was designed to be more selective for KAT6, trying to spare in the KAT7. This is the main differentiation versus Pfizer's KAT6 program. We believe this can potentially leading to less hematological toxicities. So far, we certainly starting from last year, we had this program entering connect to initiate a first-in-human study in breast cancer. The design there used to be combined with our CDK4 inhibitor, but certainly in our pipeline, there are many other potential molecules which we can combine with KAT6 in the breast cancer. But in addition to that, I think it was just last month, we also initiated our second Phase I study. This one is to exploring this KAT6 molecule in AML.

We have seen quite a bit interesting preclinical translational data about KAT6 in AML, and we're certainly looking forward to seeing this molecule how it does in AML.

Thanks so much, gentlemen, and back to the operator for another question.

Your next question comes from the line of Yaron Werber with TD Cowen.

Congrats on a really nice quarter. Question, P95 is that a really important target in your -- the lead essentially with the brain-penetrant molecule -- so it sounds like you're going to have data in lung cancer at ESMO. Can you give us a sense what we might be able to see because you're moving that into Phase III next year. And I think also pancreatic cancer achieved POC. Is there any chance we might see some of that data at ESMO? Or is that going to be in the next meeting? And is that moving to Phase III next year as well?

Yaron, thanks for the great question. And Mark, why don't you speak to that since you're closest to the detail.

Thank you, Yaron. We're very excited about our PRMT5 program and look forward to the initial disclosure that's upcoming at ESMO. Our molecule entered the clinic in the first quarter of '25. So this is our initial disclosure and therefore, will include the monotherapy Phase Ia dose escalation data, but will also include a significant number of patients who have been enrolled in expansion phases, because our molecule is designed to be CNS penetrated, we have had an emphasis on enrolling patients with non-small cell lung cancer. As you heard from Lai, we'll share some data showing that we have early evidence of clinically meaningful CNS coverage, but we will share data across tumor types, inclusive of non-small cell lung cancer, pancreatic cancer and other tumor types. Again, while we have an emphasis on lung cancer, we intend to have a broad development plan for this molecule.

Thanks so much, Mark, and back for another question, please.

Your next question comes from the line of Jessica Fye with JPMorgan.

Maybe one for Aaron and one for Mark. On the guidance increase, can you just walk through what changed most materially relative to your expectations when you last updated guidance last quarter? And then for Mark, on the CEA ADC for lung cancer, can you talk in broad strokes about the Phase III you envision running for that product next year?

Thanks, Jessica. Please Aaron and Mark.

Sure. And I'll be I'll be fairly brief, and thanks for the question, Jess. I covered, I think, many of the factors that were driving performance for the quarter. The ones I highlighted are all areas of strength for BRUKINSA whether it be the level of new patient starts we're seeing, the strength across all indications and certainly improvements in our understanding of duration of therapy and how that's manifested in demand. All these are areas of strength in the business, and candidly, ahead of our expectations at the beginning of the year. We're really pleased to see this. So ultimately, this means impact for patients, and we look forward to continue to growing the franchise as we move forward.

Thanks, Jess. Regarding the CEA ADC, as I mentioned for PRMT5, again, we're very excited to make our initial data disclosure at the upcoming ESMO because this is the first disclosure. This will include the Phase I dose escalation data as well as the expansion data. We do have a first-in-class proof of concept in non-small cell lung cancer, and we think that these data compare favorably to other investigational ADCs in the non-small cell lung cancer space. Based on these data, we want to leverage our lead mover advantage. So the initial registration opportunities will be in a later line setting, but we're actively working to generate evidence in an earlier line setting, given the strength of data that's emerging.

Thanks so much. Another question, please.

Your next question comes from the line of Faisal Khurshid with Jefferies.

This is on for Faisal. Can you just give a little more detail on your PRMT5 and RAS strategy? Would the Phase III for the PRMT5 lung cancer study be a combo or mono? And could you provide any further details on your RAS inhibitor?

So Mark, I think that's back to you.

Thank you very much for the question. RAS inhibition has proven itself to be a very important therapeutic modality, not only in pancreatic cancer, but also in non-small cell lung cancer. We're deeply committed to innovation in that space. We have a highly potent RAS on inhibitor that will enter the clinic prior to the end of this year. Similar to our PRMT5 molecule. This molecule was designed to be CNS penetrant. And therefore, we're particularly excited about the opportunities for that molecule in non-small cell lung cancer. We are certainly aware and excited about the data when a RAS on inhibitor is combined with a PRMT5 inhibitor in MTAP-deleted pancreatic cancer. We will be looking to generate evidence in that regard as swiftly as possible.

And then going back to RAS, we have additional RAS targeting molecules that we're advancing, including a KRAS targeting degrader, as well as a RAS on ADC, where RAS on inhibitor will be the payload for the molecule.

Thanks so much, and back to the operator for one more question.

Your last question comes from the line of Gregory Renza with Truist Securities.

Congrats on the quarter. John, maybe one for Aaron. And just as we look across the portfolio, when it comes to the Amgen portfolio, Aaron mentioned the growth of 25% or so. Just curious how we should be thinking about its contribution. It continuously outperforms expectations. Certainly, some nice growth there. But where do you see the portfolio going? And how should we be framing the contributor to the top line?

Thanks for the question, Aaron, why don't you wrap up Q&A, we'll close.

Sure. Thanks for the question. We're obviously very pleased with the performance of our MGM portfolio this year and really since the inception of this important collaboration. So this is a franchise with great assets. We're on the verge of launching our opportunity within Delta in the marketplace. I did touch on the last quarter, biosimilar competition that's coming for XGEVA. We'll share more on that evolution as our understanding of the situation evolves. That's not a near-term impact, but it's certainly something that could influence performance as we move beyond this year. And we'll share more details of that as our understanding of the situation comes to light.

Thanks so much, Aaron. In closing, I just want to share that we believe the company has never been better positioned. The commercial engine is really delivering the pipelines at an inflection point, the global organization is executing at a very high level. That said, there's a lot of cancer out there and it's tough, and there's still a lot of work ahead, but we're really excited about the opportunity in front of us. And we do want to just take a moment to thank the patients, their families that we're serving, the physicians, our partners and our more than 12,000 colleagues and their families who focus with urgency every day to make this progress possible. So thank you all for joining us and being part of things. Have a wonderful rest of the day. Thank you.

All right. Thank you, everyone, for joining this session. My name is Linhai Zhao, I'm the China biotech analyst.

Today, with great privilege, we have the opportunity to host the management from BeOne Medicines. On the farther right of the stage, we have Aaron Rosenberg, the CFO; and Mark Lanasa, the CMO, joining this fireside chat. So welcome.

And I think BeOne Medicines has shown very exciting data at ASCO this year and investors have been highly anticipating some exciting news from our solid tumor pipeline. Besides that, we have done extremely well for our hematology pipeline. BRUKINSA is by far the #1 BTK inhibitor globally, and we are continuing to see exciting clinical progress from our BCL-2 inhibitors and the BTK degraders.

So I think the first question, I think would be about our clinical strategy. You've taken a very disciplined, data-driven approach to prioritizing the pipeline with the 5 highlighted cornerstone programs for solid tumor, as well as a few deprioritized programs that you shared at the quarterly results. What is the go versus no-go bar for the clinical data? What is your vision on the solid tumor franchise over the next 5 years?

Thank you, Linhai, and thank you very much for having us present this morning.

So yes, we have brought a lot of molecules into the clinic, and it is our aspiration to bring additional internally discovered as well as some partnered molecules into the clinic. Through this, we have been very disciplined in our early phase approach. We think that this is critically important in allowing us to progress a large portfolio as a midsized organization.

So put simply, when a molecule is coming to the clinic, the teams are asked, what would a differentiated medicine look like for the target patient population in development? And that is something that is expected of the teams at the time of the first-in-human study. And by understanding what a differentiated medicine would look like, we're able to establish clear go/no-go criteria.

If the programs are meeting those criteria, then, great, we'll look to expand those programs. And we've highlighted 5 programs that have met those criteria and are on track to a Phase III study start. We highlighted 3 of them at the recent ASCO.

But we also announced that there were other programs that we have stopped because they weren't meeting those criteria. And these include some programs that we had previously highlighted based upon previously -- based on very strong preclinical data. So we think that that disciplined approach is really critically important to be able to progress and prioritize a broad pipeline of innovative molecules.

Yes. Can you be a little bit more particular? Preferred would be with examples. I know that differentiation or differentiated medicine can look very differently, or we have very different requirements when we are talking about different indications or different molecules.

So ultimately, it comes down to what is the target population for development. Since we recently disclosed some data, I can make a few examples.

So for example, for CDK4, what we were excited about with that molecule is really strong efficacy data with a response rate of approximately 70% across 2 different cohorts. We feel that that's clearly differentiated from what the CDK4/6 molecules deliver at a range of, say, 50% to 55% in a frontline patient population. So that hits our go criteria in combination with favorable PK and safety and whatnot. And then for GPC3, where our target patient population was hepatocellular carcinoma, there the molecule exceeded our go criteria with a response rate of 30% and a very clean safety profile.

So for both of those molecules, we have confidence that they not only deserve to go to Phase III, but can eventually be impactful medicines. We'll have a similar conversation about PRMT5 in the second half of the year. And again, we're applying that same lens to all of the molecules that we bring into the clinic, our KAT6A/B that we started in last December, again, what does a differentiated molecule look like in later-line breast cancer?

Yes. I think we're all very excited about the ASCO readout, but we can definitely discuss deeper about that later. I want to briefly touch about our pipeline or the clinical pipeline targets. We mentioned of the target to deliver 8 to 10 NMEs per year. How do you maintain the speed without sacrificing quality in clinical decision-making? And more particularly, with China being increasingly recognized as an innovation source, how would you describe BeOne's strategy to leverage China innovation given that we are targeting to deliver this amount of NMEs per year?

I can start. So what's really important to understand is that our internally delivered development work is global by its nature, that we are the leading sponsor of early-phase research in Australia, we're the leading sponsor of early-phase research in South Korea. And therefore, we're not only moving quickly, but we're moving quickly globally.

And this enables us to generate data that again enables us to have those go/no-go criteria. But also by having global patient data, we can have confidence that the data does not have significant determinations based upon ethnicity or region, and that it will meet the needs of global regulatory agencies.

We recognize that there are a lot of exciting molecules that are emerging from China as well as other global regions. Our BD approach is fundamentally global. But what we look at, again, our development model by being global in its nature, we think that that has substantial advantages over other, shall we say, regional models.

Yes. I think that's really well said. And given our global footprint, we're able to identify and seek opportunities for business development in all the geographies in which we operate. We've done excellent investments in business development with innovation that's been sourced from China. Our B7-H4 is an example of that. We recently announced a very interesting deal in the IO space for a trispecific with a company called HH Bio that emanated out of China. But we've done deals globally as well in all the geographies.

So ultimately, our clinical development organization is global first. And that puts us in a really strong position relative to competition to really deliver quality with speed to ensure that these innovations get to patients as fast as possible.

Yes. One quick follow-up on that I think is worth saying, part of BeOne's highlight on the clinical execution, and I think in more recent presentations, BeOne has been highlighting what they call the global development superhighway, right? How should we understand this competitive edge compared to other global pharmaceutical companies, especially that we are seeing more global MNCs, they are getting deals with China biopharmas that include early-stage integrations, which the biopharma -- the China biopharma companies could also be very quick in terms of getting the clinical proof-of-concept data?

Yes. So I recognize the importance and the intent of the question. Again, what I would highlight really is the global nature of our development organization. So it's important to understand that we have fully internal development capabilities across clinical development and clinical operations, statistics, regulatory and so on. But we also have in-house manufacturing, and we run our studies globally.

So yes, there may be some molecules that are able to generate limited data sets within a specific region. But when those molecules are partnered, there's always a certain amount of work that goes into the transition to the partner. And then often there will have to be a duplication of earlier data sets to ensure the generalizability of those data sets. So any speed that might have been captured through a single-region approach is then lost through the process of re-globalization.

For our CDK4 molecule, we went from the global-first patient dosed to our global-first Phase III patient dosed in only 30 months. We believe we're going to replicate that for B7-H4. Our GPC3x4-1BB will be shorter than that. So we really believe that we're industry-leading in speed, not only from Phase I to Phase III, but then also from readout to submission and so on.

Sure. And I want to briefly touch on our most recent earnings performance. I think it's another beat, strong quarter, and we also raised our full year '26 guidance. If we're looking a little bit more in detail, we can see that for the full year '26 guidance, for the EBIT level, was upgraded from $750 million to $850 million for the full year. And if we consider that in 1Q, the EBIT level was $250 million, that is more than 1/4 of the full year guidance. How should we understand the numbers here? And particularly, does the guidance leave room for higher R&D spending for the rest of the 3 quarters? And how do you balance that spending in both selling, R&D while maintaining the continuous operating leverage?

That's great, and thanks for the question. I think we've talked for a long time about our intent to run the business both as a growth organization, but also as one that does it so in a sustainable way. And sustainability is ultimately translating that growth to margin expansion, and ultimately and most importantly, free cash generation.

And I think you see those kinetics in action in our Q1 results. We feel very comfortable with the current year, that enabled us to raise, as you said, our guidance on revenue by $100 million the range, to $6.3 billion to $6.5 billion on the top line. And that translated to a bottom line improvement of $50 million across the range, to $800 million to $850 million on a GAAP operating income basis.

As you said, Q1 was quite strong in terms of its income generation. We did affirm our OpEx guide for the year. And I think that reflects our continued investment in our core capital allocation priorities. That's continuing to drive and invest in our commercial businesses that are driving profitable growth and as well as our clinical opportunities. And you saw the great data at ASCO. I'm sure we'll spend some time talking about that, as Mark alluded to earlier. And obviously, that was investment that we've contemplated in our full year guide in terms of OpEx, and that's what translates to the guidance that we updated with our Q1 results.

Sure. And I think if we talk about the earnings, we -- one thing that we have to talk about is BRUKINSA. And especially, we're talking about BRUKINSA is entering -- is already becoming the global #1, right? It's capturing more than 35% shares globally. And a natural question is, what is the room for growth further? And specifically, we've seen that for the EU part, it currently accounts for roughly 1/4 of U.S. sales. How do you see the potential in the EU market versus the U.S. market?

We're very pleased with the performance for BRUKINSA. Globally, as you said, BRUKINSA became the #1 BTKI. That eclipsed the curve toward the second half of 2025 globally; we had done so earlier in the United States. And that's really behind strong performance in all the geographies in which we operate.

We've talked historically, you were touching a bit on geographic mix, we've talked historically that our European business as an example was a little later in its launch trajectory than the United States. And important, rest of world markets are even earlier than that in terms of their launch trajectory. And you see that in the results where the United States grew in the mid-30% range, high 20s on a volume basis. Our European BRUKINSA was more like 60%. There's some FX in there, but still very strong demand-generated growth. And our rest of world markets doubled in Q1. So I think that reflects the launch life cycle of the brand.

So we do see continued opportunity in all of our geographies to continue to drive demand through new patient share. And of course, the geographies that are a little earlier in their life cycle have higher growth rates.

As we get bigger, obviously, growth rates in their percentage terms, those will naturally come down. But we continue to drive new patient starts driven behind the differentiated clinical data for BRUKINSA. At ASCO, we shared another update to our SEQUOIA data, going to [ 6.5 ] -- that unprecedented PFS at 72% over that time period. And really that's noncomparable as you look at the other medicines in the class in terms of its absolute PFS over that long of a time period. And ultimately, that's what's translating to utilization in the marketplace.

Sure. I do want to have one question specifically for sonrotoclax because we are seeing recently the good news from this drug, approved in China followed by approved in U.S. We have seen very strong conviction on this drug with -- in terms of both better tolerability and extremely encouraging high and durable and deep responses. How do you see like the early product launch? Especially, how do we see the -- how do we expect to get this drug in terms of the near-term launch? And based on the China performances or the China observations, what has been the early physician feedback on this drug?

So maybe I'll start. So my understanding from Amit, our CMO for Hematology, is that the prescriber feedback in China has been very positive, both in terms of efficacy as measured by MRD rates as well as the safety profile and the tolerability by patients, compared to what prescribers have experienced with other molecules in the class.

That said, I would say that this is similar to the feedback we've received on the development side, the CELESTIAL-301 study, our fixed-duration therapy in frontline CLL, the investigators who have been using sonrotoclax in the investigational studies are also providing positive feedback on their experience. So we're very excited about the potential for our novel BCL-2 inhibitor.

And then with BEQALZI, our brand name, obviously, the first indication that's been approved in the United States within the relapsed/refractory MCL setting. And that's a pretty narrow indication. We're very excited to get this differentiated medicine in the hands of prescribers and patients. There's significant unmet need in this relapsed/refractory MCL setting, and it's a great opportunity to gain experience.

Obviously, the larger opportunity that you referenced is with our zanubrutinib plus sonrotoclax fixed-dose combination in the frontline in CLL. That CELESTIAL-301 study is fully enrolled. Obviously, the data will have to play out.

So in the short term, we've talked about the opportunity being fairly immaterial in the very short run. Obviously, as we continue to get this in the marketplace, we'll serve those patients in the relapsed/refractory MCL setting, and look forward to the larger market opportunity. And as you said, we're really encouraged by the data as you think about a fixed-dose combination, the potential to have the kind of deep, durable responses that this combination could bring, with what we hope is efficacy and a safety profile that's comparable to continuous-use BRUKINSA. Time will tell, right, across all -- as BRUKINSA has generated such a robust data set in the short, medium and long term.

And ultimately, as you think about BRUKINSA, the differentiation in terms of efficacy in that SEQUOIA data that I mentioned, we had a really nice chart on this in our Q1 results, is really from that year 3 to year 6 time period, where you really see BRUKINSA standing with significant and durable PFS across that time period. And when you look at the other in-class competition as well as existing then base fixed-dose treatments, that's typically where you see the drop-off.

So we're really encouraged about our fixed-dose combination. Look forward to bringing the initial data set, and we hope it will be an important solution for patients. In the meantime, BRUKINSA has demonstrated significant durability, and really unprecedented durability and it's serving patients today.

Cool. And switching gears to our ASCO data. The CDK4 inhibitors, I think there are a lot of excitement about the early ORR. And we've also seen a very dose-dependent way of safety, tolerability. Can you talk a little bit more about dose selection? You chose 400 mg over 240 mg for the dosage. And how would you expect the ORR with mature follow-up? I'm aware that for the CDK4 inhibitors, the longer the maturity, you're actually going to see an increase in ORR. How do you want to comment on maturity data?

For CDK4, the maturity of the data that we presented at ASCO, the median time of follow-up or the median time on treatment was approximately 9 months. Interestingly, we do observe late emerging responses. We had 2 patients that were relatively recently detected unconfirmed responses. So these were late emerging responses.

Now that said, I wouldn't want to create a notion that we think our response rate is going to continue to climb and climb and climb from there. We're really pleased with what we have seen in terms of the response rate. And as I mentioned before, we think that it is differentiated from what one would expect from the CDK4/6 inhibitors. And that gives us confidence to move into our Phase III study.

Yes. I do want to make sure that we talk about the tolerability profile. And we're talking about the CDK4/6 versus CDK4. I think naturally, there is a trade-off between the heme toxicity versus the GI toxicity. Based on our communication with physicians, how should we think about this potential trade-off with the CDK4/6 selectivity? And particularly, what is the bar for GI toxicity to be considered as accessible based on physicians' feedback? And can you share a bit more on the mitigation tactics that we have explored for the GI tox?

Great. Again, thank you for the question. There's really 2 components there. The first relates to the heme tox safety profile. So with CDK4/6 inhibitors, it turns out that the majority of the hematologic toxicity is driven by CDK6 inhibition. And indeed, that was the core hypothesis of the molecule. By having greater 4 versus 6 selectivity, that we could drive deeper and more sustained inhibition of CDK4, which drives antitumor efficacy. That is now reflected in the high response rate, while mitigating the associated hematologic toxicity.

At the investor event that we had at ASCO, I shared our selectivity data. And indeed, we have the most selective 4-versus-6 inhibitor, with approximately 35-fold 4-versus-6 selectivity in a preclinical cellular assay. That has pulled through, in our view, based on mechanism to an unprecedented heme tolerability profile, that across 240 and 400 milligrams we only had a single Grade 3 event and no Grade 3 heme tox events at 400 milligrams.

We have had the feedback sometimes that patients don't experience hematologic toxicity. But the reality is that heme tox is the leading cause of dose reductions for the 4/6 inhibitors, and therefore, they are important. I also tried to make the point that heme tox also prohibits some combinations, and we think that there are a whole group of combinations that are available to us through having this more favorable safety profile.

Now in terms of the patient experience, the GI tolerability is also very important. What we shared in our poster was that in the fasted state, our rate of any-grade diarrhea approached 90%, and we had perhaps a 10% rate of Grade 2/Grade 3 events. However, in a small cohort of patients who had co-administration of food, that that event rate dropped substantially to 50%. And importantly, all of those events were Grade 1.

The feedback we had from investigators is that Grade 1 diarrhea is essentially very manageable. There are many successful medicines that have a moderate rate of Grade 1 diarrhea. And that's straightforward for most oncologists to manage in their daily practice. So we're very pleased to mitigate those Grade 2/Grade 3 events, which are the events that tend to lead to discontinuation -- I apologize, so your last question [Technical Difficulty] dose selection. But suffice to say, when we look at the cohorts of 240 mg and 400 mg, the response rates were quite similar. But when we do our more detailed exposure response analysis where we look at not just the dose level but actually drug exposure, we found that the 400 mg optimized our characteristics, both in terms of efficacy and safety.

We have confidence given the favorable efficacy and safety profile, that for those patients who do require a dose reduction, that they will be reducing to a very efficacious dose, if they do require dose reduction in the Phase III study.

And importantly, the study is now active. We have taken that 400 mg dose selection to global regulatory authorities who have essentially endorsed that choice, and agree that 400 mg is an appropriate dose to take into a registrational study.

Yes. That's very important to know, especially with, frankly, a lot of feedback saying that currently the regulators, they prefer like lower dosage versus higher dosage if the higher dosage doesn't show meaningful improvement.

We're absolutely aligned with the feedback of FDA's Project Optimus to move towards the lowest efficacious dose, right? We think that it's really important in terms of the overall patient experience. We and others absolutely focus, and we focus our discussion primarily on efficacy. But when you look at what constitutes a successful medicine, the patient experience vis-a-vis tolerability is also extremely important.

Yes. So a little brief follow-up on the mitigations. You mentioned the co-administration with food can effectively mitigate the GI toxicity. How are we integrating that into our Phase III protocols?

So the Phase III will require that patients take the drug with food. There's a couple-of-hour window and there's many medicines [Technical Difficulty] -- not, shall we say, problematic or burdensome to the patient [Technical Difficulty] -- a significant improvement in tolerability, medical management of low-grade diarrhea is quite straightforward, using antidiarrheals.

And that said, we continue to look to mitigate this further with, for example, in the Phase I study, we're now enrolling a cohort that's going to take primary prophylaxis with antidiarrheals and understand that impact. That's something that we can look to integrate into the protocol if need be. Again, we're very comfortable with where we are, understanding that it's a small cohort and we'll be enrolling more patients to give us greater confidence in that initial observation.

Yes. Great. And for the GPC3, you mentioned that it's kind of reached beyond your -- way beyond the go versus no-go bar. And we've seen that this molecule was not highlighted as much as the other programs previously, but it was brought up more recently highlighting the very encouraging clinical profile where we see that the Phase I data at ASCO showed very nicely controlled safety profile overall, with only single-digit percentage of Grade 3 TRAEs. And more particularly, for 4-1BB related liver toxicities, we've also seen very nice control. So what is the plan for the registrational trials in both the first line and second line plus?

Yes. And we're extremely excited about our GPC3x4-1BB, is where we have increasing confidence -- I have increasing confidence that this will be a clinically breakthrough molecule for patients with hepatocellular carcinoma. For context, at ASCO, the EMBRAVE-251 study was presented. In that study, the current standard of care, the control arm, delivered a response rate of 5%. And what we just demonstrated was that our molecule has a response rate of 30%. And importantly, it delivers a response rate of 30% actually with a better safety profile than the currently available TKIs. So we think that this is really potentially a big step forward.

There are other GPC3-targeting mechanisms such as CAR T cells or ADCs, but this is a patient population that tends to have substantial comorbidities related to liver cirrhosis. And frankly, those modalities are not well tolerated. So we really think that we are uniquely positioned in this later-line setting with a very safe and efficacious molecule. We intend to have development as monotherapy in a later-line setting.

We received a question at the ASCO investor event, "Well, what about a combination with TKI?"" We're considering that, but then we would be giving up this favorable safety profile that we have. But we also have already initiated a combination with tislelizumab, our PD-1, along with bevacizumab, to give us line of sight to a frontline opportunity as well as ultimately also early-stage, for intermediate-stage patients as well. Those cohorts are just now starting to enroll, but we're off to a good start. And we're very optimistic about not only the late-line registration opportunity, but the earlier lines as well.

Curious about the drug design for this bispecific. We've seen other 4-1BB-based bispecifics. I think a common tactic is to have differentiated binding affinity between the 4-1BB versus the other target, usually having a lower affinity for 4-1BB just to achieve conditional binding. So what is our strategy for this molecule?

Yes. The idea is similar overall, that we wanted to have conditional T cell activation really in the tumor microenvironment, not to have broad T cell activation. So indeed, the idea is that, first, what happens is through the high-affinity GPC3 anchor, that it gets anchored in the molecule and then you get local T cell activation.

It's important to highlight there are other features. We have a unique 4-1BB binder. We have made modifications to the constant chain to improve the half-life of the molecule. And we're very excited about the data. We're very excited about the platform. So you all can expect to see other tumor-associated antigen by 4-1BB targeting bispecifics coming forward for us, because we think that this might be an important platform technology where we can again improve responses with a favorable safety profile.

Sure. And you mentioned about the trispecific antibody. And I think there's no doubt that Lai seems to be very excited about that. And we've noticed that BeOne Medicines, we are a kind of a pioneer in the PD-1, obviously, has been an extremely commercially successful product. But if we came to the PD-1/VEGF field, this recent collaboration is really like the first milestone event for BeOne Medicines to enter PD-L1xVEGF. And we have the option to license this trispecific.

We know that the Phase I trial has recently been initiated. Can you share what are you looking at in this Phase I trial in order to [ create the option ]? And what is your view on the overall survival benefit that we've seen from the ivonescimab, and to share your perspective on what is our general plan for this trispecific?

Yes. I think to start at the end of your question, we recognize the data that was recently presented at ASCO for ivonescimab. HARMONi-6 study is a positive study with overall survival benefit.

Our view was twofold. So one is that it is now a highly competitive space, the PD-1 or PD-L1xVEGF. We didn't want to enter late and end up with an undifferentiated molecule. We view CTLA-4 as a mechanism that has tended to have a positive effect on overall survival. So we saw the trispecific as an opportunity to provide additional benefit with, hopefully, greater weight towards overall survival.

The preclinical data, again, was very strong. This was an IND-ready molecule. The clinical trial applications are now submitted and we anticipate to have the first patient dosed this month. Again, it's a Phase I molecule where we will have clear go/no-go criteria, and we'll be excited to see how those data unfold.

And I think just to add, I think this shows 3 elements of strategy in one deal. I think first, as Mark said, BeOne is not going to chase the seventh, eighth, ninth asset in a crowded space that doesn't support our mission, it doesn't support patients, just to have a me-too medicine. I think it highlights our business development efforts to identify interesting science and to deploy our capital in a smart and efficient way to test the hypothesis embedded in that science.

And finally, I think it showcases our global development superhighway capability where we will be able to take that potential medicine, explore, test the scientific hypothesis. And to the extent it hits, we'll move super fast. To the extent it doesn't, that's why we have a prioritization criteria.

Great. One last question. I do want to touch on our lung cancer strategy. I believe that our last significant trial in lung cancer was dated back to the trigine portfolio. And with discontinuation of EGFR CDAC program, what is the current strategy for lung cancer? We talk about the trispecifics and we have plenty of other great candidates. We have the bispecific ADCs or even trispecific ADCs that could be potentially targeting lung cancer. So just can you share a little bit more about the thoughts in lung cancer?

Yes. So we are strongly committed to lung cancer. You will see more innovative molecules from us entering the lung cancer space.

When you look at our portfolio to date, what you see are a group of molecules that capture the biologic heterogeneity of lung cancer. So we're not focused on any one target, but rather bringing benefit to multiple patient segments. We have high conviction in our PRMT5 inhibitor. We'll have our first disclosure for that molecule in the second half of the year. We're excited about our EGFR-MET-MET trispecific biologic, which is progressing well. And again, multiple other therapies, multiple ADCs in testing in lung cancer as well.

Cool. I think with that, we've reached the time. And again, thank you all for the time, especially, Mark, for the very insightful conversation. We're really looking forward to hear more updates about BeOne, particularly from the solid tumor pipeline. Thank you so much.

Thank you.

Hello, everyone. Welcome to our 2026 investor event at ASCO. My name is Liza Heapes, and I'm the Senior Director of Investor Relations at BeOne Medicines. We are very excited to host this event, both in person in Chicago and online for our global attendees. Thank you all very much for joining us. This is truly an exciting time at BeOne, and we are thrilled to walk you through our program.

Before we begin, a bit of housekeeping. I would like to remind all participants that during this presentation, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements. You can find more details in our filings with the SEC, Hong Kong Stock Exchange and Shanghai Stock Exchange.

I'm delighted that joining us to present today are John Oyler, our Co-Founder, Chairman and CEO; Dr. Lai Wang, President and Global Head of R&D; Dr. Mark Lanasa, Chief Medical Officer for Solid Tumors, who will emcee the section with our esteemed KOL guests, give program overviews and development opportunities; Dr. Shom Goel, who came in from Peter Mac in Australia to share the latest on our CDK4i clinical development data that were presented earlier today. Mark will then run us through highlights from tomorrow's Mini-Oral on our B7-H4 program; and Dr. Hong Jae Chon, joining us from CHA University in South Korea, will share data from tomorrow's Mini-Oral on our GPC3 x 4-1BB before turning it back to Mark. At the conclusion of the slide presentation, our speakers will come up for Q&A.

Now please let's welcome John Oyler, Co-Founder, Chairman and CEO.

Thanks so much, Liza. It's great to be here. I get to turn the page. So welcome. I really want to thank everyone for coming to Chicago and those of you that are joining us online. We certainly know how busy ASCO is in this time of year. And we appreciate you spending time with us and the continued partnership that you have in helping us work as one together to fight against cancer. I think that ASCO is always a defining moment of the year in oncology. And for this year, it's really an opportunity for us to step back and to show you something important about our company. It's the next phase of BeOne Medicines growth.

Today is deliberately focused on work beyond hematology. If you haven't noticed, I'm very passionate and excited about the incredible hematology franchise that we've built. And sometimes, people think I'm so excited about it that I don't understand and appreciate everything that's happening in our solid tumor portfolio. And it's true, it's hard because there's so much going on there. And really, we now have multiple programs that are accelerating this year towards late-stage development, and we have a pipeline that's increasingly positioned to drive meaningful growth. And I do want to say to the BeOne Medicines' team and all of the investigators that are working with us that we are very committed to this space and really excited and proud, so proud of everything that's been accomplished in that area.

With that said, I think we're a company that is very focused on trying to do great science. You'll see that in the pipeline today. We're a very science-oriented organization. We believe in scientific integrity and getting the best medicines to patients. I mean you have to develop the best medicines and we're committed to doing that. And I think also, as a company that's 16 years old, we've always believed that we need to find the best ways to do things. And we believe that's by working closely with the community, being one with the community to fight cancer.

As part of that process, we've built this BeOne Superhighway that you hear about, and it's taken time for us to build that, it's not easy. It's like raising a child. But at 16, BeOne Medicines is now old enough to go drive full speed on the BeOne Superhighway. And you'll hear and see evidence of how Lai and his R&D team are doing that all the time today.

So with that, I'll turn you over to my good friend and our wonderful head of R&D and business development, Lai Wang. Thank you.

Thank you, John. Thanks, everyone, for joining us tonight. BeOne is turning 16, as John pointed out. When I look back, we have gone through distinct chapters. The first chapter was our early years, about a decade of building from the ground up, that's when we designed and developed BRUKINSA and TEVIMBRA and laid the foundation for everything that follows. Then we enter the next chapter with a simple question in mind. Was that success repeatable? Or was that success a onetime achievement? Over the past 6 years, we have been working to answer that. On one hand, we built a highly productive discovery engine focused on oncology, powered by more than 1,200 research scientists and supported by a range of technology platforms.

In parallel, we built something very unique on the development side, a clinical development superhighway, a global engine designed to move programs forward with speed, scale and efficiency. These are very -- 2 very distinct capabilities. By putting them together, they change what we can do. For the first time, it feels like we are not just relying on individual assets. We are building a system that can consistently generate and deliver innovation. This is why I see 2026 as the beginning of a new chapter, one where this model comes together and starts to deliver repeatedly for patients around the globe.

I think everyone -- John said he's not going to touch on the heme, but I'm going to have one slide on heme. I think everyone is very familiar with our CLL franchise. The key point I would like to really highlight it takes 3 foundational assets to build on. It started with an anchor BRUKINSA, which set the standard care for the frontline CLL patients and comes with a combination product, BEQALZI remember the name, BEQALZI, also known as sonrotoclax, strengthening that backbone. Then finally, you need something in the relapsed/refractory setting, that's why when we designed the BTK degrader, now called tacabrutideg. Putting together, this gives us a complete framework across lines of therapy. And this is the key point. We now believe this is a model we can take beyond CLL into other tumor types.

With that strategy in mind, we have been very deliberate in how we build our disease franchise. Our strategy starts with a focus selecting a small number of disease areas where we believe we can lead and then building the depth, not just the single assets. What enabled this approach is our in-house technology stack, spanning CDAC, novel payload ADCs, you're going to see tons of that from BeOne as well as cell-therapy and emerging platforms like T cell engagers. We're not bound to a specific target or a specific platform alone. We systematically match the right biology with the right modality to build a pipeline that is deep, durable and sustainable.

The engine has clearly accelerated. From 2011 to 2020, the initial 10 years, we delivered 11 new molecular entities. Between 2021 and 2023, that's 3 years, we added another 10 NMEs, demonstrating consistent productivity and execution. The momentum stepped up again in the last 2 years with 18 NMEs across small molecules, CDAC, ADCs and bi and tri-specific antibodies, reflecting the maturation of our in-house platforms. Looking ahead, we expect to sustain this cadence of roughly 8 to 10 NMEs a year from 2026 and beyond. Innovation at BeOne is accelerating, systematic and built to scale.

Historically, BeOne solid tumor pipeline was heavily weighted towards immuno-oncology. The CDK4i chapter marks the start of the new wave with more diversified mechanisms and a clear tumor type focus. This molecule entered the clinic just 2.5 years ago, 2.5 years ago. And the Phase III now is already on the way. CDK4 is not an exception. We initiated a potential pivotal Phase II study for our GPC3 x 4-1BB, you're also going to hear about today within 2 years entering the clinic. In addition, 3 more molecules have achieved clinical proof of concept and are now moving towards registration. All are on track to start their first pivotal trial within 2.5 years of entering the clinic, some of the less than 2 years. This is a clear inflection -- reflection of the quality of our science as well as our unmatched clinical execution capability.

Today, we will share the clinical update for the first 3 assets shown on this slide with data on the remaining 2 to be shared with everyone in the second half of this year. I hope you will find the data as exciting as much as I do. With that, I will turn it over to Mark.

Thank you, Lai. Thank you all very much for joining us here tonight. Your time at ASCO is precious. We're very grateful. I had mentioned to a couple of you in conversations before starting that I'm authentically really happy, really excited to share the data. I feel like with many of you, I've been saying for a year or 2 years, we're really excited about what we're seeing with these programs. So it's great to finally be able to share the data, so you can understand why we've been and why I've been so excited.

As you just heard from Lai, our strategy in solid tumors is straightforward and ambitious to create the next CLL-like franchises from 3 solid tumor areas, breast and gynecologic cancers, GI malignancies and lung cancers. Importantly, this is not just pipeline expansion, it's a deliberate transformation with each great -- with greater breadth across targets and modalities and meaningful depth within each disease area.

This slide highlights the scale we've built with our industry-leading research and discovery organization. We now have more than 20 solid tumor assets targeting over 20 different oncogenic drivers and spanning multiple modalities. Importantly, this is not a narrow opportunity set. The diseases we're targeting represent roughly 2/3 of newly diagnosed solid tumor cases, both here in the U.S. and around the world. And by intent, each of our 3 priority areas now has multiple shots on goal across these mechanisms and disease areas of focus. We are not dependent on any single asset or outcome.

As you move across this pipeline slide, what I would like to highlight is how we're matching biology with the right modality. The depth within each disease area is by design to enable in-portfolio combinations, which we believe are the key to maximizing patient benefit. Today, I'll focus on the programs where we have the most meaningful data here at ASCO and the clearest path toward registration. These include our selective CDK4 inhibitor, a B7-H4-targeting ADC, and a first-in-class GPC3 x 4-1BB targeting bispecific. In addition to the molecules we are highlighting today, in gastrointestinal cancers, we're advancing assets like CEA ADC and our PRMT5 inhibitor. In breast and gynecologic cancers, we have several next-generation combination opportunities to build upon CDK4 data that you will see today. And in lung, we're building a portfolio that reflects the complexity of that disease with multiple approaches targeted across small molecules, biologics and ADCs.

Let's start with BGB-43395, our selective CDK4 inhibitor. We view this as a foundational asset within our breast cancer franchise with potential to redefine the standard of care in hormone receptor-positive disease. Even though CDK4/6 inhibitors are widely used in impactful medicines and are standard of care in first-line metastatic breast cancer, the class has well-recognized limitations. As you can see on this slide, neutropenia remains a major issue. It often forces dose reductions and can ultimately impact how much drug patients actually receive over time. There's also a meaningful management burden, frequent monitoring, clinic visits, which is not trivial for patients. And beyond tolerability, both primary and acquired resistance remain a significant challenge. So while the class has clearly transformed the treatment landscape, there is still a real opportunity to improve, particularly around safety, durability and overall treatment experience.

Against that backdrop, this is a very large opportunity with global sales exceeding $15 billion. What we're aiming to do is improve on all 3 of those dimensions, efficacy, tolerability and combinability. The data with BGB-43395 is very encouraging and is consistent with our therapeutic hypothesis. We're observing response rates above 70% at our Phase III doses, which is consistent with the best reported outcomes within the CDK4 selective class. At the same time, we're seeing a differentiated safety profile, particularly with respect to hematologic toxicity. Importantly, our initial registration trial in first-line metastatic breast cancer is already underway. So taken together, we believe this positions the program very well, both as a potential next-generation CDK4 and as a backbone for combination approaches.

The differentiation with 43395 is due to both potency and selectivity. As this slide illustrates, the goal is to potently inhibit CDK4 while minimizing CDK6 inhibition, which is what drives much of the hematologic toxicity with current agents. In a preclinical cellular assay, our molecule shows the highest potency against CDK4 coupled with the greatest selectivity relative to CDK6. And that's what underpins both the safety profile we're seeing and the flexibility for unique combinations. Today, we are honored to have Dr. Shom Goel, a key opinion leader in breast cancer presenting the CDK4 data update. Dr. Goel is an associate professor and clinician scientist at the University of Melbourne and the Peter MacCallum Cancer Centre. He serves as the global PI and translational PI for 4 randomized clinical trials in breast cancer and has over 60 publications, including recent works in high-impact journals such as Nature, Cancer Cell and Nature Cancer. He is the first author for the data you are about to hear, and we are excited to have Dr. Goel's insights on our selective CDK4 inhibitor and the potential impact on breast cancer treatment.

Good evening, everyone. Thank you so much, Mark, for the kind introduction. It's my pleasure to be here with you. And to share with you the data that we presented earlier today in a poster at the ASCO Annual Meeting. But let me start by orienting you to the clinical program in its full and where today's data set comes from within that program.

As you can see on this slide, the study, BGB-43395-101 is the global first-in-human Phase I study that has progressed in this stepwise fashion. On the left is when the study began back in December 2023, as you heard, with global dose escalation, and that evaluated BGB-43395 both as a monotherapy and in combination. From there, the program has moved into dose optimization shown in the middle. And the data set being presented today is highlighted in red. First, the safety expansion cohort in first-line HR-positive HER2-negative CDK4/6 inhibitor-naive breast cancer using BGB-43395 with letrozole. And as shown here, this cohort includes roughly 20 patients per dose level across 3 dose levels.

And then on the right, the program is continuing to generate data in this Phase Ib dose expansion phase. There are 40 patients enrolled in the first-line combination expansion which is the same first-line HR-positive HER2-negative CDK4/6 inhibitor-naive population with BGB-43395 plus letrozole. And importantly, we'll provide our first clinical evaluation of co-administration of this agent with food. The key point really from this slide is that this is a substantial global data set now.

And so with that context, let me move to safety first, particularly heme tox, because hematologic tolerability is a key point and differentiator for the CDK4 selective approach. So as you can see on this slide, we're looking at adverse events across 3 dose arms. We've got 240 milligrams, 400 milligrams and 600 milligrams, all given twice daily with letrozole, and what stands out immediately is the overall low frequency of hematologic toxicity. If you focus first on neutropenia, the top row in the table which is usually often a dose-limiting toxicity for CDK4/6 inhibitors, you can see that grade 3 or higher events are quite rare, just one event at the 240-milligram and none at 400 milligrams. And interestingly and importantly, even the low-grade hematologic toxicity events are uncommon. You see a similar pattern with thrombocytopenia and with anemia where all grade events are infrequent and no grade 3 events are reported at the Phase III dose, which is the 400 milligrams twice daily dose.

So I think what this table really demonstrates is a remarkably clean hematologic toxicity profile, which is consistent with what Mark showed you, being the high selectivity of this agent for CDK4 over CDK6. And clinically, that is highly meaningful because it suggests the potential to maintain dose intensity over time and to avoid the frequent heme tox, which led to dose -- leads to dose modifications that we often see with CDK4/6 inhibitors.

So let me now turn to gastrointestinal tolerability, which is the other key aspect of the safety profile here. As you can see on this slide, we are comparing outcomes in patients treated with food versus those treated without food, focusing on diarrhea, nausea and vomiting. Starting with diarrhea, without food, the overall rate is relatively high at 94% though the majority of events are low-grade and manageable. Now while the number of patients evaluated with food co-administration is currently limited at 8, that rate of diarrhea drops meaningfully to about 50%. And importantly, what we're seeing there is now limited to Grade 1 events.

And a similar pattern has been seen with nausea and with vomiting. For nausea, the rate decreases from about 61% without food to 38% with food, again, with a shift towards these lower-grade events. And for vomiting, you see a reduction from about 42% down to 13% with food. So I think the key takeaway from this slide is that the emerging data suggests that gastrointestinal toxicity from this agent is substantially mitigated through co-administration with food, reduces both the frequency of these events and also the severity of these events. Also, as noted on the left side here, there are additional mitigation strategies, which are currently being investigated, including the use of low-dose prophylactic antidiarrheals and also step-up dosing. And from a clinical perspective, the ability to actively manage these events is critical, particularly in a first-line setting where long-term tolerability is essential.

So let me now turn to efficacy. On this slide, you'll see the waterfall plots of best tumor response for 2 different dose levels, 240 milligrams and 400 milligrams, again, both in combination with letrozole. And what stands out visually is the consistent tumor shrinkage across patients at both dose levels. In the 240-milligram cohort, you can see that the majority of patients are achieving meaningful reductions in tumor burden, many beyond the threshold for partial response. And in the 400-milligram cohort, that pattern is also quite consistent with most patients achieving deep responses. And if you look at the numbers on the right, in the 240-milligram group, the confirmed overall response rate is 68.4% with an unconfirmed response rate of 73.7%. The patient with an unconfirmed response is still on treatment.

And in the 400-milligram cohort, the confirmed objective response rate is 63.2% with a similar unconfirmed response rate of 73.7%, again, with one patient with an unconfirmed response remaining on treatment. So I think if we put all that together, my impression is that this is a strong efficacy signal in the first-line for HR-positive HER2-negative disease, particularly when we consider it alongside the safety profile, which I've just reviewed with you.

So with that information in hand, let me now walk you briefly through the pivotal study design. And I'm pleased to announce that the first patient for this study was randomized at Peter MacCallum Cancer Centre in Melbourne earlier today. So as you can see on this slide, this is a randomized Phase III study in first-line HR-positive/HER2-negative advanced or metastatic breast cancer and patients are being randomized 1:1 between BGB-43395 at 400 milligrams twice a day with letrozole or a standard CDK4/6 inhibitor with letrozole.

The key eligibility criteria includes patients who received no prior systemic therapy for advanced or metastatic disease, ECOG performance status 0 or 1. And the study is powered to enroll approximately 1,056 patients. The primary endpoint is progression-free survival assessed by blinded independent central review and the secondary endpoints will include overall survival, objective response rate, duration of response, safety and patient-reported outcomes. So this design really is set to directly compare this selective CDK4 inhibitor against the current standard of care. And it's well positioned to test whether both the efficacy and the tolerability advantages that I've shown you will translate into a clinically meaningful benefit.

So to summarize, first of all, as a selective CDK4 inhibitor, what stands out to me here is the promising antitumor activity that we're observing in first-line metastatic breast cancer. As I said, we are seeing an objective response rate of around 70%, which I believe provides a strong clinical rationale to continue advancing this program, particularly in the frontline setting.

Second, on safety. I think what's encouraging is the overall favorable profile. We're seeing very infrequent low-grade hematologic toxicities and GI events that are generally manageable, especially when the drug is co-administered with food, which might help to mitigate those effects. And then third, looking ahead, we're actively planning to generate evidence in early-stage breast cancer. So that's an important next step as we think about expanding the impact of this molecule beyond the metastatic setting. And overall, taken together, we think this profile supports both continued development and a potentially meaningful role for this drug in breast cancer treatment.

Thank you for your attention. With that, I'd now like to turn it back to Mark.

Thank you, Dr. Goel. We're so excited that the first patient has now been randomized at your site in our global Phase III clinical trial. I'd like to circle back and say one of the most important implications of the safety profile is what you see on this slide, which ultimately leads to combinability. Because we're not seeing the same level of hematologic toxicity, not only high-grade events, but also low events, low-grade events, we have the unique ability to combine CDK4 with other complementary mechanisms. That includes assets within our own pipeline, such as our KAT6A/B inhibitor, our CDK2 degrader and our BCL-2 inhibitor. So this is not just about a single opportunity. It becomes a platform for in-portfolio combinations and further growth of our breast cancer portfolio.

With that, let's now turn to our B7-H4-targeting ADC. Our goal is to establish a new benchmark in ovarian cancer and other B7-H4-expressing tumors. This program has advanced very quickly, moving from first-in-human to Phase III readiness in about 2 years. We have observed a potentially best-in-class safety profile which is a critical attribute for patients with advanced cancers, but particularly in an early-line or maintenance setting. We're seeing very encouraging activity across ovarian, endometrial and triple-negative breast cancer and our emerging efficacy data enables development regardless of B7-H4 expression in ovarian cancer. Importantly, we are planning to initiate a Phase III trial in ovarian cancer before the end of the year. And we believe this combination of product attributes and timing positions us as the leading B7-H4-targeting ADC.

Let me take a minute to walk you through the slide because this is where you can see how the differentiation of our B7-H4-targeting ADC comes together. As you can see here, there are a few components that drive the overall profile of the molecule, and each of these has been very intentionally designed. First, starting with the target itself, B7-H4 is highly expressed in a number of tumors, particularly ovarian, endometrial and breast cancers, but has very limited expression in normal tissue. That gives us a strong starting point from a targeting perspective that provides a safety profile that has no apparent target-mediated toxicities.

Next is the linker, which is engineered to be stable in circulation, which helps reduce off-target toxicity but then cleavable once inside the tumor cell, allowing for payload release and bystander effect. The payload is a potent topoisomerase inhibitor with a DAR of 6. Finally, while I will not present our PK data this evening, we have observed a half-life of approximately 7 days, which supports every-3-week dosing. We presented a poster at this congress sharing detailed PK data and also explaining how adjusted ideal body weight dosing rather than total body weight dosing provides consistent exposure profile. So when you put all of these pieces together, the target selection, the antibody design, the linker stability, payload potency and consistent PK, what you get is a molecule that is designed to maximize tumor delivery while minimizing systemic exposure.

Now I'll put the Phase I trial into context. As you can see on this slide, this is a first-in-human multi-arm study evaluating the B7-H4 ADC across a range of solid tumors with a particular focus on ovarian, breast and endometrial cancers. At this point, we've completed dose escalation and have moved into dose expansion, which will also serve as our dose optimization phase. What you'll see tonight and at the Mini-Oral presentation tomorrow are the data from patients treated at dose levels under consideration for future development with sufficient follow-up to begin assessing both response rates and durability. As you'll see, the data set is still maturing, but it's already providing a clear signal, both in terms of the level of activity and the overall tolerability profile. And importantly, this is the data set that's supporting our confidence to move in the Phase III with initiation plan before the end of this year.

Let me spend a moment on safety because this is a key part of the story. Here, we are presenting data from 2 dose levels under consideration as our Phase III dose. The overall safety profile is very manageable and importantly, differentiated relative to what's been reported with other topo I conjugated ADCs with ongoing or plan development in early-line ovarian cancer. If you look across the adverse events, what stands out is that most events are low-grade, and the rates of Grade 3 and higher toxicity remain relatively limited during the period of follow-up. You can see the dose reductions in treatment interruptions are infrequent, which is important. It suggests that patients are generally able to stay on therapy and receive consistent exposure. And from a tolerability standpoint, we're not seeing a single dominant toxicity that is difficult to manage. Instead, it's a profile that appears predictable and clinically manageable. So when taken together, what this slide shows is a safety profile that we believe supports earlier-line use where tolerability becomes even more important.

Turning to efficacy. This is where you can see the real strength of the signal. As you can see on this slide, in advanced or heavily pretreated ovarian cancer, we're observing an unconfirmed response rate above 50%, with the majority of patients experiencing a reduction in tumor size. Although I am not sharing the data regarding response rate by expression, and I encourage everyone to attend our Mini-Oral presentation tomorrow morning where those data will be shared, we are observing responses across the range of B7-H4 expression, which supports a broad development approach in ovarian cancer without the need for patient selection.

Finally, let me detail how this data helps us to arrive at our planned Phase III development. As you can see, we're focusing on the first-line maintenance setting in ovarian cancer. This design is relatively straightforward, evaluating the B7-H4 ADC in combination with bevacizumab compared to bevacizumab maintenance alone in patients who have completed standard platinum chemotherapy-based first-line treatment. The maintenance paradigm is well established in ovarian cancer. There is an unmet need among patients who are not candidates for PARP inhibitor. The study primary endpoint will assess progression-free survival, along with key secondary endpoints that will help to characterize the overall benefit. And importantly, this setting allows us to introduce the drug earlier in the treatment course where we believe both the efficacy and tolerability profile can have the greatest impact. So as this slide outlines, the strategy is very focused, setting a clear, registrationally relevant setting and positioning the program for potential near-term path to approval.

To conclude, I'll turn to our exciting GPC3 x 4-1BB-targeting bispecific. This is one of the programs that best reflects how we do science, not by following the crowd, but by being deliberate about what should be possible. The field has learned the hard way that by broadly activating 4-1BB, this can create unacceptable systemic effects. So the question for us was, can we bring 4-1BB's potency forward and control where and when it is engaged? This wasn't something that we just stumbled upon. It started with a clear hypothesis. If we could focus the immune activation only where the tumor is, we could aim for real efficacy without the price of systemic toxicity.

Think of it less like turning up the volume on the entire immune system and more like designing a key that only turns the right lock. The goal is precision immune activation exactly where it's needed. And the reason we advance this program is simple. Patients with HCC run out of options very quickly. When you see how outcomes fall off after immunotherapy and tyrosine kinase inhibitors, it's not an academic problem, it's a human one, something we take profoundly personally on behalf of the people who need us. So what you'll see in the next few slides is the result of being willing to be bold to believe we could design something better and then letting the data tell the story and that brings me to where we are tonight.

Let me step back and give you a quick overview of our GPC3 x 4-1BB program and how we're thinking about the overall strategy. At a high level, BGB-B2033 is a first-in-class bispecific and our goal is to establish a new standard of care for patients with HCC and other GPC3-expressing tumors. Starting with the clinical profile, what's really notable is the monotherapy activity. As you can see, we're observing response rates over 30%, which is roughly 3x what you'd expect with current standard of care in the second-line setting.

Second, safety is a key and central part of the story here. We're seeing a highly favorable and differentiated safety profile, which opens the door to combination approaches and importantly allows us to move into earlier lines of therapy. This combination of favorable efficacy and safety is strongly differentiated from GPC3-targeting CAR Ts or ADCs and in turn enables a broader development plan with applicability to more patients.

And then third, in terms of development strategy, there are really 3 parallel paths. First is the potential pivotal expansion in late-line HCC that is already initiated. The second is that we're planning a global randomized study in the post-IO setting. And third, we're continuing enrollment in a front-line HCC triplet, which will be important in supporting development in earlier lines over time. So overall, between the level of activity, the safety profile and very deliberate development strategy, we see a clear path to building a potentially meaningful franchise.

Before getting into the data, let me take a minute to walk you through the slide because it frames the opportunity. Starting on the left, you can see the 5-year survival rates across a range of tumor types. What stands out is that liver cancer, hepatocellular carcinoma, or HCC, remains among the lowest. 5-year survival remains around 20% with only incremental improvement over time and is meaningfully below most other solid tumors. So despite some advances in therapy, outcomes remain quite poor. This is due to a combination of unique biology and patient comorbidities that are common in HCC.

Now if you move to the right of the slide, you can see the incidence and stage distribution at diagnosis. In the United States, this is not a rare disease with over 30,000 new diagnoses per year. A significant proportion of patients are diagnosed at intermediate or advanced stages. And as a result, most will ultimately require systemic therapy. Globally, as shown in the pie chart, this is also a very large and growing disease with the highest incidence in China but meaningful patient populations across Europe and Japan in addition to the United States.

So in summary, this slide highlights the combination of poor survival outcomes and substantial global disease burden that characterize HCC. And that's particularly important in the context of later-line disease where there is a desperate need for therapies that can drive meaningful responses.

Now, allow me to describe the mechanism because this is critical to understanding the clinical data. As illustrated on this slide, one arm of the B2033 bispecific binds to GPC3 on tumor cells and serves as a targeting mechanism. Once the molecule is anchored to the tumor, the 4-1BB arm engages T cells, providing a co-stimulatory signal that enhances activation, proliferation and cytotoxic function. So the key here is that the 4-1BB activation is conditional. It's happening in the presence of the GPC3-positive tumor tissue rather than systemically. You'll also see on this slide a number of design features including elements to extend the half-life and reduce off-target toxicity. The most critical design here is 4-1BB binding at a unique epitope. Those design choices are important because they help create a balance between potency and safety, which has been a major challenge for this class historically. So the hypothesis is very straightforward. Targeted 4-1BB within the tumor should drive antitumor activity while maintaining a manageable safety profile.

Now I'm very pleased to introduce Dr. Hong Jae Chon. Professor Chon is a leading clinician and investigator in hepatocellular carcinoma and currently serves as Professor of Medical Oncology at CHA University School of Medicine and Director of the Cancer Center at CHA Bundang Medical Center in Seoul, Korea. His work spans clinical trials and translational research, focusing on GI cancers, especially HCC. Professor Chon has been the global lead enroller in this Phase I study of B2033, and he will also present at the Mini-Oral session tomorrow morning. So we're very fortunate to have him with us here tonight.

With that, let me hand it over to Professor Chon.

Thank you for the kind introduction. I'm Hong Jae Chon from CHA Bundang Medical Center. Thank you, Mark. And I would like to start by building on a point that Mark made earlier. As you saw, hepatocellular carcinoma remains a disease with both substantial global incidence and few long-term survivors, particularly when we compare with other solid tumors. Even with some improvement over time, 5-year survival remains relatively low and the majority of patients are diagnosed at intermediate or advanced stages. The treatment landscape for advanced HCC has evolved with the introduction of combination immunotherapy in the first-line setting. Today, most patients roughly 75% to 90% of patients are treated with IO-based therapy upfront. However, once patients progress, the options become quite limited.

In second-line, we typically use TKIs such as sorafenib or lenvatinib. In selected patients, we can apply ramucirumab. But beyond that, as highlighted at the bottom, there is no clear standard of care after both IO and TKI therapy. So if you look at the right side of the slide, this is very well reflected in outcomes, response rate dropped significantly as patients move through lines of therapy from around 30% in the first-line setting and just less than 10% in second-line and very, very low level of -- in the third-line and beyond. So overall, this slide highlights a very clear gap, particularly in patients who progress after both immunotherapy and TKIs where effective treatment options remain limited.

Let me walk you through the 101 study design. As you can see, this is the first-in-human Phase I trial evaluating BGB-B2033. Part 1 focuses on monotherapy and begins with dose escalation, doses ranging from 1 milligram to 1,000 milligrams. And after that, it expanded into safety expansion cohort in patients with second-line or later HCC. Then as shown in the middle of the slide, we moved into dose optimization with around 50 patients enrolled evaluating active dose level in the same second-line plus population. And on the right, the program is progressing into dose expansion with around 40 patients enrolled today and a planned cutoff of 120 patients, especially in the post-IO and post-TKI setting.

In addition, as shown at the bottom, there is ongoing combination program in Part B evaluating BGB-B2033 with tislelizumab with and without bevacizumab. So overall, this study provides a structured and progressive approach moving from dose finding into dose expansion and towards a potential registrational pathway.

Now turn to efficacy. On this slide, you can see the response rate across the different dose levels: 300, 600 and 1,000 milligrams. At 300 milligrams, the confirmed objective response rate was 29%. At 600 milligrams, the confirmed objective response rate increased to 36%. And at 1,000 milligrams, the confirmed response rate is 20%. Although I would note that this cohort was relatively small, and with short follow-up. So at that time, the unconfirmed response rate was around 30% already. So if you look across all of these dose levels, what you can see is the consistent signal of activity with response rate around or above 30% at the active dose levels. The 6-month duration of response is almost 37%, again, higher than both available therapies and other GPC3-targeting investigational molecules.

Importantly, as highlighted on the right side, the patients are heavily pretreated with a median of 2 prior lines of therapy and the majority having received both immunotherapy and TKI. So we are seeing responses across a range of patient subgroups including both viral and nonviral etiology and both intrahepatic and extrahepatic disease. So overall, this slide demonstrates a meaningful and consistent efficacy signal in a population where historically, response rate has been quite low.

Let me turn to safety. As you can see on the left side of the slide, overall safety profile appears very, very favorable. Treatment-related adverse events occurred in 48% of patients with only 8% being Grade 3. No Grade 4 or 5 were reported. Serious adverse events are also limited at under 5%, and treatment discontinuation due to adverse event low at just over 3%. There have been only one dose-limiting toxicity. If you look at the right side of the slide, which shows adverse events by type, what stands out is that most events are very low grade. Most common events include AST, ALT increase, but importantly, this did not require high-dose steroids. Other events were generally manageable and occurred at a relatively lower rate. So overall, this safety profile is favorable, particularly in the context of 4-1BB-based mechanism, where historically, toxicity has been a concern.

I'd like to show 1 of my 2 -- 2 of my patient cases because I think this can help illustrate what we are seeing clinically. Let me start with first patient, and he is a 53-year-old male and diagnosed with HCC involving liver and lung and also positive for hepatitis B virus, and he had treated multiple prior treatments, including TACE and 3 prior lines of therapy, including immunotherapy and TKI. At baseline CT scan, you can see intrahepatic lesions and multiple lung metastases. But after 16 cycles of treatment, there was a substantial reduction in tumor burden and multiple lung metastases almost disappeared. In parallel with this, there was a dramatic tumor marker decrease from AFP level from over 2,500 down to the normal range. So this patient is heavily pretreated patient but achieved radiologic response and meaningful biomarker response.

A second patient is 52-year-old male and had HCC and lung metastasis, so also had hepatitis B virus and he had underwent liver resection and had received 3 prior lines of systemic therapy, including immunotherapy and TKIs. At baseline CT scan, you can clearly see the lung metastasis. However, after 2 cycles of treatment, there was substantial tumor shrinkage and almost disappeared. And again, this was accompanied by the tumor marker decrease from over 8,000 down to the normal range. This patient also was heavily pretreated patient but showed a very rapid and deep response. So -- and both of them are still ongoing and around 1 year. And I also have around 10 patients who achieved a PR and all of them are still ongoing. So I expect this compound can have very, very good duration of response.

So BGB-B2033-induced response rates are commonly observed in this treatment setting further supporting the activity signal seen in the broad data set. So what's most important is that in second-line or later HCC, we observed a response rate of above 30% with BGB-B2033 as a monotherapy. And when you look at that in context, the level of activity is comparable to what's typically seen in first-line combination immunotherapy and substantially higher than what we can see in later-line setting today. So you can see the comparison here in third-line the response rate is around just 2%, but in second-line, they are generally below 10%. Today, actually, in [indiscernible] trial in second-line, lenvatinib data showed just 5% of response rate.

So this is important. So this is a setting where historically, activity has been quite limited. And what we are seeing here is a clear step-up in efficacy and this is important because this is a monotherapy. So the ability to achieve that level of response without combination provides flexibility we can think about development going forward.

So now if you move to the right side of the slide, you can see the safety profile compared to traditional TKIs. Across key adverse events, hepatotoxicity, hand-foot syndrome, hypertension and diarrhea, what stands out is the low rate of high-grade toxicity with BGB-B2033. You will notice that Grade 3 and higher events are consistently lower than what's typically seen with lenvatinib or sorafenib. And even at the overall level, the rate of this toxicity appears more manageable. And it's important because TKIs, while active, sometimes can be difficult to tolerate and often require dose modifications. So when you look at this holistically, what this slide is showing is a combination of meaningful efficacy in a difficult setting along with a favorable and manageable safety profile and that combination is what gives us confidence, not just in the late-line opportunity, but also in the potential to move earlier and in combination setting over time. So -- and now, I will turn it back to Mark for company perspective.

Thank you so much, Professor Chon. From a development perspective, we're extremely excited by the data you presented here tonight and for tomorrow's oral presentation. This is a priority program, and we'll have the full power of our development superhighway behind it. And we recognize the patient need, the differentiation of our asset and the opportunity ahead as a first-in-class bispecific demonstrating an unprecedented combination of efficacy and safety.

Now let me walk you through how we're thinking about development. Starting on the left, 2025 to '26, this is all about establishing the foundation. We're focused on late-line HCC where we can most efficiently demonstrate proof of concept and generate registrational data. As you can see here, we've already received U.S. Fast Track and Orphan designation, which we think underscores the potential of the program. At the same time, we've expanded our 101 study to support a potential post-IO post-TKI approval pathway. And importantly, planning is already underway to initiate a global randomized study in the second-line post-IO setting. This phase is about building the core clinical and regulatory footing.

Then, as we move into '27 and '28, we will advance into earlier lines, deepening the opportunity. Here, we're starting to layer in combinations, including the tislelizumab plus bevacizumab cohort, which we expect will inform a frontline pivotal study planned for the second half of 2027. In parallel, we're broadening the scope even further looking into intermediate-stage HCC in even perioperative settings. This is where the asset begins to move earlier and into larger patient populations.

And then looking further out into 2029 and beyond, this is where we expand. At this point, we're really thinking about portfolio-level combinations and how B2033 integrates across our broader pipeline. That includes next-generation IO approaches, additional in-portfolio combinations and also novel second-line strategies aimed at patients who progress on the frontline emerging standard of care.

So taken together, this is not just a single development path. It's a long-term plan to systematically create patient impact and to build value in HCC, starting in late-line, moving earlier and ultimately expanding this foundational medicine into a multi-combination franchise built to address the needs of this substantial population of people around the world with HCC.

So to conclude, allow me to put into context what you've seen today. We see this ASCO as an inflection point for our solid tumor pipeline. Across these 3 programs, we now have clear proof-of-concept data. And importantly, each of these programs supports the potential to initiate registrational studies by the end of this year in 3 different but common tumor types. Starting with CDK4, this is in the first-line HR-positive breast cancer, where we're seeing compelling response rates along with an improved safety profile, particularly when administered with food.

Second, our B7-H4-targeting ADC in frontline ovarian cancer maintenance, here, we're seeing strong efficacy coupled with what we believe is a best-in-class safety profile. And third, the GPC3 x 4-1BB program in HCC, where we're seeing unprecedented single-agent activity with a safety profile that enables development in both later and earlier lines of therapy. Beyond those 3, we expect proof-of-concept data for 2 additional internally discovered molecules in the second half of this year, CEA ADC and PRMT5. So overall, what you're seeing is not just progress in a few isolated programs, but a broader portfolio that is systematically moving from early promise into proof of concept. And importantly, this is just the beginning with a number of additional early-stage assets advancing quickly toward that same inflection point.

This wraps up our presentation for today. I'd again like to thank Professor Goel and Professor Chon for their time and their insights. And I'll hand it back to Liza.

Thanks, Mark. As our panelists come up to the stage, please, to participate in the Q&A, let me go through some general housekeeping items. [Operator Instructions] Now let's open up.

Thank you, Liza. We have multiple questions.

Kalpit Patel, Wolfe Research. I had a question for Dr. Chon for the GPC3 x 4-1BB. Very good data there. How are you thinking about the combinability with other TKIs given the LFT increases that we've seen across various different drugs there? So thoughts there. And then there were some other data with ADC and then the CAR T for the same target at ASCO this year. So I'm just curious as to what your thoughts are there.

Thank you for -- it's a good question. And First one is the GPC3 compound has a highly favorable safety profile. So I think there are a lot of chances to have combination strategy like atezolizumab and first-line setting combination and add-on or second-line TKI and add-on. Everything is possible, I think.

And second one -- second question is also very important. There are so many GPC-targeting ADCs currently. But hepatocellular carcinoma patient is a little bit different from other solid tumors. Most of them have underlying liver disease. They are very vulnerable to liver toxicity. So the safety profile is very, very import. In this sense, I think CAR T can be a very easy way to access some targets. But if we have better alternative option, I don't think we have to insist on CAR T. Actually CAR T, even though in early-stage clinical trial, they showed very good response. But they also have high toxicity and have to go through some complicated processes like lymphodepletion and have to wait for a long time, which is not available for HCC patients, especially later line. So I think CAR-T treatment cannot be generally applied to general HCC patients. But in that sense, this bispecific antibody shows a highly favorable safety. So it is the best -- it is the most easily applicable approach for HCC patients. And ADC, actually, they also have some signal but still have high toxicity. As I mentioned, toxicity is very important in HCC patients.

And just quickly add on the sponsor's perspective about the later-line combination as you heard from Professor Chon, what we think is so exciting about this molecule is magnitude of efficacy with an extremely clean safety profile. While we believe we likely could combine TKI, we would also be giving up that really clean safety profile with that combination. So for now, we're prioritizing monotherapy development in later line, but I wouldn't want to [indiscernible] closing the door to that later-line combination.

Yaron Werber, TD Cowen. I have 2 questions and a really nice presentation. The first one on GPC3 is you're aiming to combine with the checkpoint inhibitor. Do you have any sense do you need to lower the dose potentially? Or is it safe enough you're going to get too much immune stimulation? It sounds like you're already doing that combo. And then second question on the CDK4. What's the powering of the KANDELA study for PFS? It sounds like you're starting with about 15%, 20% higher response rate. How are you thinking about durability of the PFS superiority?

Dr. Goel, maybe so Yaron, we generally -- thank you very much for the question. We generally would not disclose directly the overall powering of the study, but maybe you could talk about what would be viewed as clinically meaningful in the frontline setting in a comparative study with the existing...

Yes. Sure. Thanks for the question. So as you know, we sort of have to have a benchmark in mind for what our standard first-line therapies can currently achieve and based on first-line trials that led to approval of the existing drugs, we have figures in our head that sit around about 2 years, right? That's -- and we also look towards more contemporary data sets to help refine and inform those estimates. As you heard, the primary outcome for this study is progression-free survival. So the question is what is a meaningful improvement in progression-free survival. Yaron, my honest opinion, and this is not the way the things play out, and I understand this, but even if theoretically, one had a drug that was equivalently active, but better experience for patients, that alone, I think, would be a good thing. But here, of course, we're looking for that improved tolerability and improve potency to actually translate also into an improvement in PFS.

I would say, in my personal opinion, an improvement in PFS in the order of months would be clinically very meaningful for patients. I can't really specify this many months or that many months, but I would say something in the 4 to 6-month range would be really meaningful in my professional opinion.

To your first question about combinability with PD-1, it's a very fair question, one that we thought about in terms of there is a risk of mechanistic [indiscernible] toxicity. We mentioned at earnings that, that frontline cohort is well underway. It is early days. Professor Chon, I don't know if you have any clinical reflections on how that's going [indiscernible] in that cohort.

Actually, we have already 10 patients, but there is no toxicity issue. But I think the first-line combination of nowadays first-line setting most wisely used first-rate regimens, atezolizumab and bevacizumab combination. But nowadays, we are evaluating tislelizumab, bevacizumab and GPC3 as first line. But I think that is a very smart strategy because we have data, patient who doesn't respond to atezolizumab, they usually show the high GPC3 expression. But maybe this triple combo can compensate this kind of weakness of Atezolizumab with triple combo, I think.

Maybe I will provide qualitative statements [indiscernible] last 2 years and so we're off to a good start [indiscernible]

Maybe I'll just add a comment [indiscernible] mechanistically. This molecule was really specifically designed to be target immunotherapy with the GP end of it, but as well as on the 4-1BB side of it. We're not disclosing exactly how we design molecule in 4-1BB binding, but I can tell you it's very unique. And in a way, we're leading to tumor-local activation. So with that, also now we're having more than 50 patients with the triplet, we feel very comfortable with the combinations.

Ren Benjamin from Citizens. Congrats on all the data. Can you talk -- just sticking with the CDK4 inhibitor, can you talk a little bit about the impact of food on efficacy? Have you seen any sort of betterment in efficacy given the tolerability profile. Why you chose 400 milligrams as the dose versus 240? I guess, for Lai, given the superhighway and the speed at which you do clinical trials, can you just extrapolate based on the enrollment rates for the Phase I portion, how long a Phase III must take to read out?

So we are targeting, shall we say, aggressive enrollment time lines, given the overall positioning within the space and the fact that [indiscernible] has largely completed, if not fully completed their enrollment. That said, this is a global enrollment. We have had a team that's had a large investigator meetings here at ASCO. There's high enthusiasm for the study. So if you're looking to enroll these 1,000 patients on a globally allocated way that will meet global health authorities as quickly as possible. A qualitative statement. Shom, I don't know if you have any comments?

Yes. So in respect to your question about whether concomitant administration with food affects efficacy, I think it's fair to say that with the numbers being what they are, one can't really make a meaningful comment there. What we can say is that in the limited number of patients that we've looked at, there's no significant difference in PK as to whether the drug is co-administered with food or not. And I think that's a very important point to note.

We completed the food effect study, and there's no impact on the PK. So with no impact on PK, we do anticipate this should not have impact on the efficacy side of it.

Strong efficacy, we see not only at the selected dose of 400 milligrams, but also at the lower dose of 240 milligrams that gives us confidence there's not going to be any impact to efficacy.

Maybe just one more comment on the superhighway. Thanks for highlighting that. Certainly, we are very proud of what we have achieved with the superhighway. And hopefully, today, showing you is not just one case. Actually the all 3 programs we are delivering with the same type of discipline and the speed and the efficiency. The CDK4 program is only in the clinic in 2.5 years. The Phase III, the first patient has been randomized today. Actually, we -- not just for these events, we were really pushing and trying to get going. And in terms of how long, we need to do better than Pfizer. So in terms of the GPC3 x 4-1BB programs, that's a program now already enrolled over 200 patients, and that's only in the clinic less than 2 years. It's remarkable for HCC patients. And then in terms of B7-H4 ADC programs, similarly, in 2 years' time period, we're already ready for Phase III. We probably are starting the Phase III within 2.5 years of the molecule entering clinic.

Yigal Nochomovitz from Citi. On the B7-H4 program, I noticed that it seemed like on the waterfall plot, everyone was an ovarian cancer patient, but I believe the study also enrolled breast and endometrial. I was just curious if you didn't show that data or those weren't -- those subtypes weren't enrolled. And then just going back to the question Ren was asking on the dose for CDK4, I think you had a slightly higher confirmed ORR in the 240, and I believe I thought I saw 1 CR, but nonetheless, you're going with the 400. So if you could just expand on your thinking as to why the 400...

Yes. So for B7-H4, tonight's presentation really focused on ovarian cancer because that's where we're going to have our initial Phase III study start. But at tomorrow's Mini-Oral, we will disclose data in the additional tumor types. The overall design of that study, dose escalation and expansion and now these tumor type expansions, what we're sharing is the dose escalation and safety expansion or backfill cohorts, there's some, shall we say, enrichment of ovarian from the investigators. It was looking good in ovarian, so they enrolled a lot of patients with ovarian. There are fewer patients with triple-negative breast cancer and endometrial cancer, but we'll share those data at the Mini-Oral tomorrow. We're excited about those data, and we leave that there's a development path in those additional indications that's open to us.

Maybe if I can start for the CDK4 dose rationale, I appreciate the point that you're making that with roughly 20 patients enrolled across those 2 cohorts, the response rates are essentially the same. We, of course, on the back end, do detailed population PK analyses, exposure response analyses. And we felt confident that 400 milligrams provided the best balance of efficacy and safety the highest probability of success most likely for patient benefit. We shared all that data with the FDA, and that data selection was endorsed by FDA during our Phase III start-up.

Jess Fye, JPMorgan. For the GPC3 x 4-1BB bispecific how many patients of single-arm data do you think you would need to file for accelerated approval post-IO, post-TKI and how many of those would need to be Western patients? And then for B7-H4, what's the proportion of ovarian patients who meet that criteria for the maintenance trial you described like there's still disease or PR after frontline bevacizumab plus chemo and PARP ineligible?

Thank you, Jess. So thankfully, for ovarian cancer, the majority of patients will achieve PR, CR stable disease after the frontline therapy, roughly 90%. So thankfully, there are a few patients who are refractory from the beginning. The distribution of patients who are eligible for PARP inhibitor versus not the proportion of patients who are HRD versus HRP is roughly 40-60, something like that. So we do think that it's a substantial proportion of the frontline ovarian cancer population who would be eligible for the study. How many patients? Oh, yes. So this is speculative. As we talked about at our most recent earnings call, we have expanded our 101 study. We've added a cohort to increase the sample size of late-line monotherapy and that double pretreated patient population to 120 patients. However, the global regulatory consultations related to that patient number are ongoing. That said, in the context of having a response rate of greater than 30% with a highly favorable safety profile, standard of care of only 5%. We're optimistic going into those conversations, but that's our rationale. But we haven't had those conversations yet or we're having them right now.

Etzer Darout, Barclays. A couple of maybe strategy questions. One on B7-H4 ADC that conversation with physicians that have talked about the need or importance for a biomarker strategy in various cancers. And you've noted a couple of times around sort of maybe an all-comers approach. So I wanted to have your thinking around there as you sort of progress these different tumor types into pivotal studies?

And then secondly, on the 4-1BB program, and we've seen other bispecific pairings where there's just been failures. But given sort of the level of activity you're seeing with your GPC3 program, I'm curious about what is it about GPC3 where you're seeing this level of activity? And are there other bispecific [indiscernible] that you view as more compelling given what you're seeing with the GPC3 x 4-1BB?

Yes. So Lai, would you like to talk about additional iterations on the 4-1BB?

Sure. In terms of the 4-1BB again, this is uniquely designed 4-1BB binder. The reason we started with GPC3 and part of people will think that's very crazy because initially, the 4-1BB monoclonal antibody certainly had a liver toxicity. We believe that GPC3 is highly expressed in the cancer cell, but not in the normal liver cell. That gave us the comfort to move forward with GPC3 X 4-1BB. We actually have a [indiscernible] program in our pipeline now to targeting various different type of tumors. We believe this MOA should not only help in HCC, with the platform we have set up, we are looking forward to bringing the other molecule into the clinic in the upcoming -- next few months to a year. And that will be -- this is actually -- I'm very excited about this platform. I think this potentially can be applicable to many different type of tumors.

And also just to add to that, a lot of people work on the CD3 T-cell engagers for solid tumor. However, unfortunately, for solid tumor, not that many clean TAA available really for CD3 MOA but I think the 4-1BB is a little bit different. The MOA there and the internal selectivity requirement is a little bit different compared to CD3 and also 4-1BB is preventing the T-cell exhaustion. So in a way, in this microsupressed environment within a cold solid tumor, 4-1BB might come up to be a better way to activating T cells. Of course, we need more data to really test the hypothesis, but it's a really interesting area. We're going to really explore and put a lot of effort behind.

Your question on B7-H4 is a really important question. I think what it comes back to ultimately is clinicians are thinking about differentiation and what they're selecting when they have a group of different molecules to select from. So perhaps the treatment algorithm for ovarian cancer can be summarized that patients receive their frontline chemotherapy with platinum and taxol and then patients are essentially dichotomized as part eligible or not, and is biomarker testing needed for PARP selection. So I do think that then having a second biomarker to triage to which EDC is an additional level of complexity and it would be attractive to not have to run that second biomarker in the circumstance where you're not giving something meaningfully for efficacy. So again, we'll share our biomarker data tomorrow. I think that we are not asking patients to give something up whether their B7-H4 is high or B7-H4 is low. And then the other critical part of differentiation, particularly maintenance is the safety. We have a very clean safety profile, unlike HER-2 targeted ADCs, which have stomatitis, which can be quite problematic, we have low rates of hematologic toxicity. HER2 is in biomarker selected subgroup. So we think that there are a number of factors that would align towards having biomarker selected approach being favorable in this patient set.

It's Leo from RBC Capital Markets. I wanted to ask on the CDK4 maybe for Dr. Goel. I just wanted to ask on your clinical perspective on safety here. I guess, to what extent is the lower heme toxicity a must have given the current real-world management rather than a nice to have? And I guess, would it make you change your use given you may have more experience with prior CDK4/6 agents? And then maybe if I can squeeze one. And related to that, if the GI toxicity doesn't improve meaningfully, but the heme profile stays favorable, I guess, how does that change your view of how the drug would fit in?

Okay. So there's a lot there. Let's start with the heme. So the low rates of heme tox, that's been seen with this drug, to me, this is very important. It's not just something that is a low number on paper. And there's a few reasons for that. One is that what that indicates to me really is the selectivity that the drug has for CDK4 over CDK6. That's what I see that as a readout of and you saw the preclinical numbers from Mark to support that. And what that in turn suggests is that the thesis -- one of the theses behind these drugs is that by sparing CDK6 and reducing neutropenia, it allows us to hit CDK4 harder, right? So in that sense, I think it's more than just a low number. It potentially has deep biologic implications for the durability of cell cycle control. That's one point.

Second point to remember, and it is not a trivial one, is that with our existing CDK4/6 inhibitors, there are a fraction of patients who actually come off therapy on account of hematologic toxicities. If you look at the first-line studies with the existing drugs, I think depending on the agent, between 5% and 10% of patients came off therapy for toxicity and a large number of those were heme tox. So I think again, by mitigating heme tox, I feel that you have less patients that go down that road.

And then I guess, thirdly, just slightly as a tangential point and one that Mark mentioned, more forward-looking, I think that the lack of significant heme tox also opens up opportunities when we're thinking about combinations in the future. As many of you know, the field is moving towards triplet regimens for ER-positive disease. And I think less heme tox you have with your foundation, with your hormone therapy and CDK4, the greater your options for triplets.

With respect to the GI tox, first of all, I would say the numbers that we've seen today in terms of concomitant administration with food are relatively small. But my sense, and I've looked after a number of patients on this agent is that the concomitant administration with food. That effect, I mean time will tell with larger numbers, but my sense, my clinical sense is that there is something real there.

Your question was what if it's not the case? So I can also talk to the experience of the patients I look after who took the drug in the fasted state and also point to some data that was on our poster today, but which wasn't in my presentation, looking at the prevalence of Grade 2-3 diarrhea over time. If you look at that data, what you'll see is that by the time you get to cycle 3, there's a real drop-off in the rate of Grade 2-3 diarrhea and that, that just continues to tail off to even lower numbers as patients continue on treatment. And that is not because patients were coming off therapy for diarrhea in the first cycle, no one came off therapy because of diarrhea.

To sort of turn that into a more simple sort of anecdotal sort of nature, my experience with the agent has generally been that people have very manageable GI toxicity. If needed, low-dose intermittent loperamide, patients and doctors learn very quickly during that first 1 to 2 cycles, how to manage it and get on top of it. And after that, our experience has been that it is a very manageable thing. So I don't think even if the concomitant administration with food, that data doesn't play out. I don't think that, that would necessarily limit my view of the long-term potential for the drug.

Thank you, Dr. Goel. I think we have time for one more question.

Yanan Zhu, Wells Fargo. I have 2 questions on CDK4 inhibitor and one on HCC. On the CDK4, I was wondering if you could frame the relative efficacy here compared with Pfizer's asset in a similar stage -- in a similar setting. And then just note there are significant dose interruption and dose reduction in the study due to the diarrhea effect. With food, that's in the data, but with patients taking it with food and being able to better tolerate the regimen, could we expect even better efficacy just given the level of dose reduction seen in the current data?

On the HCC, it's a quick question. Given the high prevalence of HCC in China, what proportion of patients in your pivotal study could come from China and be okay with the FDA?

Sure. So I can start with the CDK4 questions. So I think doing sort of meaningful comparisons across different studies with different agents, honestly, is difficult with the number of patients that we've seen the data from. And so anything to sort of say, oh, this or that is very speculative. I think what I can say is from the data that I showed you today, both at 240 and 400-milligram doses of BGB-43395, the objective response rate compares very favorably to what we have seen in the global randomized trials with the currently approved CDK4/6 inhibitors. So that's very encouraging. But showing data from a limited number of patients with either agent, I can't really speak to comparative efficacy. And I'm just trying to recall what your second question was.

[indiscernible].

Yes, yes, the food. So I think that this is again speculative my answer here, but if the GI toxicity is significantly mitigated through concomitant taking food and yes, you would expect let's see how this plays out over time that, that would lead to fewer dose reductions. But I think to then take another step, and we want to maximize relative dose intensity, right? That is a good thing and fewer dose reductions maximizes relative dose intensity. But again, it would only be speculation to say and therefore, that would translate to deltas in efficacy.

If I can address your second question regarding regulatory expectation. To be very clear for everybody, we have not had that conversation with FDA yet. So this is purely my opinion based on prior experience and speculation. My prior experience is that FDA will not view that question from the perspective of there are a lot of patients in Asia, but rather is this a common disease or a rare disease in the United States and there are patients eligible for enrollment. And as I mentioned, this is actually a common disease in the United States with an incident rate between 30,000 and 40,000 patients. So I suspect that FDA's position will be that they expect that we will have a typical proportion of U.S. representation in the Phase III study. And the overall allocation may be weighted a little bit towards Asia potentially. But as the study -- as with all of our studies, we will ensure that the regional allocation meets the need of all major regulatory agencies.

Okay. Thank you all very much for participating in our panel tonight. And now would you -- Lai, would you bring us to a close?

Yes. Thank you. I'm very happy to share a few closing remarks. First, this is an inflection point in our solid tumor program history. In just 2.5 years, our first wave of new assets has already delivered 5 POCs, including 3 we highlighted today. Second, momentum is building. The next wave is coming with our next-generation IOs beyond more than what you have seen from the public domain about our trispecific. We have other things which we will bring to the clinic very soon. Also the 4-1BB bispecifics, thanks for the question, we are very excited about this MOA. And in addition to that, we'll also have novel payload ADCs following right behind.

And finally, this is about more than just individual assets. We have talked about this many times tonight. This is about innovation, execution at scale, powered by our franchise model, world-class discovery and our global development superhighway. Thank you for spending your precious time with us today, and we truly appreciate your time and interest and engagement. We hope you enjoy the rest of ASCO and a safe trip home. Thank you.

Good day, everyone. Welcome to BeOne Medicines Q1 2026 Earnings Call Webcast. [Operator Instructions] At this time, I would like to turn the call over to the company.

Hello and welcome. Thanks for joining us today. I'm Dan Maller, Head of Investor Relations at BeOne Medicines. Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentation on the Investor Relations section of our website ir.beonemedicines.com.

I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most periodic -- recent periodic report filed with the SEC.

Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation. Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our IR website, along with our earnings release. All information in this presentation is as of the date of this presentation, and we undertake no duty to update such information unless required by law.

Now turning to today's call. As outlined on Slide 3, John Oyler, our Co-Founder, Chairman and CEO, will provide a business update. Aaron Rosenberg, our CFO, will provide an update on our first quarter financial results and 2026 guidance. And Lai Wang, President and Global Head of R&D; will discuss our R&D and pipeline progress. We will then open the call to questions. And joining the team for the Q&A portion of the call will be Xiaobin Wu, President and Chief Operating Officer; Matt Shaulis, General Manager of North America; Mark Lanasa, Chief Medical Officer for solid tumors; and Amit Agarwal, Chief Medical Officer for hematology.

I'll now pass the call over to John. John?

Thank you, Dan, and welcome, everyone, and thank you for your time today. We entered 2026 with tremendous momentum and our Q1 performance reflects strong execution across the business and a very solid start to the year. From a financial perspective, we achieved significant product revenue growth and GAAP earnings per ADS. These results underpin our confidence to raise our 2026 revenue guidance range by $100 million as Aaron will discuss later.

Our foundational hematology franchise consisting of BRUKINSA, sonro and our BTK CDAC is rapidly progressing with approvals, launches and key pivotal trial milestones expected in the near term. Both our heme franchise and our solid tumor pipeline will be on display at ASCO and EHA, where we have over 60 acceptances. At ASCO, we will present proof-of-concept data from 3 exciting solid tumor programs moving into late-stage clinical trials, which Lai will tell you more about shortly.

I'll begin today by highlighting the exceptional commercial and clinical progress of BRUKINSA, which has firmly established itself as the foundational BTK inhibitor. BRUKINSA continued its global leadership in the growing BTK market with first quarter sales of $1.1 billion, representing growth of 38%. We are seeing strong performance in all markets and all indications. BRUKINSA's large, consistent and expanding body of clinical and real-world evidence has elevated the benchmark for what is possible in CLL.

We believe that the data shows that only BRUKINSA provides the long-term outcomes that patients and physicians should expect and should demand. From its inception, BRUKINSA was designed to provide the best-in-class 24/7 BTK inhibition. Our hypothesis was that achieving complete and sustained BTK inhibition would result in a superior therapeutic profile and that has been borne out in the almost 7 years since, which I'll cover in the next few slides.

At ASH 2025 BRUKINSA set a new standard in frontline CLL with 6-year progression-free survival reported at 74% and overall survival of 84%. Adjusting for COVID, those are 77% for PFS and 87% for OS at 6 years.

CLL is an indolent disease and admittedly, much of the data across the various medicines for the first 3 years looks similar, but outcomes beyond this are what truly matter to patients. So this slide builds on the scatter plot, but focuses on the landmark reported PFS at years 3 through 6 across Phase III trials in frontline CLL.

On the left, we see the data for BRUKINSA and the 2 continuous BTK inhibitors. Recognizing the limitations of cross-trial comparisons, the early landmark PFS rates for BRUKINSA are higher and continue to diverge over time. In year 6, that reaches a delta of 12%, the equivalent of 1 in 8 patients not progressing.

On the right, we see an even more pronounced delta between BRUKINSA's landmark PFS and that of fixed duration regimens such as VO. In year 6, that's a delta of 21% or roughly 1 in 5 patients. In the unmutated population, which is the majority of CLL patients, the difference between continuous BRUKINSA and VO is 27%, which is more than 1 in 4 patients who started the study.

Now AbbVie has not reported the long-term landmark PFS data to be fully represented on this chart. But I will note that despite AMPLIFY being studied in a young fit population, which has a median age of 61 versus SEQUOIA's median age of 70. It has the lowest PFS of any regimen at 3 years. The last AMPLIFY data cut was April 30, 2024, over 2 years ago. An additional follow-up data has not been provided though. Of course, it exists.

BRUKINSA is the only BTK inhibitor that has demonstrated superiority on efficacy versus ibrutinib in a head-to-head trial. Here, we can see the Kaplan-Meier curves from BRUKINSA and the other BTK inhibitors in their respective head-to-head trials versus ibrutinib in relapsed/refractory BTK naive CLL patients.

BRUKINSA demonstrated superiority with a hazard ratio of 0.69 and a p-value of 0.001. When we presented the initial early cut of these data to the CLL community, the universal feedback was, this is great. But in an indolent disease, we need to see longer follow-up. And there was an important scientific reason for that. Ibrutinib has known tolerability issues that could potentially influence the patient's ability to stay on the therapy during early treatment.

In the ELEVATE-RR study, acalabrutinib had previously showed early PFS separation from ibrutinib, but that early separation was not sustained. As you can see in the middle panel, acalabrutinib actually crossed over and became numerically worse than ibrutinib at roughly 33 months and reported a hazard ratio of one. And again, while early separation was an encouraging signal, CLL prescribers wanted to see with BRUKINSA sustained separation with longer follow-up to be convinced.

You can see that in ALPINE, BRUKINSA showed exactly that. After these data were presented, the adoption of BRUKINSA began in earnest. Pirto with a very short follow-up period of only 18 months shows the weakest early separation versus ibrutinib with a hazard ratio of 0.845 and a p-value of 0.4102. The CLL community needs to see much longer follow-up data from pirto. But given this curve, pirto may face challenges demonstrating statistical superiority on PFS.

So what about tolerability? Pirto is self-described as a third-generation BTK inhibitor, with the hope that it would be more tolerable than the second-generation covalent BTK inhibitors. In reality, the BRUIN-314 study, Pirto demonstrated numerically more adverse events leading to discontinuation than ibrutinib. This is important because it has potential ramifications for use in specific subgroups such as older patients.

Notably, in the BRUIN-313 trial in first-line CLL, the average age of patients randomized to pirto was 65 years old, roughly 5 years younger than the respective first-line trials for both of the second-generation covalent BTKis. But taken together, pirto's limited follow-up, lack of differentiation on efficacy and tolerability over ibrutinib and its mechanistic rationale designed for covalent BTKi resistance do not support moving it from the relapsed setting, where it currently plays a much-needed role.

BRUKINSA's comprehensive body of evidence continues to expand. It consistently is supporting it as the foundational best-in-class BTK inhibitor. Last quarter, we highlighted 3 published studies that illustrate BRUKINSA's efficacy and safety benefits over the existing fixed duration regimens, VO, IV and AV. And at ASCO will present new evidence from over 58,000 real-world patient data sets, each of which demonstrate the significant real-world benefits of BRUKINSA.

While BRUKINSA's momentum as the foundational BTK continues, we're aggressively moving to redefine the fixed duration treatment landscape with our next-generation foundational BCL-2 inhibitor, sonro. We intentionally designed sonro to be 14x more potent and 6x more selective than venetoclax and with a much shorter half-life to minimize drug accumulation. This differentiated profile may enable a simpler ramp-up compared to the burdensome monitoring that is required by the first-generation agent.

The trial studying this optimized ramp-up schedule is progressing well. Sonro's first approvals are as monotherapy but its true transformative potential lies in combination with BRUKINSA. The clinical data that we're generating with the combination of BRUKINSA and sonro is truly exciting. In the 101 trial shown here, ZS demonstrated a uMRD rate of above 90%, a remarkably flat PFS curve and a favorable safety profile.

This compares very favorably with AV on the right, where in a much healthier, younger population, they saw uMRD of only 34%. We look forward to sharing updated data from this trial at ASCO. With 3 Phase studies underway, the ZS combination has the potential to change the first-line CLL treatment paradigm and enable BeOne to participate in half of the market where today we have no presence.

Finally, I want to highlight the progress of our BTK CDAC, a novel potential therapy for patients who have progressed on other treatments. Our BTK CDAC is first-in-class. It shows complete BTK degradation and it holds a clear mechanistic advantage in terms of BTK mutation coverage.

Data presented at ASH 2025 showcased its profound efficacy in heavily pretreated patients, including those with mutations conferring resistance to both covalent and non-covalent BTK inhibitors. In our Phase I/II study, the patients receiving the recommended 200-milligram dose achieved an outstanding 94.4% overall response rate with responses deepening consistently over time.

Based on the strong efficacy and favorable safety profile of the molecule, we're advancing a highly ambitious clinical development plan, including several Phase III trials that are well underway. We've guided to a potentially accelerated approval submission in the U.S. relapsed/refractory CLL in the second half of this year.

In summary, our foundational hematology franchise has never been stronger. BRUKINSA is driving continued global revenue growth. Sonro is poised to disrupt the fixed duration market, and our BTK CDAC is leading the next wave of innovation in CLL. Only BeOne is uniquely equipped to provide the best-in-class therapies for every CLL patient regardless of their stage of disease.

We're looking forward to ASCO and EHA this year, where we will have a large leadership presence highlighting our foundational medicines in heme and our 3 rising stars from the solid tumor portfolio, which Lai will tell us more about shortly.

With that, I'll pass it over to Aaron to provide our financial update.

Thanks, John. In Q1, we sustained strong business momentum across our product portfolio. Product revenue reached $1.5 billion in the quarter, representing 34% year-over-year growth. BRUKINSA global revenues totaled $1.1 billion, with strong growth and performance across all approved markets and indications.

In the U.S., BRUKINSA Q1 sales were $761 million, principally driven by volume growth of approximately 28% versus Q1 2025. The U.S. saw a mid-single-digit pricing benefit on a year-over-year basis with nonrecurring gross to net favorability of approximately $20 million in the period. Excluding these items, we continue to expect relatively stable pricing in 2026, consistent with prior commentary.

Q1 results reflect the typical seasonality patterns seen across the BTKi class, including inventory dynamics and one fewer shipping week in the first quarter. The business performed nicely relative to our range of expectations for the quarter with increasingly positive demand signals in March, which have carried through to April. We are confident around performance in the U.S. for the year, and this is reflected in our guidance update.

Meanwhile, TEVIMBRA reported a 20% increase with sustained market leadership in China despite the competitive environment. We are pleased with contributions from launch markets with approximately half of the growth for TEVIMBRA coming from markets outside of China. In-licensed and other products also showed continued strength, growing 27% year-over-year including robust performance from our Amgen in-licensed portfolio.

XGEVA continued to perform very well in the quarter with $90 million of revenue. Of note, we did see several biosimilar entrants filed for approval in April, which could lead to enhanced competition for XGEVA. We are pleased with the early market reception for sonrotoclax, our foundational next-generation BCL-2 inhibitor approved in China for post-BTKi CLL/SLL and relapsed/refractory MCL.

We continue our solid execution across all geographies. The U.S. remains our largest market, generating $766 million with year-over-year growth of 36%. China revenue totaled $465 million, a 17% increase compared to the first quarter of 2025, of which 5% was driven by foreign exchange. We continue to see good performance and sustained leadership from TEVIMBRA and BRUKINSA.

Europe contributed $191 million, representing growth of 64%. Foreign exchange contributed approximately 11% of this growth given euro strengthening on a year-over-year basis. We continue to drive demand growth for BRUKINSA in Europe in all major markets, and there remains plenty of opportunity to increase brand share, given BRUKINSA's differentiated long-term data across all patient types. While the AV combination has yet to achieve broad market reimbursement, we have observed BCL-2 BTKi fixed-dose treatments gaining traction in some early markets.

As we've discussed, Europe is a more mature market for these fixed dose treatments given the legacy availability of venetoclax plus ibrutinib. The long-term data is clear on the efficacy and durability of BRUKINSA across all patient risk factors particularly for the large unmutated population, which we expect will continue to support growth moving forward. Rest of World markets grew 104% driven by market expansions and new launches in key markets such as Japan and Brazil.

Now turning to the other components of our GAAP P&L. Gross margin improved to 89% from approximately 85% in the prior year. This improvement primarily reflects the benefits from favorable product mix, price and cost efficiencies. Operating expenses grew by 16%, totaling $1.1 billion as we are investing to support our commercial growth and rapidly advance our innovative pipeline. The weighting of growth between SG&A and R&D is expected to normalize over the course of the year, with both converging toward rates consistent with the overall OpEx growth implied by our full year guidance.

Income from operations totaled $250 million, an increase from $11 million in the prior period. Income tax expense totaled $32 million for the first quarter, primarily reflecting cash tax expenses in certain geographies. Altogether, net income totaled $227 million with GAAP diluted earnings per ADS of $1.96.

Our non-GAAP P&L includes adjustments for typical items with a full reconciliation provided in the appendix. Non-GAAP income from operations totaled $414 million in the first quarter up from $139 million in the prior period. And non-GAAP net income came in at $375 million for the first quarter, which translates to diluted non-GAAP earnings per ADS of $3.24. We generated free cash flow of $161 million in the first quarter, an increase of $173 million over the prior period. Note that operating and free cash flow is typically lower in the first quarter due to working capital seasonality.

Now turning to our 2026 financial guidance update. We like what we see so far in the U.S. with strong demand growth and with relatively stable net pricing. Growth is anticipated in all markets and will benefit from continued global expansion and we anticipate modest full year initial contributions from our launches of zanidatamab and sonro. And our guide incorporates all current and anticipated competitive market dynamics. Given our Q1 performance and assessment of recent trends, we now project 2026 revenue to be between $6.3 billion to $6.5 billion, an increase of $100 million across the range.

Our estimate of GAAP gross margin remains in the high 80% range with continued benefit from mix and a full year of productivity from improvements implemented last year. GAAP operating expense expectations are unchanged between $4.7 billion and $4.9 billion. Given our top line improvement, GAAP operating income estimates are updated to be between $750 million and $850 million with a corresponding change in non-GAAP operating income.

In summary, we are pleased with our start to the year and are confident with how 2026 is shaping up.

And with that, I'd like to pass the call over to Lai.

Thank you, Aaron. Hello, everyone. Thank you for joining us today. This slide highlights recent progress across BeOne's pipeline. In hematology, BRUKINSA's MANGROVE Phase III study in treatment-naive mantle cell lymphoma remains on track with interim PFS readout expected next month, supporting a potential first chemo-free regimen in this setting.

Sonro is approaching a key inflection with U.S. PDUFA decision expected soon alongside EU submission and ESMO guideline inclusion. Our BTK CDAC continued to advance with potentially pivotal Phase II programs in relapsed/refractory CLL and Waldenström, and the Phase III head-to-head study versus pirto is on track to complete enrollment in early 2027.

In solid tumors, TEVIMBRA received U.S. priority review in HER2-positive gastric cancer. In parallel, the CDK4 inhibitor has activated its first Phase III site under the GPC3 x 4-1BB bispecific is enrolling a potentially pivotal HCC study.

In addition, we acquired an exclusive option to license a novel PD-1 VEGF CTLA-4 trispecific, which is expected to enter the clinic in June. In immunology, we made a data-driven decision not to pursue IRAK4 in rheumatoid arthritis, while the BTK CDAC CSU Phase II study is on track to initiate by year-end. The progress you just saw reflects the very deliberate way we are building our pipeline.

Our strategy starts with focus, selecting a small number of disease areas where we believe we can lead and then building depth not just the single asset. What enables this approach is our in-house technology stack, expanding CDAC's novel payload ADCs, cell therapy and emerging platforms like T cell engagers. We're not bound to a specific target or platform alone. We systematically match the right biology with the right modality to build a pipeline that is deep and sustainable.

The engine has clearly accelerated from 2011 to 2020. We delivered 11 new molecular entities building the foundation with assets like zanu and the tisle. Between 2021 and 2023, we added another 10 NMEs, demonstrating consistent productivity and execution. The momentum stepped up again in the last 2 years with 18 NMEs across small molecules, CDAC, ADC and trispecific antibodies, reflecting the maturation of our in-house platforms.

Looking ahead, we expect to sustain a cadence of roughly 8 to 10 NMEs per year from 2026 and beyond, innovation that BeOne is accelerating systematic and built to scale. As our innovation engine accelerates, it is producing a broad but intentionally focused pipeline across our key disease areas. We have built depth with multiple mechanisms and modalities coexisting within the same indications. This is important because it creates unique opportunities for proprietary combinations developed entirely within our own portfolio, which drives higher return on investment rather than relying on external assets. 2026 marks a true inflection year for our solid tumor portfolio.

After several years of disciplined build-out, we now have a new wave of programs advancing toward registration. In breast cancer, our CDK4 inhibitor is moving to late-stage development in a large, well-established setting, while the B7-H4 ADC continues to advance with encouraging signals in gynecological and breast cancers.

In liver cancer, the GPC3 x 4-1BB bispecific represents a focused, first-in-class approach designed specifically for HCC with a potentially pivotal study actively enrolling. We're also advancing our PRMT5i inhibitor, which has already been evaluated in first-line settings, underscoring its potential relevance in earlier lines of therapy. Finally, based on the exciting early data, we are planning pivotal trials for our CEA ADC, further strengthening the solid tumor portfolio.

Taken together, our solid tumor pipeline is clearly shifting from early promise to late-stage execution with multiple programs advancing towards meaningful late-stage milestones. While several of these programs we highlighted are in large well-understood cancers, such as CDK4 in breast cancer, there remains less appreciation for the opportunity in hepatocellular carcinoma, HCC. As we said at JP, there is much work left to do in cancer and HCC is a clear example. As the sixth most common cancer worldwide, it is the third leading cause of cancer death, reflecting dismal 5-year survival rates that are well below many other major cancers.

A truly differentiated, potentially game-changing approach in this setting can meaningfully improve patient outcomes and expand what is already a multibillion-dollar market. The unmet medical need, you just saw in HCC demands not only innovation, but the ability to execute with a sense of urgency. Our first-in-class program, GPC3 x 4-1BB is a clear demonstration of our unprecedented clinical execution capability.

We moved from first-in-human dosing to enrolling the first patient in a potentially registrational study in just 19 months. This is exceptionally fast for a novel bispecific in solid tumor. Dose escalation was completed under 6 weeks per cohort. We have enrolled over 200 patients in 20 months, including over 45 first-line HCC patients treated in combination with tisle and bev, giving us early experience across clinical meaningful settings. Along the way, the program has received a fast track and orphan drug designation by FDA.

At the bottom of this slide is the simple view of the potential pivotal study design with ORR per IRC as the primary endpoint. ASCO 2026 will be an important moment for BeOne. We have 24 abstracts accepted, including 3 oral presentations, underscoring both the breadth and the momentum of our pipeline. You will see the clinical updates across key programs, including our CDK4 inhibitor, B7-H4 ADC and the GPC3 x 4-1BB. Please join us at our ASCO Investor Relations event on June 1 to learn more about our clinical data and why we are so excited about these assets.

At BeOne, we move quickly to clinical proof of concept and advance only programs with the strongest data into late-stage development. You can see how that discipline is being applied across the portfolio and the actions we are taking this year. We will have additional data disclosure this year for programs such as PRMT5i and the CEA ADC, while new assets like ADAM9 ADC and the KLRG1 have recently entered the clinic.

At the same time, we have made a data-driven deprioritization decisions in programs such as CDK2 inhibitor, EGFR CDAC, MAT2A inhibitor and the PanKRAS inhibitor, allowing us to reallocate resources towards the potentially highest impact opportunities. This is exactly how our strategy is intended to work, move faster to proof of concept, identify the most promising candidates and invest aggressively to maximize patient impact.

In addition to our focus on our internal breakthroughs, we are further strengthening our pipeline through selective external innovation. BON-110 is a good example of the approach and it represents a potential backbone for our solid tumor portfolio. What differentiates the trispecific from PD-1 VEGF bispecific is the addition of a CTLA-4, which gives the potential for deeper and more durable immune activation.

Importantly, this creates a broad opportunity for proprietary combinations across our pipeline, including ADCs and 4-1BB-based programs. This program -- this is on track to enter clinic next month. We have covered most of the milestones already, so I will just call out 3 remaining 2026 catalysts.

First, we expect to initiate the sonro Phase III study in second-line plus multiple myeloma later this year, extending our BCL-2 strategy into a new important patient population. Second, in the half -- in the second half of this year, assuming the data is supportive, we expect an accelerated approval submission for our BTK CDAC in relapsed/refractory CLL. And finally, we anticipate a U.S. approval for TEVIMBRA in first-line HER2-positive gastric cancer, marking a meaningful regulatory milestone in solid tumors.

I will now turn it back to John.

Thanks, Lai. We'll now open the call to Q&A. Can you please limit the number of questions to ensure that we have time to hear from as many attendees as possible.

Operator, can you please go ahead?

[Operator Instructions] Our first question is from Yigal Nochomovitz from Citigroup.

John, you've consistently highlighted BRUKINSA as the only BTK to demonstrate superiority versus ibrutinib in ALPINE, as you just noted on Slide 10. I'm just curious because one of your competitors, Lilly, has also been highlighting pirto's performance versus as recently as some of their materials in the recent earnings call stating 76% risk reduction versus ibrutinib in treatment naive and 27% PFS risk reduction in relapsed/refractory BTK naive. So I'm just wondering if you could help contextualize that and sort of sort out the apparent disconnect there.

Thanks for the question. I appreciate it. And I think that's probably best handled by Amit.

Yes. Happy to take that, John. Thank you for that question. So unequivocally, what we're saying is correct. BRUKINSA is the only BTKi to demonstrate superiority to ibrutinib in a head-to-head study. So before I talk about some of the specific problems with the pirto claims, let me just talk about a couple of important study conduct principles.

So in an open-label study, when you have 2 arms being compared, the standard industry practice based on regulatory guidance is to actually look at the data assessed by an independent review committee or an IRC rather than relying on investigator assessments. This is for the obvious reason that investigator assessments can favor the experimental arm over the control arm. Also, it is important to ensure that there is no discordance in the investigator and IRC results, and I'll come back to that in a minute.

A second important aspect is that there should be predefined alpha allocation for the subgroups being tested and the order of testing itself. So all of the claims have to be based on alpha-allocated predefined subgroups rather than exploratory subgroups.

So with that, to talk a little bit more specifically about the BRUIN-314 based claims. Now what you may have seen in some of the presentations is a claim on risk reduction compared to ibrutinib in the relapse setting of about 26%. But if you actually look at the IRC data and John had this in his previous -- in his presentation, what you see is that there are only 2 events that separate the 2 arms.

So the pirto has reported 48 events and the ibrutinib arm has noted 50 events. So if you compare this to the investigator curves, you can see that there is a significant discordance,and this really highlights the importance of the IRC curves. Now with the 2 event difference here, the likelihood of this comparison showing statistical significance even with longer follow-up seems to be very low and John made the important point that with ibrutinib in particular, as patients are able to tolerate it, we've seen what happened with the ELEVATE-RR study as well.

Now moving on to the treatment-naive group, the claims are even more questionable. Because this is a very small subgroup of the overall trial population. And according to the JCO paper is not even listed in the hierarchy of testing. So this is not a predefined group. And moreover, even in this group, when you look at the IRC-assessed difference, that is not statistically significant.

And finally, for the treatment-naive group, given the extremely short follow-up of the BRUIN study, questions around long-term safety, treatment sequencing as well as overall benefits over other BTK inhibitors remains quite questionable.

So I think really to conclude what I can say is based on all of this data, BRUKINSA remains the only BTK inhibitor to have shown clear superiority. Thank you.

Thanks Amit. And I don't think that's a like technical statistical answer. I think this is the governing chart, IRC, that the industry recognizes and as Amit shared, the data is what the data is. So anyway, we're very comfortable with that statement.

Okay, thank you. Operator, can we have next question please?

Our next question is from Kalpit Patel from Wolfe Research.

One on BRUKINSA's CELESTIAL-TNCLL trial. We were expecting uMRD results, but we didn't see that on the slide deck. So curious on the update there. And then second, for the degrader, the CDAC, what hurdle are you targeting? What efficacy hurdle for filing for accelerated approval?

Thanks so much. Those are great questions, but I think we're back to you, Amit.

Yes, happy to take those as well. Thank you, John. So for the CELESTIAL uMRD question, let me start by talking a little bit about how that study is set up. So just as a quick reminder, the CELESTIAL-301 study effectively has dual primary end points. One is the uMRD at the end of the treatment in the 2 arms and the other is PFS or progression-free survival.

So in our case, progression-free survival is the traditional regulatory end point and is the base case for our filing. So we expect PFS to be the endpoint that will support regulatory approval for that regimen. UMRD is not currently accepted as a regulatory end point but obviously remains scientifically very interesting as well as there's efforts ongoing from a regulatory perspective as well.

So in Q3 of this year, our IDMC will review the uMRD data across the arms and tell us whether statistical significance has been met or not. Irrespective of the outcomes for UMRD, we would disclose that externally at the next proximate opportunity and the study will continue to the PFS readout, essentially unchanged with no change in the study conduct.

Now it is worth noting that demonstrating statistical significance versus VO is an extremely high bar. And if positive, the CELESTIAL-301 study would be the first study to show uMRD superiority for a BTK and BCL-2 combination over VO. In prior large studies, VO has shown the highest benchmark uMRD rates. So just as an example, if you look at the recently reported CLL17 trial, the uMRD rates for VO are 73.3% and for VI they are 47.2%.

Even with the uMRD rate difference of 25% in the 2 arms, the PFS for VO and VI are essentially superimposable. So you can imagine that even if the ZS uMRD rates are on par with the VO rates, we will actually feel quite good about the likelihood of demonstrating PFS benefit. Based on this data and the data that we've seen to date with the SONRO-101 study, we remain very confident in achieving the PFS endpoint, even if uMRD is not statistically significant.

Also, we have a separate ongoing Phase III head-to-head versus AV, which we feel, based on the data presented so far represents a meaningfully lower bar for uMRD than VO in terms of the MRD rates. And either trial can enable global registration in that frontline setting. So we look forward to bringing ZS to patients based on these 2 trials.

Now quickly, just on the degrader. We've been enrolling patients in -- the relapsed/refractory patients in a Phase II study. And as far as benchmarks are concerned, I think this is an evolving area depending on what are considered available and approved therapies in the U.S. But certainly, based on that study and -- as well as the studies run with pirtobrutinib as monotherapy, we're sort of looking at the benchmark of somewhere between 50% to 70% depending on the population.

Thanks so much for the answer. And could we have the next question please?

Our next question is from Jessica Fye from JPMorgan.

I was just hoping if you could give us a status update of what inning you think we're in of BRUKINSA's launch in Europe? And then for the BTK CDAC, which I believe you suggested could be launching next year in relapsed/refractory CLL following potential filing later this year. Can you talk about how we should think about the initial launch ramp for that one?

Perhaps I can kind of answer the first question. I'm not very good at innings because I'm from Pittsburgh and our baseball team is not so great. But I think as we all know, Europe takes a while to launch and to work your way on to reimbursement. And I think we've always been behind there versus the U.S. We're very encouraged by what we see, but I think that it's still pretty early in those days, and we see the opportunity for substantial growth for BRUKINSA as a single agent. Of course, with the combination when sonro comes into play, we think this is game-changing, and the opportunity for that is just tremendous in every country across the world. That's the first question.

The second question on the CDAC launch ramp, I think that's a question that we could refer to Matt.

Glad to take that question around CDAC launch ramp. I think you've already heard from Amit and also from John about aspects of the CDAC clinical profile, which we anticipate will be very strong and particularly note the head-to-head trial design versus pirto on those later lines of therapy.

So in terms of overall launch ramp, we think that it should be relatively robust. Would anticipate a typical S-shaped uptake curve, but again, we think it's a well-prepared market, and we're confident about its prospects.

And I think one of the nice things about that program and sonro is both of these largely leverage the existing infrastructure that we have in place which is great for us and makes it much easier effort, but it's also economically highly favorable. So that's a great thing about having several programs that overlap on the clinicians that are using those medicines.

Thank you so much. Can we have the next question, please?

Our next question is from Leonid Timashev from RBC.

Just wanted to ask on the immunology programs. It looks like CSU is moving ahead potentially to a Phase II, I guess, is that suggesting that you're encouraged by what you're seeing out of the Phase Ib. And related to that, could you maybe provide some color on why the IRAK4 and RA was discontinued?

Sure. I think probably Lai, you are best to answer that question, please.

Yes. We are planning to initiate the Phase II for our BTK CDAC program in the CSU by the end of the year. In terms of -- based on the current data we have seen from the Phase I study. In terms for the IRAK4 in the rheumatoid arthritis, we decide to not further pursue the trial based on emerging new data. We're in the process of analyzing the data and decide the next steps for this program.

All right. Operator, could we have the next question, please?

Our next question is from Ziyi Chen from Goldman Sachs.

Congrats on a very strong first quarter. Just one question regarding the recent deal on the HH160, the PD-1 VEGF CTLA-4 trispecific. Could you share a bit more about your view on the asset and particularly amid the competition of emerging PD-1 VEGF bispecific and also different strategy for trispecific? And also talking about the Fc silent strategy, it's definitely going to be reduced toxicity of the CTLA-4 but also it's going to lose potentially T-reg depletion. So what is your view on that?

Sure. Thank you so much for the question. Again, I think we'll go right back to Lai.

Yes. This molecule we call BON-110, previously for the HH160, was engineered to simultaneously blocking the 3 well-established pathway, and there certainly has been bispecific between the PD-1 VEGF and the PD-1 CTLA-4 demonstrating clinical activity. We believe by adding the CTLA-4 arm, we will present potential differentiation from the current existing bispecifics. As for the tuning out the Fc function is to exactly to the point you raised is to try to mitigate the tox concern. We do believe from preclinical data, this kind of engineering will be able to still retain largely the efficacy by removing some of the safety liabilities.

Thank you. All right. We have another question, please?

Our next question comes from Gregory Renza from Truist Securities.

Congrats on the quarter. Maybe I'll weave in Aaron here for a bit and just ask a bit on the guidance. Aaron, you acknowledged that you like what you see with the growth in the markets, but also some assessment of recent trends. Perhaps you could just elaborate further on the pieces that enable you to feel confident about revenue performance for the rest of the year?

And if you could, if I may just ask a bit about, some of the factors to consider when it comes to the net pricing. I think we heard you mention consistency, but just wanted to give you an opportunity to elaborate further on maybe some of those headwinds, but also pressures if they are, by and large, passed into guidance at this point.

Great. Thanks for the question, Greg. So as I said in the prepared remarks, we really do like what we see and the setup for the year. Q1 came in on expectations, but particularly, we were encouraged by performance in the United States, both in March and into April.

You mentioned price. When we issued our original guidance, we talked about relatively stable net pricing. We feel very confident in that as we enter the year, given where we are with our various contracting opportunities. So we feel really good about that moving forward in the -- for the balance of 2026. I did touch on in Q1, we had $20 million or so of nonrecurring gross to net. So that obviously occurred in Q1, and we anticipate that will pass through for the year.

So overall, we really like where the business is sitting, strength in the United States, but really strong performance across all of our geographies. I think you see really strong growth with our European business. our China business continues to perform and demonstrate leadership and we're still in very -- using Jessica's analogy very early innings in Rest of World where the business doubled again in the first quarter. So we really like to set up. That's what gives us confidence for the guidance update with the $100 million improvement across the range.

All right. Thank you, Aaron. Could we move to another question, please?

Our next question is from Michael Schmidt from Guggenheim.

Congrats on the great first quarter here. Perhaps switching back to the pipeline, a question about the GPC3 x 4-1BB bispecific where sounds like there's things are starting to emerge that are quite interesting. And perhaps could you just comment a bit more about the pivotal study in second-line HCC. How should we think about the efficacy bar in this setting? It seems like there's an ORR readout planned. And then longer term, how do you think about the overall opportunity for this asset, perhaps in frontline HCC and other opportunities.

Thanks for the question. Good to hear your voice, and perhaps we can have Mark answer that. And if Mark doesn't jump in, we'll have Lai answer that. Maybe he's been disconnected.

So happy to address this question. In terms of the -- we're in the process of having the discussion with the health authorities to discuss about the bar. You will see our -- the Phase I data at this year's ASCO. The abstract should be released soon, but we will have further data updates at the ASCO oral presentation as well as at our investor relationship -- relation events. We're quite confident about the early data we have seen with this asset.

And certainly, we have already enrolled over 40 patients in the frontline HCC in combination with tislelizumab as well as bevacizumab. The early data is quite encouraging. We're looking forward to bring this effective medicine to patients around the globe with HCC.

Thanks so much, Lai. Could we jump to the next question?

Our next question is from Reni Benjamin from Citizens.

Congratulations on a great quarter. My question is regarding sonrotoclax and the launch in China. Can you talk a little bit about kind of how that's going, kind of is it tracking like BRUKINSA did? Or is it tracking according to internal expectations? And maybe related to that, what do you think might be the competitive dynamics once sonrotoclax is approved here in the U.S., even though it will be for MCL, any sort of on-label or potential off-label use that might impact BRUKINSA or the CLL market as a whole?

Thanks for the question. Xiaobin, do you want to start? Maybe I can finish.

Yes. So the launch is very encouraging. In China, we got approval in January and 8 days later, we launched the product. So far, YTD, we have over 300 hospitals across the country started to treat patients in China. And also sonrotoclax is also included in China, in the CSCO guideline for first-line CLL, second-line CLL and also second-line mantle cell and also for the AML. So second line AML is also listed in the guideline. And we are very, very happy the initial feedback from hospital is very encouraging. So this is China situation.

Thanks so much, Xiaobin. I think that with the launch in the U.S., we're very encouraged by everything we see with sonro. As we've described it's a more potent, more selective, specifically designed PK parameters to try to make this a very differentiated and more effective medicine. We believe that will be the case in the initial indication, where it's approved as a single agent. And the combination data, it's just in our minds, game-changing.

Now you have to work your way to approvals before you're an official commercial product, and we are working our way through that process. At the same time, we will take the data that we have, and we'll share it with the guideline committees all across the world and see if they are willing to have those join the guidelines, and it's great data. So hopefully, there's some chance that, that can occur. But we're very, very excited about this as game-changing medicine and many indications based on the data we see today.

Okay. Thank you so much. Could we take another question or 2, and then we probably have to wrap up.

Our next question is from Yaron Werber from TD Cowen.

Great. Maybe a couple of questions. Just the first one, you mentioned a little bit that AV, Aaron, is gaining some traction in some markets. I wasn't sure if those were sort of ex U.S., and I don't know if you can expand on that. And then secondly, on the CDK4 inhibitor at ASCO, any sense sort of what can we expect? How mature would the durability data be at that point on efficacy?

Thanks, Yaron. Nice to hear your voice, too. You stuck in 2 questions there. I think on the AV question, I think that what Aaron was referring to probably is the statements that they've made that they're having some international success in some perspective. I think from our point of view, it's not something that we've seen widely in the U.S., and it's hard for us to track exactly.

From the CDK4 perspective, at ASCO, I do believe that we have Mark back connected. So let's see if he can handle that question, and we can hear him.

Thank you, John, and I hope you could hear me okay. Thank you, Yaron, for the question. We're very excited to share our updated data at ASCO for our CDK4 program. We encourage everyone listening to the call to visit our poster, which will be on Monday morning of ASCO. We will be sharing data from approximately 60 patients who are frontline for stage IV disease treated in combination with letrozole. What we will show is a strong response rate across a range of doses tested that informed our Phase III dose selection.

We'll also be showing early but encouraging data about the beneficial effect of food and improving the GI tolerability profile. Because the anticipated progression-free survival for frontline breast cancer is over 2 years, the maturity still remains quite low at this time. But again, we're very excited to share the early efficacy and safety data.

Okay. Next question, please. Thank you, Mark.

Our final question is from Sean Laaman from Morgan Stanley.

John, in the business, you're showing some really strong operating leverage, and you've now got meaningfully positive operating income and net income. Maybe it's a question for Aaron. But looking out, how would you characterize sort of growth in OpEx versus the top line and just the efficiencies that you're really showing in your R&D engine.

Great. Thanks for the question, Sean. I happen to -- this happens to be amongst my favorite questions because that means our pipeline has so much opportunity is going to make such a difference for patients. And ultimately, as you know, that's what creates value in this industry. We don't provide long-term guidance, but I've shared a number of times. We really have 2 objectives as we think about managing the business financially. The first is that we are undoubtedly a growth company. You see that in our performance and in our guidance. And the second is to do that in a sustainable way, which means driving continuous operating leverage.

Now we've talked about moving toward margin expansion continuously but in a measured way that matches the opportunity in front of us. So we really like the setup to be able to hit on both of those objectives and look forward to running the business and making a difference relative to our purpose for the long term.

Thanks a lot, Aaron. And I do want to thank everyone for participating in the call. I think, again, in summary, we delivered a very strong first quarter and a solid start to 2026. We executed against our priorities. We drove revenue growth, and we're raising our full year outlook. At the same time, as you can see, the pipeline is entering a really critical phase of execution with foundational strength in hematology and a clear inflection point in solid tumors as our programs are advancing into later-stage development.

We have demonstrated, again, the power of the BeOne super highway and our strategic competitive advantage that we have in executing, which help make investment in R&D more attractive in our organization than other places in the industry. And again, the aspiration and vision of our company, which we feel closer to than we ever have is to be the company that is creating the most impact for cancer patients globally.

That means lots of medicines and lots of indications that are truly game changing for patients. And I feel more confident today than I ever have that we're on a path to being that company not in decades, but in years. I really want to thank the patients and the families that we serve, our physicians and our partners and our more than 12,000 colleagues and their families whose focus and urgency make our progress possible.

We're really encouraged by the momentum. We're confident where we're headed, and we're focused on developing medicines that are great for patients. So thank you all so much for joining us today, and have a wonderful week.

Good day, everyone. Welcome to BeOne Medicines Q4 and Full Year 2025 Earnings Call. [Operator Instructions]

At this time, I would like to turn the call over to the company.

Hello, and welcome. Thanks for joining us today. I'm Dan Maller, Head of Investor Relations at BeOne Medicines.

Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentation on the Investor Relations section of our website, ir.beonemedicines.com.

I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most recent periodic report filed with the SEC.

Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation. Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our Investor Relations website along with our earnings release. And all information in this presentation is as of the date of this presentation, We undertake no duty to update such information unless required by law.

Now turning to today's call as outlined on Slide 3. John Oyler, our Co-Founder, Chairman and CEO, will provide a business update, including commentary on our foundational CLL franchise; Aaron Rosenberg, our CFO, will provide an update on our fourth quarter financial results and 2026 financial guidance; and Lai Wang, President and Global Head of R&D, will discuss our R&D and pipeline progress.

We will then open the call to questions. Joining the team for the Q&A portion of the call will be Xiaobin Wu, President and Chief Operating Officer; Matt Shaulis, General Manager of North America; Mark Lanasa, CMO for Solid tumors; and Amit Agarwal, CMO for Hematology.

I'll now pass the call over to John. John?

Thanks, Dan, and thank you, everyone, for joining us today. Q4 marked another solid quarter of execution and a really strong finish to the year and what a year it was. 2025 certainly lived up to its promise as a year of inflection for BeOne. From a financial perspective, we delivered on our commitments, achieving significant product revenue growth, GAAP profitability and meaningful cash flow generation.

In 2025, our foundational BTK inhibitor, BRUKINSA, became #1, both in the U.S. and globally. And as you can see on this slide, the gap between BRUKINSA and the competition is widening. And that's not just a commercial achievement, it's a scientific one. BRUKINSA's long-term data have consistently raised the bar in CLL, setting a new standard for efficacy and safety. These results are reinforced by an expanding body of clinical and real-world evidence, all of which support the program's best-in-class hypothesis.

CLL is a $12 billion and growing market due to remarkable therapeutic innovation and improvement in patient outcomes over the past 15 years, but it wasn't always that way. As recently as the mid-2000s, patients with CLL received fixed duration chemo and outcomes were quite poor.

In fact, the median progression-free survival for patients taking chlorambucil was less than 1 year. In 2008, bendamustine was approved and used in combination with rituximab and the use became widespread, providing substantial benefit over the first chemo-based regimens. 6-year progression-free survival increased to 32%, which was better, but still not great. The FDA approval of ibrutinib in 2016 marked the first chemo-free option and a seminal innovation for patients.

Anchored by data that were superior to chemo, the field switched away from fixed duration approaches to continuous BTK inhibition. Why? Because it provided the best long-term outcomes for patients. You can see ibrutinib's 6-year progression-free survival and overall survival of approximately 61% and 77%, respectively. At the same time, the field was developing new fixed duration treatments that were enabled by the discovery of BCL-2 inhibition and the approval of venetoclax. These ven-based approaches greatly improved upon historic chemo-based regimens, and they began to approach the long-term benefits provided by the 2 continuous BTKIs, albeit with approximately 10% delta in 6-year progression-free survival.

However, the VI regimen was not approved by the FDA and the addition of obinutuzumab to ven has significant safety challenges, which I'm going to touch on later. As good as continuous use ibrutinib was, the molecule was not optimized for potency or selectivity. The second approved BTK inhibitor, acalabrutinib, was designed to be more selective than ibrutinib and to have a very short half-life of roughly 1 hour with the hypothesis that these changes would translate to a more favorable safety profile, including fewer cardiac adverse events.

And in that respect, acala achieved its goal, demonstrating statistically significant improvement in afib in the ELEVATE-RR study. However, in that same study, acala demonstrated non-inferior PFS compared to ibrutinib. As shown on this scatter plot, acala's 6-year progression-free survival and overall survival of 62% and 76% in treatment-naive CLL is nearly superimposable on ibrutinib. But innovation never stops. The bar set by the first 2 continuous treatments would be raised yet again by a differentiated foundational medicine, enter BRUKINSA.

BRUKINSA was designed from inception to be both more potent and more selective than ibrutinib with complete 24/7 target coverage. We took that preclinical hypothesis into the clinic where in head-to-head global Phase III trial, BRUKINSA demonstrated superior efficacy to ibrutinib and a more favorable safety profile. And this includes statistically significant improvement in afib. And at ASH 2025, BRUKINSA set a new bar for long-term patient outcomes. Here, we can see 6-year progression-free survival and overall survival of 74% and 84%. And adjusting these for COVID, those are 77% and 87%, respectively.

Now I really appreciate you bearing with me as I know I've spent a lot of time on this slide, but the data, as you can see here, is really important. These data clearly established BRUKINSA as a foundational standard against which all current and all future regimens must be compared and the long-term outcomes that patients and physicians should expect and demand. At BeOne, we believe that true innovation comes from improving upon the best. BRUKINSA did just that when it demonstrated superiority in terms of safety and efficacy over ibrutinib. No other BTK inhibitor can make that claim.

Here, we see the Kaplan-Meier curves from head-to-head trials of BRUKINSA and other BTK inhibitors versus ibrutinib in relapsed/refractory BTK-naive CLL patients. And this is as assessed by Independent Review Committee or IRC. In all of these studies, the IRC assessed PFS is the predefined key secondary endpoint to demonstrate superiority over ibrutinib.

In the ALPINE trial, BRUKINSA showed the greatest early separation from ibrutinib and remains separated with a hazard ratio of 0.69 and a p-value of 0.001, demonstrating statistical superiority on PFS. We presented longer-term follow-up data from that study at ASH just a few months ago. In the ELEVATE-RR study, acala showed early PFS separation from ibrutinib, albeit less than BRUKINSA, but that early separation was not sustained. As you can see in the middle chart, acala crossed over and became numerically worse than ibrutinib at roughly 33 months. ELEVATE-RR ultimately reported a hazard ratio of 1.

And this brings me to pirtobrutinib, a non-covalent BTK inhibitor, which recently reported data from its head-to-head trial against ibrutinib in CLL. On the right, we see the curves from relapsed/refractory BTKi naive cohort of BRUIN-314, which comprised 2/3 of the enrolled patients in that trial. You can see that pirto with only 18 months of follow-up shows the least early separation versus ibrutinib with a hazard ratio of 0.845 and a p-value of 0.4102. We need to see much longer follow-up from BRUIN-314 based on the minimal early separation in these short-term curves, and pirto may face an uphill battle and showing statistical superiority to ibrutinib in PFS.

Now if you've learned anything about BeOne Medicines over our 15 years of existence, it's that we're never satisfied with the status quo. And despite the incredible progress the industry has made, it's hard not to dream about the next chapter of CLL innovation. And we think it's time to start talking about a cure.

And with that, we proposed 3 aspirational goals for the next wave of innovation in CLL: The first one is an obvious one, life expectancy equal to that of the general population matched for geography and age for any patient diagnosed with CLL. Second, for patients who prefer a time-limited therapy, any regimen must deliver long-term outcomes that are at least as good as the best continuous treatment available. And finally, any treatment designed to offer long-term life expectancy must also deliver quality of life, ease of use and convenience.

Applying these aspirations to the scatter plot clearly implies the need for further improvements on what's currently available. And we do believe that BeOne is the only company with the foundational assets in our CLL portfolio and pipeline to take us there. The next chapter of CLL innovation is going to come from options that address the unmet needs and deliver the best long-term outcomes for patients.

So what about fixed duration? There's a clear desire from some patients and physicians for fixed duration options that provide a break from treatment. For fixed duration to change the treatment paradigm, it must elicit a deep response, demonstrate sustained progression-free survival, be safe with only minimal infection risk over continuous BTKi and be convenient to administer. And we would argue it must be compared to the foundational CLL medicine, BRUKINSA.

Naturally, patients want to be off treatment. But just as they want to know what they're gaining, every patient also wants to know what they're giving up. If that's overall survival, it's important that this is considered in the shared decision-making. So how do current fixed duration options compare to BRUKINSA? In our opinion, not very well.

Existing ven-based BTKi regimens have liabilities that have limited their uptake and approval. These include underwhelming efficacy as seen in the AMPLIFY trial, where the AV combination had an inferior depth of response compared to chemo, demonstrating an undetectable MRD of only 34% despite AMPLIFY enrolling a young, fit and low-risk frontline population. In fact, AV's PFS at 3 years follow-up was roughly the same as BRUKINSA's at 6 years. And it's quite noteworthy that we haven't seen an updated cut from AMPLIFY for nearly 2 years.

And similarly, with respect to safety, AV and VI have limitations due to ven, a less potent and less selective first-generation BCL-2 inhibitor. In terms of convenience, the low depth of response for AV may result in most patients having to be treated for far longer than 1 year to reach an undetectable MRD. In addition, ven requires cumbersome patient monitoring due to its long half-life and TLS risk, which calls into question the convenience benefit of this all-oral regimen.

At the highest level, the primary benefit of fixed duration therapy is the treatment-free interval, during which patients are not exposed to the potential side effects of ongoing therapy. In CLL, this means avoiding the agents that suppress rapid B-cell expansion, which allow for immune recovery and a reduced risk of infection.

So fixed duration therapies should lower infection risk over time, not raise it. The CLL17 trial studied fixed duration VO and VI versus continuous ibrutinib, and it was presented at ASH a few months ago. The chart on the left shows the CLL17 trial data, which tells a clear and quite concerning story. First, after 1 year of VO, severe infections continue to climb for 3 years while the patient was off treatment, as seen in blue. These infections are serious, often requiring hospitalization and IV antibiotics.

Second, even after 4 years, severe infections were still higher with VO than with continuous ibrutinib despite the 3-year treatment-free period. As a reminder, BRUKINSA demonstrated roughly 1/3 fewer grade 3/4 infections versus ibrutinib in the ALPINE study. The VO arm also showed a 67% nominally increased risk of death versus ibrutinib. These findings are quite consistent with data from other recent studies, such as AMPLIFY, where the AVO regimen was not FDA approved. In fact, the FDA specifically called out the higher death rate due to infections from the AVO arm.

In our view, this profile stands in direct opposition to what patients want and deserve from a fixed duration treatment. And if you now look at the table on the right, for the highest risk patients, roughly half of all CLL patients, VO shows notably lower PFS. This data shows that patients have an approximately 50% higher chance of progressing within 6 years. 50%.

Look, there's a narrative that the current fixed duration options are good. And if someone I love was diagnosed with CLL, my first inclination might also be towards fixed duration. But if I knew the disease had potentially 50% higher chance of progressing within 6 years. And if I knew that fixed duration wasn't reducing the risk of serious infection over 4 years, just accelerating it into the earlier years, I certainly would encourage them to think twice. The risk-benefit profile of current fixed duration regimens simply does not justify a shift away from established continuous BTKi therapy.

The evidence that existing time-limited therapies may not provide long-term outcomes comparable with BRUKINSA continues to build. Here, we can see 3 recently published match-adjusted indirect comparisons of BRUKINSA versus AV, VI and VO, which reached that conclusion. And these reflect the early trends we're seeing in real-world data. Our goal for patients that prefer a fixed duration treatment option is simple. We aim to develop a more efficacious time-limited regimen that does not come with caveats or accommodations. And we believe ZS is that therapy.

The clinical data being generated by combining the best-in-class BTK inhibitor with a potentially best-in-class BCL-2 inhibitor just looks different. With all the caveats of cross-trial comparison, ZS has demonstrated the highest undetectable MRD rate, the highest PFS for the respective follow-up when compared to other ven-based fixed duration therapies. ZS shows a favorable safety profile with fewer high-grade adverse events and no deaths.

And in terms of patient convenience, we've not yet observed any clinical or laboratory TLS, and we're very optimistic that for most patients, only one clinic visit during ramp-up will be required after zanu lead-in. Today, the CLL landscape is roughly split evenly into patients who receive continuous BTK inhibitors and those who receive some form of fixed duration treatment. And currently, BRUKINSA captures approximately half of the continuous BTK segment of the market. ZS will enable BeOne to participate in the other half of the market where today we have no presence.

In summary, BeOne remains the only company with fully owned potentially best-in-class assets across 3 foundational MOAs in CLL: BRUKINSA, sonro and our BTK CDAC. As I said earlier, we think it is time to start talking about a cure. All 3 of these foundational assets, whether it's monotherapy or in combination, represent the next chapter in CLL innovation, raising the bar for patients everywhere.

Now I'll pass it over to Aaron to provide the financial update.

Thanks, John. I'm pleased to share our fourth quarter and full year results as we delivered against all of the financial commitments that we established in the beginning of 2025.

Product revenue reached $1.5 billion in the fourth quarter, representing 32% year-over-year growth. BRUKINSA global revenues totaled $1.1 billion, growing 38% with strong performance across all geographies. For full year 2025, BRUKINSA global revenues were $3.9 billion, representing growth of 49%. And as John shared earlier, BRUKINSA has established itself as the leading BTKi globally by an increasing margin as we closed 2025.

In the U.S., BRUKINSA fourth quarter sales were $845 million, driven by volume growth of approximately 30% versus Q4 2024. Our leadership is directly linked to the differentiated breadth, quality and consistency of BRUKINSA's clinical data, including those shared at ASH 2025. Pricing dynamics in the United States were consistent with commentary provided last quarter with a mid-single-digit pricing benefit on a year-over-year basis.

These results include the previously mentioned typical seasonality benefits seen in the fourth quarter of the year for both current year performance and the 2024 baseline. Meanwhile, TEVIMBRA reported an 18% increase, reflecting continued market leadership in China. This growth was supplemented by contributions from launch markets. Our in-licensed products also showed continued strength, growing 9% year-over-year.

We continue to observe solid execution across geographies. The U.S. remains our largest market, generating $850 million with year-over-year growth of 38% China revenue totaled $399 million, an 11% increase compared to the fourth quarter of 2024, supported by TEVIMBRA and BRUKINSA's market leadership and growth from our in-licensed assets. Europe contributed $174 million, with 53% year-over-year growth as we continue our launch trajectory with BRUKINSA with increased share across all major markets. And Rest of World markets grew 74%, driven by market expansion and new launches.

Now turning to the other components of our GAAP P&L, and my commentary will be on a full year basis, unless otherwise noted. Gross margin improved to 87% from approximately 84% in the prior year. This year-over-year improvement primarily reflects the benefits from favorable product mix, price and product cost efficiencies. Operating expenses grew by 12%, totaling $4.2 billion as we are investing with discipline to support our commercial growth and rapidly advance our innovative pipeline. Income from operations totaled $447 million, showcasing the inflection in 2025 to a company that is at scale and profitable.

Bridging from operating to net income, other income and expense included a nonrecurring $40 million equity investment impairment in the fourth quarter. Income tax expense totaled $130 million for 2025, increasing from $112 million in 2024, including $25 million of nonrecurring tax expenses and $20 million of timing-related tax expenses in certain geographies. These effects, in part driven by our valuation allowance status, disproportionately impacted the fourth quarter. Altogether and including these onetime items, net income reached $287 million in GAAP -- with GAAP diluted earnings per ADS of $2.53.

Our non-GAAP P&L includes adjustments for typical items with a full reconciliation provided in the appendix. Non-GAAP income from operations totaled $1.1 billion in fiscal 2025, up from $45 million in 2024. And non-GAAP net income came in at $918 million for full year 2025, which translates to diluted non-GAAP earnings per ADS of $8.09. We continued our strong trend of cash flow generation with free cash flow of $380 million in Q4. Full year 2025 free cash flow was over $940 million.

Now turning to our 2026 financial guidance. We expect another strong year of revenue growth with continued global leadership for BRUKINSA. We anticipate that the U.S. will continue to see strong demand growth with relatively stable net pricing. Growth is anticipated in all markets and will benefit from continued global expansion in important rest of world markets. We anticipate modest initial contributions from our launches of sonrotoclax and zanidatamab as physicians begin to gain experience with these medicines ahead of launches in their respective larger market opportunities. We are pleased that these practice-changing medicines are becoming available to patients as they fulfill important unmet medical needs.

In total, we project 2026 revenue to be between $6.2 billion to $6.4 billion. As you model quarterly phasing for 2026, please recall that we expect similar seasonality in shipping weeks in Q1 2026 as we observed in Q1 2025. And therefore, we believe it is more useful to consider year-over-year growth rates in this upcoming period. Our GAAP gross margin percentage is expected to be in the high 80% range with continued benefit from mix and a full year of productivity from improvements implemented last year.

Operating expenses on a GAAP basis are anticipated to be between $4.7 billion and $4.9 billion. This level of investment ensures we are positioned to capture the full value of our commercial and late-stage pipeline opportunities. GAAP operating income is expected to be between $700 million and $800 million and non-GAAP operating income is expected to be between $1.4 billion and $1.5 billion. In terms of other income and expenses, we expect expenses to be between $25 million to $50 million. This includes interest expense associated with the Royalty Pharma arrangement.

Turning to income taxes, where we have historically been in a valuation allowance, whereby our accumulated deferred tax assets have a reserve against them. Given our recent history of earnings, we believe that there may be sufficient positive evidence to recognize a portion of these assets in 2026. The exact timing and magnitude are uncertain, but we believe that a potential reversal would result in a material tax benefit to the income tax provision when recognized. When this reversal occurs, we will reflect deferred taxes in our financial statements, and our effective tax rate will become a more meaningful and predictable metric. We will provide additional updates on income taxes throughout the year.

In summary, we are pleased with our performance in 2025 and like our setup for continued growth and financial strengthening as reflected in our 2026 guidance. I would be remiss if I did not take this opportunity to thank our global teams across all parts of BeOne for their incredible dedication to our company's purpose and the corresponding results that can be seen so clearly in our financial performance.

And with that, I'd like to pass the call over to Lai.

Thank you, Aaron. Hi, everyone. Thanks for joining us today. 2025 has been a standout year for BeOne R&D. Most notably, it was a breakout year for sonro. We achieved our first global approvals in China for relapsed/refractory MCL and CLL. In addition, regulatory submissions for relapsed/refractory MCL are under review in both the U.S. and the EU, with FDA approval expected in the first half of this year.

Our BTK degrader continues to advance steadily towards registration. In 2025, we initiated 3 Phase III studies, including a head-to-head trial versus pirto. In solid tumors, we also made a strong progress. TEVEMBRA delivered a positive Phase III readout in HER2 positive gastric cancer in combination with zanidatamab and chemotherapy. Importantly, the next wave of innovation is here. In 2025 alone, 5 assets achieved clinical PoC. And over the past 2 years, we have advanced 17 new molecule entities into the clinic.

BeOne has moved through two defining chapters in our history. In the first 10 years, we built from the ground up. With limited capabilities, we delivered two breakthrough medicines, BRUKINSA and TEVEMBRA and prove that BeOne could innovate at the highest level.

The second chapter over the past 5 years was about scale and readiness. We invested heavily to build a powerful discovery engine and a truly differentiated global clinical development super highway, transforming BeOne from a company with isolated wins into one capable of repeatable success. Today, we're positioned better than ever to deliver a continuous stream of innovation. 2026 marks the beginning of a new era for BeOne.

Over the next 3 years, we are focused on four priorities. First, we will deepen our leadership in CLL, building on our 3 foundational medicines. Second, we'll expand across hematological malignancies, including indolent and aggressive lymphomas as well as AML. Third, we'll establish BeOne as an oncology powerhouse in solid tumors, with leadership in 3 strategically chosen subtypes driven by both internal innovation and external partnerships. And finally, we plan to advance one to two potential cornerstone immunology assets towards registration. It took us 15 years to build our foundational CLL franchise. We believe we can move faster and do even better across other diseases. With greater scale and a sense of urgency, we can reach far more patients than ever before.

In CLL, today BRUKINSA is approved for both treatment-naive and relapsed/refractory patients, giving us a strong foundation. Looking ahead, in the frontline setting, BRUKINSA will serve as the foundational therapy either as continued use for patients who prefer finite therapy as a potentially best-in-class fixed duration regimen in combination with sonro. In the relapsed/refractory setting, BeOne will offer BTK-CDAC anchored therapies, we see a potential accelerated approval opportunity for our BTK CDAC as a continuous use monotherapy as early as next year. There are 3 Phase III studies ongoing to establish strong evidence versus current standard of care.

Beyond that, we believe the BTK CDAC and sonro combination has the potential to deliver best-in-class fixed duration therapy for relapsed/refractory patients with strong efficacy, safety and convenience. A Phase III study is being planned. Finally, we are also developing an alternative fixed duration option, combining sonro with anti-CD20 therapies, currently being tested head-to-head against venetoclax in a Phase III study.

We are also advancing our 3 foundational hematology assets across non-CLL indications. These molecules have demonstrated strong activity across multiple B-cell malignancies, including mantle cell lymphoma, Waldenström's macroglobulinemia, follicular lymphoma and marginal zone lymphoma. We're particularly excited about the Phase III interim analysis for zanu in combination with rituximab in treatment-naive mantle cell lymphoma expected in the first half of this year. If successful, this would represent the first chemotherapy-free regimen in this setting. In addition, we're expanding into multiple myeloma with plans to initiate a pivotal Phase III study in combination with CD38 antibody and dexamethasone by the end of this year.

2026 will also be the year we expand beyond BTK and BCL-2 MOAs in the hematology-oncology. A new wave of assets is entering the clinic, led by our proprietary, off-the-shelf iPSC-derived gamma delta T-cell therapy with 12 genetic engineering modifications. This program is highly differentiated and designed to overcome many of the limitations of the existing off-shelf cell therapies. I'm very excited about its potential in the clinic. In parallel, we're advancing T-cell engagers and T-cell boosters for B-cell malignancies particularly for aggressive lymphomas to address challenges such as tumor antigen loss and inadequate or unsustained T-cell activation.

For AML and MDS, we are building a focused portfolio to address the significant unmet medical need. Beyond sonro, this includes a first-in indication KAT6 inhibitor, supported by strong translational data and a next-generation Menin inhibitor designed to overcome all known resistance mutations. We also have additional undisclosed preclinical programs underway that will continue to fuel our future pipeline. In summary, we have built a hematology portfolio defined by durability, differentiation and depth, positioning BeOne for sustained impact well beyond our current leadership areas. With that, let me turn to solid tumors.

Previously, our solid tumor focus was largely on immuno-oncology. Over the last 2 years, we have fundamentally reengineered the portfolio, shifting towards critical oncogenic signaling pathways across breast, gynecological, lung and gastrointestinal cancers, using multiple therapeutic modalities. As you can see on the slide, we now have more than 20 assets across these focused disease areas. Among them, 5 programs have achieved proof of concept in 2025, and I will walk you through these key assets now.

First, based on strong emerging efficacy and the safety data from Phase I expansion cohorts, we plan to initiate a Phase III trial in frontline hormone receptor-positive breast cancer in the first half of 2026. The safety profile suggests potentially best-in-class hematological safety with manageable gastrointestinal toxicity. The Phase III study will compare BGB-43395 against the physician's choice of CDK4/6 inhibitor in combination with letrozole with progression-free survival by central radiology review as a primary endpoint.

Beyond the CDK4, we have 4 additional solid tumor programs advancing rapidly towards registration, all supported by compelling and evolving clinical data. B7H4 ADC, encouraging activity in gynecological cancers and the triple-negative breast cancer. A Phase III study is expected to start within 1 year. GPC3x41BB bispecific, the strength of the positive data from this program has been a pleasant surprise, showing very exciting monotherapy signals in PD-1 pretreated HCC patients in its first-in-human study. A pivotal trial will be initiated before year-end.

PRMT5 inhibitor, this asset stands out with a potentially best-in-class potency, selectivity and brain penetration. Based on emerging Phase I data, we accelerated this program into frontline non-small cell lung cancer. CEA ADC, we are seeing promising monotherapy activity in heavily pretreated patients and are planning for the pivotal trials.

It is important to note that all 4 assets have been in the clinic for less than 2 years and the 3 for less than 18 months. This is a level of focus, efficiency and execution we aim to deliver across the portfolio. Together, these 5 PoC assets represent a step change in BeOne solid tumor impact with multiple modalities, rapid clinical execution and a clear path to registration, we are no longer building a pipeline, we are building a solid tumor franchise, and this is only the beginning.

To complement our growing portfolio, we have also invested heavily in clinical execution capability. We now call this our global clinical development super highway, designed to deliver industry-leading speed, quality and reliability. Let me give you a few examples. Over the past 2 years, we have completed around 200 dose escalation cohorts across multiple first-in-human studies with a median of just 1.5 months per cohort. The industry norm is roughly 3 months. In late-stage development, last year, we completed enrollment of CELESTIAL TN CLL study with around 700 CL patients across 20 countries and more than 200 sites in just 14 months. And as you know, CLL is not an easy indication to enroll.

On the regulatory side, our most recent NDA filing, sonro's initial filing with the FDA in mantle cell lymphoma was completed within 1 month of top line data. Industry standards are typically 4 to 6 months. Finally, we're equipping the super highways with AI and automation. Today, we can already deliver near real-time data analysis and insights across all early stage clinical trials. Over the next 2 to 3 years, we expect AI and automation to unlock even greater gains in speed, quality and decision-making. This global clinical super highway is a core competitive advantage for BeOne. We look forward to sharing continued progress in future updates.

Very quickly, on 2026 catalysts, I have touched on most of them already, so let me highlight a few key ones I haven't mentioned yet. First, we just initiated a global Phase III study of ZS versus AV in treatment-naive CLL directly comparing two all-oral fixed-duration regimens. Second, in the first half of this year, we expect to file tislelizumab for HER2-positive gastric cancer in combination with zanidatamab and chemo. And finally, in immunology, we anticipate multiple proof-of-concept readouts this year, including BTK CDAC in CSU and IRAK4 CDAC in RA.

I will now turn it back to John.

Thank you so much, Lai, for the comments. Really appreciate it.

I think with that, we're going to jump to Q&A. And operator, please limit the number of questions to ensure we have time to hear from as many attendees as possible, but please go ahead.

[Operator Instructions] Our first question comes from Michael Schmidt at Guggenheim Partners.

I had a commercial question around the BTK inhibitor market and BRUKINSA. Specifically, could you comment some more on how you think about potential net pricing development in the BTK inhibitor market longer term, especially as we see your competitor products enter the CMS drug price negotiation program this year and next?

Yes. Thank you. Nice to hear from you. I think from the perspective in this space, as we've tried to lay out, this is a very differentiated value proposition with BRUKINSA versus any of the current therapies that are on the market, whether it's safety profile or whether it's just the long-term PFS and overall survival. This is, in our mind, a best-in-class product that has demonstrated the translation of its mechanism of action into real clinical results. And I think at this point, certainly, there are challenges for those other products, but we're just standing by the value that the products are creating for patients, and it's there. That's why we're showing it to you.

Can we jump into the next question, please?

Yes, our next question comes from Yaron Werber with Cowen.

Congrats on really a lot of progress. I have a question that I think a lot of us have been getting. In the guidance, what are you assuming in terms of competition from AV or Jaypirca probably sort of late, late in the year? And then maybe secondly, in terms of sonro for MCL, both in China and in the U.S., can you just help us think through a little bit kind of what's in the initial opportunity?

So Matt, perhaps you can answer that a little bit, and then we can jump to Xiaobin.

Sure. Yes. I can provide some perspective on AMPLIFY and then Jaypirca as well. As you know, AVO was not approved. And as we've discussed before, AV, while approved, was studied only in a very young and very fit patient population, which had a median age of around 61. So we think those are some natural limitations there.

Moreover, I think that we continue to be very confident in the clinical profile of BRUKINSA. We've outlined, as you heard from John, the importance of meeting some criteria for treatment in CLL, deep and durable remissions, PFS, safety and convenience. And we see that AV doesn't live up to that standard. Certainly, on MRD and PFS, it's very straightforward with safety and tolerability. I think that situation holds true. And then the convenience is still tied to some of the cumbersome nature of utilization.

Now as for Jaypirca, we have seen some data back at ASH. And overall, that body of evidence doesn't yield the level of compelling data that we think is going to really change the treatment paradigm in the earlier lines of therapy. Particularly, we continue to hear from clinicians that, that evidence does not rise to the level of burning a line of therapy with a continuous BTK and that they will continue to position Jaypirca after the continuous BTKs. And obviously, in our case, that bodes really well for BRUKINSA.

So China approved beginning of this year, 2026. And we launched so quickly after that approval. And since launch, this is about 6 weeks and the reaction in the market has been very positive. We medicated or doctor prescribed for over 300 patients.

And the approved indication is relapsed refractory mantle cell lymphoma and CLL. And so far, the safety profile has been also very good. So no major safety concern observed. So there's a very positive experience from all the major China hematology centers. It looks like very positive. And we are aiming definitely to be a market leader for the BCL-2 market going forward. This two approved BCL-2 in China. One is the venetoclax and another one is China local lisa.

Our next question comes from Ziyi Chen with Goldman Sachs.

Congrats on the results. I got one question on the immunology pipeline you mentioned about. I think this is probably the first time during the earnings briefing, you mentioned about immunology is going to be the next thing out of the 4 pillars you're going to be working on.

So Lai mentioned about there are going to be 1 or 2 cornerstone therapies that you could potentially pursue and move into pivotal studies for immunology. Could you elaborate a little bit more about what's going to be the strategy for the immunology beyond hematology and solid tumor that BeOne already been very strong at? And what's going to be over the next few years, what's going to be the path and a journey towards becoming some meaningful player in immunology?

Please, Lai. And thanks for the question.

Thanks for the question. In our preclinical pipeline, we have roughly about 20% of our assets are focused on immunology. We acknowledge we're still a young player in the immunology space. For us, we're going to be opportunistic, looking for potential opportunity to be the first-in-class or best-in-class. Our goal is in the next about 2 to 3 years to identify 1 or 2 molecules, which we feel like can be a cornerstone assets for us to build around.

So we're looking forward to share with you the updates in the upcoming additional earnings calls. But there are some very exciting molecules we're really developing at this moment. Some of that is already in the clinical stage.

Can we have another question, please?

Yes. The next question comes from Yigal Nochomovitz from Citi.

I just wanted to -- you made some excellent arguments regarding the fixed duration and the inferior options today versus continuous BTK. But I just wonder if you could just clarify, if ZS does become the fixed duration regimen of choice and the standard of care in treatment-naive, could you just clarify how you're not going to sacrifice the long-duration revenues with continuous BRUKINSA? I think that would be helpful to understand a bit better, please.

Sure. Aaron is going to answer to that.

Thanks for the question, Yigal. And you've seen the different forms of the pie chart that John shared in his slides. In the current dynamics, that's a view on the U.S. the dynamics aren't too dissimilar outside the U.S., although fixed-dose treatment for BTK BCL-2 combinations are a bit more mature in Europe.

About half the market is receiving fixed-dose treatment, half is receiving continuous use. And as you saw in that view, we're currently getting about 50% on a new patient basis for BRUKINSA. So what we're trying to state really clearly there is the combination of sonro plus zanubrutinib opens up 50% of the market where we don't play at all today. So from that dimension, and as we continue to mature candidly in our market share within the continuous use class alone with BRUKINSA, we view this as very market expanding.

Yes. I think the promise is there, and we're hopeful that the data translates as positively as we've seen so far. It really could fulfill the promise and the story that's being told now about fixed duration. And were that to happen, that would be a really wonderful thing, but it would place us in a truly, truly unique position.

I think regardless of that for this 50% of the population that is already on fixed duration, if we're anywhere near the data we're showing at this moment, it's just on every one of those boxes, checking what would be required to be a best-in-class medicine. So we're really, really excited about this opportunity. We just need to wait a little bit for a little more data to mature from that perspective.

Our next question comes from Reni Benjamin at Citizens JMP.

Congratulations on a great year and the guidance that's provided. I guess my question is regarding the BTK degrader. You had some pretty encouraging data that was presented at ASH. I thought that there was a potential for an accelerated approval in the first half of this year. I think it's been pushed out to the second half.

Can you just kind of confirm that I'm reading that right? And can you provide some color as to what's causing the pushout and how we should be thinking about the first approval?

Great question. Amit, will you please respond?

Yes. Thank you for the question, Reni. So I don't think there's been a change in terms of the timing and kind of how we're thinking about this. Obviously, this is a single-arm approach.

And so in terms of what we're looking at there is based on a single-arm trial. And so we're following that data and look forward to having the interactions with the FDA midyear and file based on our interactions with the FDA. So there's really no change in terms of the timing there.

Our next question comes from Sean Laaman at Morgan Stanley.

Just trying to understand a bit better the long runway of growth potential for BRUKINSA here. You did $3.9 billion, I think, for the year at around 40% growth. Calquence did -- I think they did double-digit growth to get to $3.5 billion and IMBRUVICA is growing negative mid-teens, but still did $2 billion.

So that's about $3.5 billion where BRUKINSA is not operating, if you like. And clearly winning the battle against IMBRUVICA, but given the compelling data that you have to show best-in-class, what's the tipping point? Or what's the wrestle here to really start eating into that Calquence share?

Aaron, would you like to answer that?

Thanks, Sean. And as we've been talking, we certainly feel very confident in the totality of the evidence for BRUKINSA. And ultimately, the dynamics you're describing in terms of our performance in the marketplace, it's the data that's resonating and ultimately translating to the growth that you've described.

As you look at the market share slide that we showed in the deck, on a new patient share, we're currently getting about 50% of the continuous use BTK market. We are the global market leader, but we're not quite at 50% yet because we continue to mature into that profile. So as you think about the growth for our business is the continued maturation into our growth profile. And certainly, we believe having the best-in-class medicine in the continuous use BTK space, there's more than ample opportunity to continue to grow share over time.

And I think our challenge is really just get people to look at the data. It speaks for itself. That is a portion of the data that we're sharing on this call, whether it's the long-term data, whether it's the head-to-head data, whether it's the combination data versus their combination data, every place you look, the story is the same.

And there's work being done in real-world data from that perspective, too. But I just think it's this overwhelming body of evidence. And that's the challenge. Of course, we're the only person that wants to share that information. The rest of the industry, it may not be in their best interest. But it's really, really important that we share it for patients so that they're getting the best medicine.

Our next question comes from Chen Chen with UBS.

So my question is on B7H4 ADC. And actually, I think this is not in the model or in the valuation right now, but I heard that you are going to initiate Phase III like within the next 12 months. So may I know that's been -- so the clinical trial would be initiated in the first half or the second half?

And also, it has shown some promising efficacy and safety in gynecology and some breast cancers. So may we know like in which indication are you going to initiate a Phase III trial? And also, I think the B7H4 ADC is roughly like at least like 12 months later than our peers, B7H4 ADC. So what are the differentiation of this molecule?

Thanks for the question. Mark, could you address that, please?

Thank you very much for the question. So we're really pleased with the progress that's been made with our B7H4 targeting ADC. This has progressed swiftly through Phase I dose escalation. And as you heard from Lai, we are planning to disclose efficacy and safety data for the dose escalation in the first half of the year at a major medical congress.

We recognize that the competitive landscape that there are a number of competing molecules, both within B7H4 and more broadly within the topo 1 conjugated ADC space, particularly in breast and gynecologic malignancies, which is why we're moving with urgency. I think that we will be able to speak in more detail regarding the differentiation of our compound once we disclose the data.

But suffice to say, we're very happy with the emerging efficacy data and think that we also have a nice safety profile with no target-mediated toxicities beyond what one would expect for a topo 1 conjugated ADC and a good hematologic safety profile. So it's checking all the boxes to be on a path for a Phase III study start as soon as possible. And again, we'll be able to share more details about first indication for Phase III versus subsequent indications for Phase III as we disclose data throughout the year.

Thanks, Mark. And could we take 2 more questions, please?

Yes. Our next question comes from Leonid Timashev with RBC Capital Markets.

I wanted to ask on the BTK degrader development pathway, specifically on the Phase IIIs. I guess, given you're going to have a potential accelerated approval and you're running 3 Phase III studies, I guess, what's the incremental value of each of those studies? I guess do you need ultimately all 3 to fully realize the opportunity? Or do you think you're still going to have rapid uptake as the data starts to flow in over time?

Amit, would you like to answer that question?

Yes. Thank you for that question. I think from a BTK degrader perspective, again, we're very encouraged by the data that we've seen so far. We do think that this is going to really be a foundational treatment as a BTK asset for the future. And in terms of the Phase III, I think we're answering important questions with the Phase III studies that we have right now, particularly with the 2 global Phase III studies. I think one is in a slightly later line with the investigator's choice as the control arm. And then the other study is really a head-to-head study against pirtobrutinib.

And so we do see incremental value, especially from that pirtobrutinib study to be able to show that as far as that population is concerned, the BTK degrader has a really sort of clear role in terms of the monotherapy. And then beyond that, we are obviously, as Lai showed, working on a BTK degrader plus sonro combination as well. And so you'll continue to see us generate more data there.

Thanks, Amit. And are there any more questions? Or should we wrap up now?

We have one more question from Rebecca Liang from Bernstein.

Congratulations on the great results. So you showed a very interesting chart on the patient share between fixed duration and continuous therapies.

I'm wondering how you see the future development between BRUKINSA and sonro. After sonro plus BRUKINSA becomes a viable option. Given that now the fixed duration therapy has half of the patient share, but obviously, much lower commercial sales.

So venetoclax, for example, only selling around $2 billion to $3 billion versus the whole BTK market at around $10 billion because of the limitation of fixed duration in treatment duration. So how do you see the future commercial -- the sales split between the 2 products, even if there's maybe no immediate guidance for the long-term peak sales, but qualitatively, the split between the 2 products?

First of all, I would clarify that although half the patients in CLL in that pie chart are listed as fixed duration, they're not all getting then. There's all sorts of other things, even chemo surprisingly, that is still being given to patients.

So first of all, as we move into that segment of the class, I think ven has been very limited by its usability, especially in the community setting. So I think that having a fixed duration treatment that can replace, I don't know, I'd say, some of these less evidence-based fixed duration treatments in that half that are being used broadly in the community center, I think, is a huge, huge value to patients. And we would expect with the quality of the early data from that, that this really could be a unique product combination within that 50% of the market for sure.

To be clear, there's lots of patients that have different prognosis in CLL. And if we jump back to that, you have deletion 17p in unmutated patients. You also have mutated patients. About half of them are high-risk factor patients. And those patients are hard to handle, for sure. And they're very hard for the current fixed duration therapies to address. I don't have the slide number, maybe someone will flash it to me. But when you go back to the slide that showed on the left-hand side, the infection rates associated with VO. On the right-hand side, you could look at the numbers there. When you look at unmutated patients and deletion 17p patients, really, the outcomes are not good at all. And that's because this is a harder disease to fight.

And our hope is it would be great if our SZ doublet, which is all-oral and easy to use and seems pretty safe, can treat all patients indefinitely, and that's truly, truly a cure. But we don't have long-term follow-up yet on that. I think the early data makes it appear this is going to be better than any fixed duration evidence-based therapy that you've seen to date. But we need time for that all to mature.

And although it could be possible that this therapy even in the highest risk patients is very compelling and can be as efficacious as continuous use BRUKINSA. It's a high bar. It's a really high bar. And you just go back and look on that scatter plot where VO is on the scatter plot versus continuous ibrutinib, which is the comparison that's made in CLL 17. Well, that's not the relevant comparison. The relevant comparison is continuous BRUKINSA which, of course, has much better-looking 6-year data from a patient and physician perspective.

So we need to see how the thing evolves, but it will take time. It will take more than 6 years to understand and establish for those high-risk patients. Is this really something that's as good as and competitive with long-term continuous BRUKINSA use. It'd be great if it is, but nobody can be sure of that.

And anyway, thank you so much for the question. And I'd like to thank everybody for today's discussion. It really marks the close of a strong fourth quarter, and it's a pivotal full year for BeOne. And I think as you just heard, 2025 was defined by really flawless commercial execution and accelerated R&D momentum across our whole business. And I do believe that our performance reflects what truly differentiates BeOne as a company. It's our commitment to scientific excellence, our exceptional speed, our relentless focus on developing the best long-term outcomes for all patients.

And on behalf of everyone here, I really want to thank the broader oncology community, the patients and families who inspire our work, the clinicians who partner with us every day and our almost 12,000 employees all around the world who continue to raise the bar. I truly believe that together, we're how the world stops cancer. And as we enter 2026, we're more confident than ever in the opportunity ahead of us.

So thank you again, everyone, for your time today, and have a wonderful week.

Great. Good morning, everyone. My name is Jess Fye. I'm a large cap biotech analyst at JPMorgan, and we're continuing the 44th Annual Healthcare Conference today with BeOne. First, you're going to hear a presentation from the company, and then we're going to go into a little Q&A. If you are in the room, raise your hand, we can pass you a mic. [Operator Instructions]

But with that out of the way, let me pass it over to the company's Co-Founder, Chair and CEO, John Oyler.

Great. Thank you so much, Jess, and thank you all for being here. It's interesting 44 years. I think I've been coming for about 25 and I really want to say how proud I am of the industry that it's made such an impact in our fight against cancer.

Over this time across a broad range of cancers, the impact on overall 5-year survival has been meaningful and dramatic. And you can see that here. Now we see critical new therapeutic modalities that were months met with skepticism, and they're just beginning to become very important in treating cancer and other diseases. And we're only seeing the tip of the iceberg right now. And this is what makes me really excited about the real impact we can have for patients.

But with that said, there's still a lot to do. 10 million people across the world are dying from cancer every year, 10 million. And that's the reason I'm here. It's the reason I wake up early in the morning. By the way, those of you here early in the morning, thank you for waking up early in the morning to join us in our fight against cancer and fighting for life in this industry. We're really committed as a company to doing this. It's why we changed our ticker to ONC to [indiscernible]. It's why we're relentlessly focused on innovation and on speed.

Cancer is an incredibly formidable foe, but we're not going anywhere. Together as an industry, we're here and we're how the world stops cancer because we must. I'd like you to note our customary disclosures. I'd like to start today with a brief look back at 2025. This was an incredible year of inflection for BeOne. From a financial perspective, we made an important commitment at this conference last year, significant product revenue growth, GAAP profitability and meaningful cash flow generation and we delivered on every one of them, and we're just getting started.

2025 saw our foundational BTK inhibitor, BRUKINSA become #1 both in the U.S. and globally. That's not just a commercial achievement. It's a scientific one. Our long-term data has now raised the bar and set a new standard for efficacy and safety and CLL treatment, which we'll explore further today. And our pipeline made incredible progress in 2025. In heme, Sonro, our foundational BCL2 inhibitor received breakthrough designation and priority review in the U.S. for relapsed MCL. And recently, it received its first-ever regulatory approvals.

Sonro had 4 regulatory approval submissions in total in 2025 and we also initiated 5 Phase III trials across a broader heme franchise. In solid tumors, we saw positive topline results for the Tisle Zani triplet combo in first-line HER2-positive gastric cancer, which showed a clinically meaningful improvement over the standard of care. Six assets achieved proof of concept across 4 modalities and 5 new molecules entered the clinic. These accomplishments set us up incredibly well for 2026 and beyond.

So let's talk about CLL. CLL is a $12 billion in growing market today due to the tremendous therapeutic innovation and improvements in patient outcomes over the past 15 years. But it wasn't always this way and it wasn't this way when I started coming to this meeting. As recently as the mid-2000s, patients with CLL received fixed duration chemo, and the results were poor.

In fact, the median progression-free survival for frontline patients taking chlorambucil was less than 1 year. This chart shows 6-year overall survival on the x-axis and 6-year PFS on the Y-axis. Only roughly 1 out of 5 patients with CLL survived 6 years and 1 out of 10 did not see their cancer progress.

In 2008, bendamustine was approved, and the use of benda plus rituximab became widely used in early 2010, and it provided substantial benefit over the first chemo regimens. As you can see, 6-year PFS increased to 32% and nearly half the patients survived 6 years. So this was better, but still not great.

In 2016, the FDA approval of ibrutinib for frontline CLL marked the first chemo-free option in CLL, and it was a seminal innovation for patients, anchored by data that were superior to chemo, the field switched away from fixed duration therapy to continuous treatment BTK, and this was because it provided the best long-term outcomes for patients. You can see ibrutinib 6-year progression-free survival and overall survival, approximately 61% and 77%, respectively.

At the same time, the field was beginning to explore fixed-duration treatments that were enabled by the discovery of BCL-2 inhibition and the approval of venetoclax. These ven-based approaches greatly improved upon historic chemo-based fixed duration regimens, and they began to approach, albeit with a 10% negative delta in the 6-year progression-free survival. The level that we could see in the long-term benefit of continuous BTK.

However, the VI regimen was not approved by the U.S. FDA and the addition of obinutuzumab to ven has significant safety challenges, which I'll touch on later. As impressive as continuous use ibrutinib was on efficacy, the molecule was not optimized for selectivity and it showed cardiac tox related issues. The second approved BTK inhibitor, acala was designed to address this and to be more selective than ibrutinib and to have a very short half-life, just about an hour with the hypothesis that these changes would translate to a more favorable safety profile, including fewer cardiac adverse events.

And in that respect, acala achieved its goal, it demonstrated statistically significant improvement in AFib in the ELEVATE-RR study. However, in that same study, acala demonstrated non-inferior PFS compared to ibrutinib.

Interestingly, as shown on this chart, acala's 6-year PFS and overall survival of 62% and 76% is nearly superimposable on ibrutinib in terms of efficacy and long-term patient benefit. But the field didn't remain static. The bar set by the first 2 continuous treatments was to be raised yet again, by a differentiated foundational medicine, enter BRUKINSA.

BRUKINSA was designed from inception to be both more potent and more selective than ibrutinib, with complete and sustainable 24/7 target coverage. We took that preclinical hypothesis into the clinic where BRUKINSA demonstrated both superior efficacy to ibrutinib and a more favorable safety profile in head-to-head global Phase III trial.

At ASH 2025, BRUKINSA set a new bar for long-term outcomes for patients with CLL. Here, you can see 6-year progression-free survival and overall survival of 74% and 84%. If you adjust for COVID, those are 77% and 87%, respectively. With these data, BRUKINSA has established the foundational standard against which all future regimens must be compared. And the long-term outcomes for patients and physicians should expect and demand these type of results. As I'll discuss later, we really do believe in the promise of fixed duration treatment, but not at the expense of PFS, of OS and of safety. These data are the data that every oncologist, every health care professional, policymaker and patients should see and discuss when they're facing a treatment.

At BeOne, we're relentlessly focused on developing innovative medicines that develop the best long-term outcomes for patients. Because behind each one of these data points, actually our lives. This is Lynn. I had the privilege of meeting her last year. Lynn was diagnosed with CLL 6 years ago. Her specific type is Deletion 17p, which is high risk, which traditionally had meant much poorer outcomes prior to BRUKINSA. Over half of all CLL diagnoses are considered high risk. And for these patients, fixed-duration treatments have not shown to be as efficacious as continuous therapy.

Lynn is thriving today, thanks to continuous BRUKINSA. She's a loving partner. She's a mother, she's a grandmother. And from my perspective, she's a real force to be rocking with. Her journey reminds us that behind every innovation are real people and their lives and the lives of their families are changed. Lynn's gratitude and resilience continues to inspire the team every day. And it's because of her in thousands of patients that are similar that we get up early every morning, and we fight with all we have for every improvement possible against this disease against progression and against side effects. Lynn's story is why we all do what we do.

At BeOne, we believe true innovation comes from improving upon the best. Here on the left, you can see the Kaplan-Meier curves from the ALPINE trial of BRUKINSA versus ibrutinib. It's in relapsed/refractory BTK naive CLL patients. In the ALPINE trial, BRUKINSA separates from ibrutinib and remain separated with a hazard ratio of 0.69 and a p-value of 0.001, which demonstrates statistical superiority over PFS.

When we presented this initially, the early cut of this data to the CLO community, the universal feedback was nice data, but we need longer follow-up. And there were 2 important scientific reasons for that. First, ibrutinib was known to have tolerability issues that could potentially influence patients' ability to stay on therapy during treatment.

And secondly, the ELEVATE-RR study acalabrutinib showed some early PFS separation from ibrutinib, but that separation was not sustained. As you can see on the right, acala crossed over and became numerically worse than ibrutinib at roughly 33 months. ELEVATE-RR ultimately reported a hazard ratio of 1 and its last reported data cutoff with September 15, 2020.

While early separation was an encouraging signal, the CLL prescribers wanted to see sustained separation with longer follow-up to be convinced. And you can see that in ALPINE BRUKINSA's longer follow-up, showed exactly that. After these data were presented, the adoption of BRUKINSA began in earnest. We continue to present data from this study, including the 6-year follow-up at ASH in December, a month ago. That brings me to pirto, a noncovalent BTK inhibitor, which recently reported data from its head-to-head trial against ibrutinib in CLL.

On the right, we see the curves from the relapsed/refractory BTK naive cohort of BRUIN 314. And this comprises of 2/3 of the patients enrolled in that trial. Importantly, the curve shown here for both studies were all assessed by Independent Review Committee or IRC. And this is the global regulatory standard for all oncology trials. It's the global standard because it corrects for potential bias associated with investigator-assessed outcomes in an open-label study such as these. In both studies, the IRC PFS was also the predefined key secondary endpoint to demonstrate superiority over ibrutinib.

You can see that with pirto with only 18 months of follow-up, it does not show meaningful early separation versus ibrutinib. There's a hazard ratio of 0.845 and a p-value of 0.41. Just look at the data. With the caveat of cross-trial comparisons, there was roughly a 12% separation at 24 months for zanu in Alpine, which was sustained roughly a 5% to 6% at 24 months for acalabrutinib in ELEVATE-RR, which was short-lived and roughly 3% and for pirto at 18 months in BRUIN 314. So we certainly need longer-term follow-up data for BRUIN 314, but based on the minimal early separation in these short-term curves, pirto may face quite an uphill battle in showing statistical superiority to ibrutinib on PFS.

Let me switch to safety because part of the hypothesis around this molecule was a safer molecule. From a safety standpoint, the data are similarly underwhelming. Despite their hypothesis, pirto did not show a meaningful safety difference versus ibrutinib across clinically important metrics such as infections, cytopenias and AEs leading to treatment discontinuation and ibrutinib is the least selective of all the covalent BTKs.

In contrast, as you see below, BRUKINSA has consistently shown long-term safety benefits versus ibrutinib. Taken together, the efficacy and safety data do not support moving pirto beyond the relapsed setting, where it currently does play a much-needed role for patients that have progressed on covalent BTK inhibitors. We do believe the next chapter of CLL innovation will continue and will come from options that address unmet needs and deliver on the best long-term outcomes for patients. There's a clear desire from patients and physicians for fixed duration first-line options that will provide a break from treatment.

For fixed duration therapies to change the treatment paradigm, they must elicit a deep response, demonstrate sustained progression-free survival, be safe with only minimal infection risk over continuous BTKI and be convenient to administer.

And we would argue they must now be compared to the foundational CLL medicine, BRUKINSA. These criteria are not being met by the current fixed duration options. Existing ven-based BTK regimens have liabilities that have limited their uptake in approval. These include underwhelming efficacy as demonstrated at ASH 2024 with the AMPLIFY trial where the AV combination actually had inferior depth of response, UMRD, to its comparator, chemo, and which may result in patients being treated for much longer than 1 year.

In this respect, the absence of longer-term data from AMPLIFY at ASH this year was quite noteworthy. And similarly, with respect to safety, the VI regimen contains ibrutinib, which is cardiotoxic. As a reminder, neither AV or VI regimens are approved in the U.S.

Lastly, then as a convenience challenge due to its long half-life and TLS risk, which requires cumbersome patient monitoring. At the highest level, the primary benefit of fixed duration therapy is the treatment-free interval during which patients are not exposed to the potential side effects of ongoing therapy.

In CLL, this means avoiding continuous BTK agents that suppress rapid B cell expansion, allowing for immune expansion and a reduction of risk of infection. So fixed duration therapies should lower infection risk over time, not raise it. The CLL 17 trial presented at ASH this year, studied fixturation VO and VI versus continuous ibrutinib and was presented last month. The chart on the left shows this trial data which tells a clear and quite concerning story.

First, after 1 year of VO, there was roughly a doubling of severe infections and these continued to climb for 3 years, even while the patient was off treatment. It's seen in blue. These infections are serious, often requiring hospitalization and IV antibiotics.

Second, even after 4 years, severe infections were still higher with VO than with continuous ibrutinib despite the 3-year treatment-free period. This is potentially because Obin, a CD20 directed monoclonal antibody has shown to cause prolonged depletion of both B cells as well as some populations of T and NK cells. And thus, it may severely impact the overall immune function.

In contrast, rather than destroy the B-cells, the BTK inhibitors prevent the B-cell proliferation by blocking BTK, a key signaling node in the cell activation pathway. The VO arm also showed 67% nominally increased risk of death versus ibrutinib. These findings, they're quite consistent with data from other recent studies, such as AMPLIFY.

In our view, that profile stands in direct opposition to what patients want and what patients deserve from a fixed duration treatment. In contrast, in ALPINE, BRUKINSA demonstrated 2/3 the rate of grade 3/4 infections versus ibrutinib. And if you now look at the table on the right for the highest-risk patients, IGHV unmutated, or deletion 17p, roughly over half of all CLL patients VO shows a notably lower PFS.

In summary, the risk-benefit profile of VO simply does not justify a shift away from established continuous BTK therapy. We do believe the next innovation in frontline CLL will come from combining our best-in-class foundational medicines. BRUKINSA plus a better design, more potent and selective BCL-2 inhibitor, sonrotoclox. As you can see in this slide, this combination checks all the boxes and it's poised to be the first regimen that delivers truly on the promise of fixed duration.

Our confidence in ZS is based on the totality of clinical data. But there's key aspects of the data that we find exceptionally compelling. Here, you can see the undetectable MRD rates and time to blood MRD from our Phase I trial which was presented at ASH last month. All of the data from our heme franchise is generating, these might be the most compelling when they're shown to KOLs with whom we meet.

Let me explain. First, the combination of ZS can drive very high rates of deep response. Secondly, and perhaps most impressively, it does so exceptionally quickly with kinetics previously unseen in any other trials of drugs targeting similar mechanisms. This type of deep response is what we're looking for in fix duration regimen to give physicians and patients the confidence to stop therapy and to still achieve positive long-term outcomes.

The CLL landscape is roughly split evenly into patients who received BTK inhibitors and those who receive some form of fixed duration treatment, whether ven-based CD20 chemo or other. We believe that ZS will fundamentally change the treatment paradigm for patients who want effective therapy without lifelong treatment. This will enable BeOne to access a segment of the market that we previously have had no presence in. And therefore, we view this as a market-expanding opportunity relative to continuous BTK BRUKINSA.

Innovation in frontline CLL is vital, but we must also address the growing unmet need in relapsed setting. While pirto has been successful in addressing the C481 mutation. Over time, we've learned this is just one of many potential mutations that can occur. Therefore, we've pioneered fundamentally a new modality, our first-in-class BTK-CDAC to address this important patient unmet medical need. This CDAC is both first-in-class and best-in-class, and it leads the way in the next novel foundation modality related for relapsed CLL.

Regarding its potency, as shown on the left, we observed similar DC50 and 90 values for our BTK to the nearest competitor molecule in head-to-head BTK degradation assays in both human and whole blood B cells. We also have shown complete target degradation at 1/4 of our moving forward dose.

And we believe that our BTK-CDAC holds a clear mechanistic advantage in terms of BTK mutation coverage, which is shown on the right. The robust clinical activity that we see with this molecule in heavily pre-treated patients is extremely exciting.

In our Phase I trial, the BTK-CDAC demonstrated an overall response rate of 86% with a median follow-up of 18 months, and the 12-month PFS is now mature at 79%, a very favorable profile compared with pirto in a similar patient population. These data from the -- form the base of our confidence in our ongoing phase III head-to-head trial versus pirto in relapsed setting and we believe this program can redefine what's possible for patients who relapse after BTK therapy.

In summary, BeOne is the only company offering potential best-in-class foundational medicines for every CLL patient type, and we'll continue our relentless approach to fighting CLL and other heme malignancies. 2026 promises to be a milestone rich year for our foundational heme franchise. We expect Phase III data from the BRUKINSA Mangrove trial in frontline MCL. We're really excited about that. And the first U.S. approval in relapsed MCL and initial global launches for Sonro. We expect accelerated approval submission for our potentially pivotal Phase II BTK-CDAC trial in relapsed CLL. And in addition, we're planning new Phase III trial initiations and multiple exciting new molecules will enter the clinic.

The BeOne story starts with CLL because it's an illustrative example of how our capabilities have come together to create significant patient impact. CLL is just the first case. But I'm here to tell you the next wave of BeOne innovation, it's already here.

In the last decade, we've become a scaled, proven and highly efficient R&D powerhouse. Our R&D team now comprises of about 4,800 people, making us one of the largest oncology-focused teams worldwide. We have deep expertise in designing small molecule inhibitors and biologics and our emerging leaders in protein degradation buy and tri-specific antibodies and ADCs. The sheer output of our research organization is remarkable, and it places us among the most prolific in the industry, irrespective of market cap. For example, in the last 18 months alone, we put 15 new molecular entities in the clinic. But it's not just numbers, each molecule has differentiated therapeutic hypothesis with best-in-class and first-in-class potential. And with our capabilities now at scale, we have the ability to deliver between 8 to 10 NMEs into the clinic each year.

I'm frequently asked, what's the part of the BeOne story that's not yet widely appreciated. And for years, I'd say, it's the huge competitive advantages and capabilities that we're investing in and building. But now I think that's much more understood when people see our speed, our cost, our productivity. But today, it's certainly the untapped potential value of our pipeline. This chart helps illustrate that point. We believe that BeOne is punching well above its weight from a pipeline productivity perspective.

In our third quarter earnings call, we highlighted 4 solid tumor programs achieving proof-of-concept in 2025. These include the CDK4, B7-H4 ADC, PRMT5 and GPC3 4-1BB. Today, I'm happy to add a fifth program, our CEA-ADC. Each of these programs has achieved clinical proof of concept with key potential differentiation and they're moving rapidly into late-stage development. Each represents a significant market opportunity and each will have external data catalysts this year.

At BeOne, we aspire to become the world's leading oncology company. And in our relatively short 15-year history, this lofty goal is becoming a reality before our very eyes. BeOne was purpose-built to discover, develop and deliver breakthrough medicines to more patients faster and to do so sustainably and at scale. We analyzed each step of the drug development ecosystem, optimizing for speed, cost, quality and scale. It wasn't easy. It took a tremendous amount of capital and human effort, but it certainly was worth it.

Because today, our fully integrated in-house model is a truly unique strategic advantage, both for our internal innovation and also for our external partners and collaborators. We call this capability, the BeOne Global Development Super Highway.

When you consider that clinical trials comprise the vast majority of the time and cost to develop medicines to patients, it's very surprising to me that the traditional industry model outsources clinical development to CROs. We took a different approach. From the beginning, we believe that this and manufacturing should be a core capability, not something to be outsourced.

So we built an integrated global organization of nearly 6,000 colleagues across clinical development and manufacturing. What's the secret? How do we accomplish it all? It's that we have people that are dedicated and motivated and driven to action. It's that we're delivering innovation at a pace that is comparable to the largest MNCs in the industry. It's that we're able to have fast proof of concept, which is the most important value inflection point in our industry. It's that we're able to be decisive and prioritize the most impactful and differentiated medicines that we have. And it's that being internal, we can move fast.

We can employ technology and enroll patients at a speed if you can. The results overall are unquestionably incredible. These are a few examples of how the global super highway enables industry-leading execution across development and registration. Over the past 2 years, we completed 200 dose escalation cohorts with a median time of 1.5 months per cohort.

We've spoken a lot about the exciting data being generated by ZS, while we enrolled 700 patients in the Phase III CELESTIAL trial in just 14 months across 20 countries, and we achieved the U.S. Sonro filing in record time 2 months from data cutoff and 1 month from the top line data. I'm often asked, how can we enroll patients so fast? This slide shows our global infrastructure that enables geographically diverse patient enrollment at greater speed.

The trials enrolled are with global intent and are designed to meet specific agency requirements such as the FDA's Project Optimis. This is one of the many areas we've optimized that leads to time advantages compared to traditional CRO-based model for drug development. And from a financial perspective, we're in a strong position. We generated over $350 million in free cash flow in Q3, and we have a solid balance sheet with over $4 billion in cash.

We've proven we can scale globally and that we can do it profitably. From a capital allocation standpoint, we'll continue to invest in commercial assets across geographies that drive profitable growth. We'll continue to fully invest in our prolific and innovative pipeline to maximize long-term value for patients and shareholders. And we'll continue to pursue value-creating business development, including opportunities that leverage our global development superhighway.

I started my presentation today with how proud I am to be part of an industry that's made such an impact in its fight against cancer. And yet, I think all of us can agree it's simply not enough. That's why at BeOne Medicines, 2026 isn't just another year on the calendar, it's another promise. A promise that we'll keep pushing boundaries, will keep relentlessly innovating and we'll deliver therapies that can truly transform lives. Every breakthrough, every trial, every molecule in our pipeline is a step closer to a world where cancer is not a life sentence, but it's just a challenge, which we can overcome.

For the sake of all patients like Lynn and the 10 million more who simply want to be, we must all fight together as one. Thank you.

So considering the breadth of the company's pipeline, what's the framework that you use to make decisions regarding what to resource?

I think that one of the things we're trying to do is have a very, very robust early set of opportunities that we can prioritize from. Because it's hard when you're a smaller company to prioritize and stop programs that are initiatives. From that perspective, we invest heavily in the early stage of research and development which most of the industry does not. And then we try to apply a much higher hurdle rate. That hurdle rate is the traditional things that companies think about the commercial opportunity, the patient opportunity, the competitive landscape.

But in all of those frameworks, I think having many more things to prioritize, you do stop a lot of things, but it lets you set an incredibly high bar, which has led so far to assets in the clinic that are very, very compelling.

And maybe kind of related to that kind of prioritization, right? So with the company transitioning to profitability, from here, how should investors think about the potential for margin expansion? And kind of what's the time frame over which BeOne could achieve margins on par with other global large caps?

Well, my exceptional CFO doesn't provide long-term guidance, but has communicated very clearly a dual mandate of the company. One is growth but the other is margin expansion over time. And I think, although in doing that, we do have the benefit of a time with incredible breakthroughs, all of these new technologies. We have this incredible team and this advanced and advantaged global super highway. And we want to think about the right ways to create long-term value with that.

So those are things we bear in mind, but we're committed to those 2 concepts in the framework of let's help patients and let's do the right thing for the long term.

Okay. And then you spent a lot of time in the presentation talking about kind of the data in CLL we just thinking about the kind of the volume opportunity for the BTKIs in CLL. And what does that look like from here?

Well, I think we've talked about the industry currently being $12 billion, $13 billion and growing. I think we do see, as fixed duration, options come to market, which we believe ZS will be that actually do meet the requirements that can be much larger share. We think this is a very unique combination that is likely to have data that so far, no one has any data that looks anything like it.

So from that perspective, that expansion into that setting, where there's a lot of fixed duration treatment right now that probably isn't as efficacious that probably isn't as high priced, there's a real expansion opportunity there. At the same time, I think in the fundamental continuous BTK therapy space, we still are -- we're the #1 player, but we're sharing the market with 2 other major players. We've crossed over and will continue in our mind, given the data to expand in that segment, too.

And then just thinking about kind of Sonro and how it fits into your CLL strategy and the pie chart you showed that was kind of like half fixed duration, but 1/4 is sort of other. Do you need Sonro in a fixed duration combo to crack into that half of the market? Or like is that only accessible with a fixed duration option? Or can you get there with mono BRUKINSA?

Look, I think mono BRUKINSA looks different as we showed with the long-term data than the other continuous BTKIs. I think that data alone, if you didn't have Sonro, it starts to raise some questions about some of the fixed duration treatment that you've seen in the past. There's reasons why you'd make that choice over ibrutinib if the cardiotox isn't there, if the PFS and OS long term looks better, I think it does, again, change the bar and it may change that decision-making process.

It certainly would, in my mind, if I were a patient. So yes, I think there's continued opportunity there.

Maybe switching gears a little bit. What gives you the confidence to pursue a frontline trial for BGB-43395?

The reason that we have that confidence, I think, is the data that we have collected and generated in the first-line setting. We haven't presented that data because it was too immature yet at a scientific meeting. So it's what we're seeing from that perspective and the conversations we're having with KOLs. As we've said, we're going to share that data at a scientific meeting in cancer as soon as we can. But I think we have the confidence to tell the investment community we're moving in that direction.

Something to watch out for. And it looks like we're out of time. So we're going to stop right there. And thank you, guys.

Thanks, everyone, for coming early, appreciate it.

All right. Good afternoon, everyone. Thanks for joining us here for Jefferies Global Healthcare Conference in London. My name is Clara Dong. I'm a biotech analyst here at Jefferies. So it's my absolute pleasure to have the BeOne team here joining us here on the stage.

We have CEO of BeOne, John Oyler; Aaron Rosenberg, CFO; and Mark Lanasa, the Chief Medical Officer of Solid Tumor. Welcome.

So it's been a really eventful year for BeOne, I have to say, with your name change, achieving profitability and BTK inhibitor BRUKINSA is now leading the global revenue. And I have to say BeOne is probably among the fastest-growing biotech companies today. So for those less -- might be less familiar with BeOne, can you talk about what makes BeOne's strategy and development platform or infrastructure very unique for enabling those milestones here?

Sure. Thank you for the question, and it's a pleasure to be here again this year. Very exciting times. We are a company that from the beginning, decided to do things quite differently. And we felt if we really want to transform the way medicine is made, have more attractive R&D returns, we needed to change the way we did things. And the vast majority of the money spent to make an oncology medicine, and we fight cancer is really spent in clinical trials, probably 75% to 90% of the cost of the medicine delivered to a patient.

So as a result, we from the beginning had a plan to go out and build our own infrastructure. And today, we have what we call the BeOne Global Super Highway, which is about 6,000 people all over the globe, 2,000 in manufacturing, 4,000 in clinical trials in 40 to 50 countries all around the world, running our own trials. So we're not working with third parties in the same way. And that lets us be faster. It lets us go places. They're less interested in or they aren't, and it lets us collect high-quality data quickly and cost effectively. I think this is fundamentally very different than almost any company in the industry. And it's very, very unique to us.

From that perspective, we also have a strong research team. We're very science-based. We put 16 new molecular entities in the clinic in the last 2 years, and we expect that to be increasing, not decreasing over time. And from that perspective, we have great products that are late stage in hematology, BRUKINSA, which is a wonderful commercial medicine already for patients with lymphoma, but then we're in earlier stages in solid tumor and doing a little bit in I&I. So that's a little bit about our company.

And since you mentioned the R&D capability, I mean, BeOne has built a really extended pipeline across multiple modalities, small molecules, degraders, ADCs and anything I can think of across oncology areas. And what gives you confidence that BeOne can remain highly competitive across all those areas?

Well, we're in a lot of the modalities, but not all. We haven't been a major player in CAR-T or radiopharm or cell and gene therapy, some other areas, we've been less focused on. But clearly, we've built with great scale in many of these areas. In protein degradation, I think we are probably one of the most prolific R&D companies in the world with 3 programs in the clinic and I think 20 preclinical programs at this moment.

From the other perspective in biologics, as I had mentioned, we build our own manufacturing, which gives us the ability as we're doing R&D and even are to be able to leverage that and move quickly and cost effectively. We learned that the hard way by working with third parties, and we really struggled to do that. It was slow, and it was very expensive. But as a result, we're doing a lot in biologics, a lot of bispecifics, trispecifics or ADCs. And by ADC, it doesn't have to be a toxin. Your payload could be something else. It could even be a degrader. So I think we do feel like we're able to do a lot in research in these areas, be very strong. And in addition to that, when they move forward into the clinic, because we've built this BeOne Global Super Highway that has got cost and time advantages that we really can pursue these and understand what's working and what isn't and triage and wind up with some incredibly impactful medicines for patients.

And as a global company, you're operating in many, many regions and your drugs are selling across the globe. And maybe could you break down the geographic diversity of your revenue base? And what kind of efforts are you making to kind of further expand the company's global footprint?

Great. Thank you for the question, and we're very proud of the financial performance for the company in 2025. We've talked about this being an incredible inflection point, and that's really showing itself across the financial profile. With respect to the globalization of our business, where we sit today, if you look at Q3 results, which we just announced, more than 50%, I believe it's 52% of our business is in the United States. We are growing significantly with our European business that printed a 71% year-over-year growth and now accounts for 12% of sales. And we're growing even more rapidly in rest of world countries with 133% year-over-year growth in the third quarter in many important markets like Japan just coming online earlier this year. So we continue to globalize. I'd expect over the longer horizon, we will continue to have a profile that looks very much like any major biopharmaceutical that's in a mature phase.

And maybe a relevant question is maybe talk about your manufacturing scale across the globe as well.

Sure. So we certainly have, as John mentioned, significant operations from a manufacturing perspective. We do follow a regional model that includes significant investments in the United States, where we have investments and partners for our small molecule production as well as the investment that we made in our biologics facility just outside Princeton, New Jersey, where we invested more than $800 million. It will be the future home of our production for TEVIMBRA, our PD-1 for the U.S. and other markets around the world.

Great. And let's now talk about your CLL franchise, which is really a key pillar of BeOne story here. So maybe could you provide a high-level overview of your CLL strategy? And then what's your really ambition in CLL? What's your vision?

I think in CLL, our vision is to make the best medicines and be able to provide the right treatment for any patient with any type of CLL at any stage. From that perspective, we have 3 important medicine or potential medicines in this space. Our BTK inhibitor, BRUKINSA, which is approved and which I think, as we mentioned, is the #1 revenue-generating BTK in the world. It is a molecule that was designed to be in all disease compartments 24/7 a day with superior PK, high potency, high selectivity. And the belief was if you want to fight cancer, you're better off sustainably inhibiting at every moment and preventing that cancer from growing. That data is broad and impressive.

And most recently, our ASH abstract published, which shows the 6-year data and 6-year follow-up for BRUKINSA. It's 74% milestone PFS, which is double digits better than results previously reported by any monotherapy BTK in this space. So it's really impressive data. And that's the PFS data. The OS data is quite similar. So we're very excited to share that later this year, but it's consistent with everything we've seen. We've run a head-to-head with ibrutinib. It showed superiority. One of the other BTKs ran a head-to-head, it didn't. And actually, at the time the study was last reported, it was numerically worse. So I think from that perspective, we believe this is the continuous therapy treatment of choice already. It's established from that perspective. And there's a breadth of data, including the data we'll report at ASH, including lots of real-world data. But the more you look at it, the clearer it is that, that hypothesis was a strong one.

From the other perspective with our BCL-2, we've shared some data about its kinetics. And basically, when you look at its speed and depth of MRD negativity, so your inability to measure CLL in blood, what we've seen is a much faster and deeper response than we've ever seen with a venetoclax set of combinations with a BTK. And roughly in a 6-month period, you can see a deeper response than in 15 months with, say, AV or IV, for example. From that perspective, once you have a year's worth of treatment, the 15-month full course, you're seeing a much, much deeper response. And it's not just in the mutated population, which traditionally is the population that the venetoclax-based therapies have done well in. It's also in the unmutated population, which that has not been true for.

So from that perspective, it really looks like this is a combination that can do things that other fixed duration therapy hasn't. And that's really important because right now, only half the patients are getting continuous therapy in first-line CLL. And roughly half of those patients, maybe a little less are on BRUKINSA today. So as we think about this combination, it really lets us broaden that. I think 20% of patients are on venetoclax or combinations thereof in the first-line setting. So it really is helpful to this franchise. But more importantly, with the data, the way it looks, I think it's going to be very, very helpful to patients.

The third piece of our CLL franchise is our BTK degrader. And we're really excited about this because the covalent BTKs have similar mutations. They overlap, there's some differences. But there's a noncovalent medicine, pirto that was developed to kind of try to address some of these mutations. And it doesn't address all of them, but it addresses some. And it's approved in relapsed/refractory setting. The beautiful thing about the degrader mechanistically is it looks like it has much broader applicability and so we also have a lot of early data in the second- and third-line settings from that perspective, which compares extremely favorably with the pirto data. And a year ago, almost a year ago, we announced we'd be starting a head-to-head study against pirto. And so that's in progress from that perspective. And we're very excited about that for relapsed/refractory patients. And then again, there's many other combinations from these. So really, we're incredibly excited about the prospect for CLL patients and our ability to help them no matter what their subtype is or what their line of therapy is.

I see you are talking about the fixed duration regimen here. So I want to talk about your kind of clinical strategy for running Phase III head-to-head trials versus standard of care with both BCL-2 Sonro and BTK degrader. Maybe just talk to us about why are you running those Phase III head-to-head trials? And why is this strategy so important?

I think we also ran BRUKINSA against ibrutinib. It's because the data supports it and because that's the fundamental question that matters to patients. So we're not afraid of that. And of course, we analyze the risk, and we're not wild cowboys taking stupid risks. But when you look at the data that exists and that is in hand, those are very warranted studies. And we're running our BCL-2 sonro plus BRUKINSA against VO. VO is good. Other people didn't do that. We're running against that despite the fact it's a high hurdle. We're doing it. We're running against AV. I'm sorry, against -- we're running against pirto with the degrader. We're not afraid to do these studies because the data supports them.

By the way, if you are successful in those studies, it ends all the questions. It ends all the nonsense about it. You've shown you're the best medicine. The commercial market is there, and it's clear for you. And I think that we've done that historically in the company. You'll continue to see us do that where we find it warranted, and we're excited and happy to be doing that. I think from the other perspective, in the CLL space, the only thing we ask is for people to look at the data, it's so clear when you actually look at the clinical data. There's been a lot of noise about fixed duration therapy. There was a lot of noise about the recent data, it's not that recent, -- the data that came out over a year ago, which was the combination of acala plus venetoclax. This is going to sweep the market. It's going to take the whole market.

Well, it was supposed to be approved 6 months ago, we're waiting on the data. We haven't seen the follow-up data. The approval in the United States has been delayed. In Europe, it was approved. But in that study, the milestone PFS at 3 years, which is only 21 months off therapy, the first 15 months you're on therapy, it's pretty close to our 6-year milestone data that I just mentioned. And we're fighting cancer. Patients want efficacy when they have cancer. And so I think that all we ask is people look at the data. Clinicians look at the data, patients look at the data, you all look at the data. We think it's, at this point, increasingly clear.

And maybe if we can talk about the time line for sonrotoclax and BTK degrader to enter the market globally. And then how should we think about the CLL market in the long run? Do you think the BCL-2 inhibitor and BTK degrader will actually expand the CLL market?

Thank you, Clara. Yes. So our expectation is that we'll be presenting data at this year's ASH for sonrotoclax and our expectation is that will lead to initial approvals in the United States and globally for sonrotoclax in 2026 and that we have potentially registrational cohorts that are enrolling for the BTK degrader that could enable a first market approval for the BTK degrader in 2027. So these molecules will be coming soon. And we think that, as John was saying, this will present an option for patients despite or regardless of what molecular subtype they have and regardless of where they are in their patient journey.

And then beyond CLL franchise, you also have a very, very broad pipeline in solid tumors. So I also want to talk about that. And across your solid tumor programs, I mean, we hear a lot of discussion on the CDK4 inhibitors, and you did commit to initiating a Phase III trial in the frontline HR-positive/HER2-negative breast cancer next year. So maybe just talk to us about what you've seen with your CDK4 inhibitors and to support your -- such a rapid development path.

So it's a very exciting time within the solid tumor portfolio. As John mentioned, we brought 16 new molecular entities into the clinic over the past 2 years, the majority of them in the solid tumor space. At the earnings call that we just had, we highlighted 4 programs that we believe are progressing towards a Phase III study start, not only the CDK4 but also PRMT5, B7-H4 ADC and our GPC3 x 4-1BB bispecific. For CDK4 specifically, we have enrolled cohorts of patients in the frontline setting as well as the second-line setting and frontline, it's in combination with letrozole. What we're seeing in that patient population is a high response rate higher than what one would expect for the approved CDK4/6 inhibitors. And we think that, that will pull through to ultimately have improved PFS. We are intending to start a Phase III study for our CDK4 inhibitor in the frontline in combination with a nonsteroidal aromatase inhibitor, which we believe will show superior PFS over the currently approved CDK4/6 inhibitors. That study will start by the end of the first half of '26.

And you just mentioned other preclinical and early-stage clinical products in your pipeline. So maybe talk to us about what's the differentiation of your PRMT5 inhibitor as well.

So for all of the medicines we bring into the clinic, our aspiration is to develop first-in-class and best-in-class medicines. And to do that, everything that we bring forward needs to have what we believe is substantial preclinical differentiation that is reasonably likely to yield clinical differentiation. So in the case of our PRMT5 molecule, what that means is that preclinically, we have the most potent PRMT5 inhibitor of any clinical stage asset. This greatest potency also leads to the greatest selectivity. And critically, it was designed to be CNS penetrant, which we view as a really essential characteristic, particularly in non-small cell lung cancer, where, unfortunately, CNS metastases occur in about 30% of patients.

So that molecule is off to a great start. It's only been in the clinic for 10 months. But again, using our development super highway, we've enrolled over 100 patients in approximately 10 months' time. We're seeing responses across multiple tumor types, including non-small cell lung cancer, pancreatic cancer and other less common tumor types.

And maybe we can also touch briefly on your BTK degrader platform. I mean this platform is highlighted by a very promising data in BTK degrader. So you also have a KRAS degrader and EGFR degrader. So maybe talk to us a little bit about those 2 programs as well.

So as you heard from John, we're very excited about the data that's emerging from our BTK degrader. We've initiated Phase III studies. We also have an IRAK4 degrader, which we recently disclosed has met its clinical proof of concept with high target degradation in target tissue of skin. We think that this is a potential first-in-class molecule for I&I indications and recently started a Phase II study in rheumatoid arthritis. We're very excited about degraders as an entity because of their catalytic mechanism of action that has advantages over small molecule inhibitors, which require a one-to-one stoichiometry to inhibit specific enzymes.

So as you mentioned, we have an EGFR degrader that's in the clinic that's progressing well. We've disclosed other targets. For example, we have a CDK2 degrader, which should enter the clinic by the end of this year and provides another opportunity to hit CDK2 in a differentiated way that can be combined with our CDK4. And we also have a pan-KRAS degrader coming forward, which we think mechanistically is very attractive in KRAS because amplifications could be a mechanism of resistance. So by actually removing the protein, you can prevent amplification, you can prevent conversion from the off state to the enzymatically on state.

And then with such a broad pipeline, maybe a question to you, Aaron. How does BeOne invest in R&D and kind of balance your internal invest in R&D versus maybe outside asset acquisition or BD activities?

Sure. Thank you. So we're very pleased with how our financial profile and particularly our balance sheet has evolved over the course of the year. We continue to operate against 2 mandates. One is we are a high-growth oncology company. On the other hand, we will do so in a sustainable way. And you see that in our financial performance. In the beginning of the year, we committed to GAAP operating income and cash flow generation for the year. If you look at our Q3 results with $125 million in net income and $354 million of free cash flow, I think we're well underway to achieve those goals.

As we think about the longer term, and I didn't provide perspective on '26 specifically, but in my prepared remarks in the third quarter, we did talk about how the pace of our margin expansion will be measured given all of the incredible opportunities that you just heard from Mark in terms of investment in more than 20 Phase III trials next year. So we continue to operate with discipline.

I think to your first order question, the key focus is making sure you're investing in the right programs, you're testing your hypotheses and you have a very high bar that you don't sacrifice. And with the depth and breadth of our pipeline and so many opportunities, we're able to maintain that high bar without question.

In terms of capital allocation, I think our priorities around capital allocation are unchanged. It's about investing to grow the business. It's about investing in the pipeline. And we'll continue to be active on the business development side. And certainly, with our balance sheet position, we have additional strategic flexibility in that regard. But we're really disciplined on prosecuting the wealth of opportunities we have coming out of our internal engine and looking for complementary assets related to those pipeline assets.

Got it. And maybe for the last minute or so, I also want to touch on AI. So in the world of AI, maybe tell us how is BeOne leveraging AI in drug discovery and development? And how do you expect this to have -- what kind of impact would you expect on the efficiency and innovation across your pipeline?

Sure. I think there's lots of areas in which it's being used in an ad hoc fashion as a tool in research with structure folding and other things. We're certainly doing a lot of that in manufacturing, same thing for process optimization and other areas. Those, I think, are very straightforward. I think we see a huge opportunity in the clinical trial side of things from that perspective. And overall, I think there's great promise, but it's hard. AI is very good when there's huge data sets in predicting what new ideas, new things could be.

In the area of overall drug discovery, a lot of the data is very fragmented and not public. A lot of the data is not high quality and in legacy systems. And so it's a harder problem that just is going to take some time and energy. But the system is only as good as the data that it's built upon. And for overall drug discovery, predicting what's going to work in a disease state. That data needs some time and energy, and we needed to involve a bit and probably have a system where we have more access. The real key to unlocking that would be tapping into real-world data, which right now is not high quality, unfortunately.

Great. Thank you, everybody, for tuning in person and online. That concludes our session here. Thank you.

Let's chat with BeOne Medicines. My name is Michael Schmidt, senior biotech analyst with Guggenheim. And it's my great pleasure to welcome Aaron Rosenberg, CFO of BeOne as well as John Scotti, Head of Strategy. Welcome. Thanks for joining us.

Thank you for having us.

So there are a lot of exciting things happening at BeOne Medicines. BeOne is one of the fastest-growing large biotech companies in my view. And this is the first year in its history really that the company has reached profitability. At the same time, BeOne has one of the deepest product pipelines in the industry. And so if you maybe step back for one second, Aaron, what are the key competitive advantages of the platform as you see it?

Great. And thank you again for having us. So we could probably spend the entire time, I think, talking about the differentiating features of BeOne Medicines. So we'll focus on a few. And I think what we often point to is our fully integrated CRO-free clinical development organization. Clearly, we have incredible discovery capabilities. You see that in action in our performance, putting 10 internally developed NMEs into the clinic in 2024 and 16 since that time to date.

And clearly, we have that capability in basic science. But what we recognized upon our founding was the critical importance of clinical development in terms of realizing the value of that innovation ultimately to the patient. Core to our mission is this focus on access, global access and in fact, to many parts of the world that typically the industry doesn't serve. And we looked at how do you solve that problem. It was recognized how much expense and development and time goes into the clinical development process. I think we often talk about 70% of the cost of developing medicines is in the clinical development process.

So to solve that problem, the company invested in a vertically integrated clinical development organization that has now more than 3,600 clinical development professionals. And now that extends to our global manufacturing capability. And the value of that is our ability to take our inventions and bring them to market with incredible speed and time advantages. And just to bring it to sort of what does it mean in practicality, I think we point to a few examples. We can look at some of our really exciting solid tumor candidates, say, our CDK4, where I think when we look at this program, we started maybe 3 years behind competition, give or take.

And now we've closed that gap as we've announced our intent to go with our first-line pivotal trial in the mid part of next year, maybe cut that down to about 15 months. We look at our CELESTIAL trial in treatment-naive CLL for sonro plus zanu, and we enrolled that study in about 14 months from start to finish. So you think about what really matters in this industry, that's being able to develop your medicines with incredible time advantages, and we're seeing that in action through that capability.

Right. So obviously, so a super efficient development platform. You also have been very successful commercially though. And so BRUKINSA, your anchor product in a way, has now captured sort of the leading market share in the BTK inhibitor market. And so yes, maybe let's touch a bit about that. And what is driving BRUKINSA growth right now in this stage of its life cycle?

Sure. I think when you talk about BRUKINSA, it starts with the medicine. This medicine was designed from inception to be fundamentally different with 24/7 target inhibition. And ultimately, that design has played itself out in the incredible differentiated data profile. And we're really excited to share a lot at the upcoming ASH, one of which is the 72-month data, SEQUOIA data, which really shows how durable BRUKINSA is in terms of sustained PFS with 74% landmark PFS, 77% on a COVID-adjusted basis. This is really unprecedented.

And when you think about particularly CLL, the importance of sustained long-term PFS for patients because this is an indolent disease, and often, you look at other medicines in the class, both existing and emerging, it's really 2 to 3 years is just not enough to see that sustained durability of the mechanism. And we're seeing that with BRUKINSA in a fundamentally differentiated way. And what does that mean? That's translated to its impact on both for patients and what's happening in the real world with prescriptions.

So what's driving BRUKINSA? Clearly, we're doing incredibly well in the United States with 47% growth on a year-over-year basis in our most recent report, more than 40% volume. We are the leader within our China business from market share by far. And we're really in the earlier days of launch globally. You think about in our European business, where we grew 71% on a year-over-year basis, much earlier in the product launch cycle where we're growing share across all the major markets. And there are many markets around the world where we're much even earlier in launch, and we're seeing incredible growth.

So we're really excited about BRUKINSA, what it's doing for patients and what it means for the long-term sustainability of our franchise. Obviously, this is the foundation of our CLL franchise. I'm sure we'll talk more about our pipeline assets, but this is really where it starts, and we're really pleased with the performance and ultimately, what this medicine is doing for patients every day.

Great. And so as we think about the CLL market longer term and especially around market dynamics, how will the potential increased uptake of fixed duration regimen affect the market opportunity longer term? And maybe stepping back, how do you think about fixed duration treatments in general in the CLL space? And do you expect them to gain more uptake? And if so, how will it affect the market overall?

Sure. So why don't I start and I'll invite John to jump in as well. So first and foremost, we're big believers in finite treatments. But we do believe that they need to meet 4 specific criteria, and we've talked about this a lot in our various discussions with investors.

First is to have a deep response measured through uMRD. The second is to have deep and sustained PFS and really looking at continuous use BRUKINSA as that benchmark. And we just talked about the 72-month SEQUOIA data. The third is having a safety profile that's no worse than what you can get today with continuous use BRUKINSA, and that's obviously a very high benchmark. And then lastly, when you're talking about fixed duration therapy, it's having the convenience effect. And what we know is while ven is a very effective medicine, it's actually very difficult to administer. And that's really limited its uptake.

So when we look at existing offerings for fixed duration treatment with respect to ven-based treatments, it really doesn't meet the mark across any of those 4 variables. So we're really excited, of course, about our potential combination with sonro plus BRUKINSA, which we believe meet all 4 of those criteria, and we can talk a bit more about the data. In terms of the market opportunity, as we come with our treatment around zanu and sonro, this is really a market expanding opportunity. And this is even before we get into our BTK CDAC.

Today, continue -- if you focus on the U.S. as an example, today, continuous use BTKs are basically getting about 50% of the market, of which we're, call it, we're getting approximately half. About 20%, 25% is getting a ven-based regimen and then CD20s and chemo-based therapies are getting the balance. So there is a significant opportunity to grow the entire market to bring an offering that solves patient needs for that fixed-dose treatment as well as the subset of patients that continuous use BTK will continue to be the right offering.

So overall, we see this as a market-expanding opportunity. And what BeOne Medicines is doing is bring offerings that can fill all portions of the patient journey. So whether you're treatment-naive and you're seeking a fixed-dose treatment, continuous use BTK and certainly in the relapsed/refractory setting that between BRUKINSA, sonro and our BTK CDAC that we can really fulfil all patient need, and that's really what we're seeking to bring.

Maybe I can just add, if we talk about then sonrotoclax and adding on to what Aaron said. If you step back and you think about then, it's a great drug actually. It's nearly a $3 billion drug. It's still growing. But its use, as Aaron mentioned, is effectively capped the academic setting, primarily in CLL, and there's reasons associated with that, that have to do with the fundamental characteristics of the molecule and the convenience challenges associated with the TLS ramp-up, the lab monitoring, et cetera, as we all know.

And so when you think about a drug like sonrotoclax, which is our BCL-2 inhibitor, we essentially designed a molecule that is 14-fold more potent, it's sixfold more selective, and there's a half-life of 5 hours, which is very different from the 26-hour half-life of venetoclax. And that's important because there's no drug accumulation. So number one, we have a molecule that is hitting the target harder. It's doing so with a wider therapeutic index, and it's doing so in a way that we hope will enable much broader access outside of the academic setting. And that's why we view this as a market expanding opportunity.

Great. I'll come back to sonrotoclax in a second, but you did mention that you completed enrolment of the CELESTIAL-301 study earlier this year, which is obviously built on some very exciting Phase II data that I think you'll update again at ASH. But on the earnings call recently, you also announced another Phase III study of the same combination head-to-head versus venetoclax, acalabrutinib. So what drove the decision to add the second study?

So maybe I can answer that one. I think when you think about the way this market has evolved and if you start first with BRUKINSA, we have, as Aaron mentioned, an overwhelming body of evidence from human PK to head-to-head trials to real-world evidence that this is the best-in-class BTK inhibitor. And yet, despite all that, there are still some physicians that ask us, well, where is your head-to-head data against acalabrutinib?

And I think when you think about SZ, which, as you know, we have an ongoing study against VO, which is the CELESTIAL-301 study that's fully enrolled as of February of this year. That is the standard of care in the U.S. from a fixed duration standpoint. And this is a company that is unafraid of running head-to-head trials because we view them as critical to delivering the best drugs to patients. And fast forward to AV, our view is that ultimately, we want to dispel any doubt that could possibly exist in the market that SZ when it eventually hopefully is approved and used in CLL is the best regimen against any comparator that exists in the market. And that's really the genesis for the trial.

Ultimately, we feel very confident about the trial because if you look at the AMPLIFY data of AV, they had 34% MRD. And what we're seeing in Phase I with ZS is 92%. So it looks very different. And again, this is due primarily most likely to this characteristics of sonrotoclax, et cetera. And ultimately, to Aaron's point earlier, our goal is to deliver a fixed duration regimen that patients and physicians can feel confident enough that they have achieved a deep enough response. So when they stop therapy, they can sustain long-term outcomes that are comparable to what we're seeing with BRUKINSA, which we really do feel like is the bar. Aaron referenced the 7-year -- 6-year 74% COVID unadjusted 77% COVID-adjusted PFS. That's our goal.

All right. Super helpful. And then maybe just one more on the CLL space. So you talked about the value of the long follow-up you have on the BRUKINSA data, the multitude of trials that are ongoing, fixed duration, et cetera. And so as we think about non-covalent BTK inhibitors entering the space, how do you think that will shape the landscape?

Yes. Maybe I can take that one as well. So we're all aware of the BRUIN 314 study, which is the pirtobrutinib head-to-head against ibrutinib that was in the ASH abstracts. So just keep in mind, this was a mixed population study, about 2/3 of it were relapsed/refractory, 1/3 was frontline. And when we look at the data, particularly in the relapsed/refractory setting, we compare those to our data, which is zanubrutinib against ibrutinib in the ALPINE trial in which we demonstrated head-to-head superiority on PFS.

If you look at their data at 18 months follow-up, they have about a 9% delta in response rate versus ibrutinib. If you look at our data, again, cross-trial comparisons and all the caveats that go along with that. But if you look at our data, our delta versus ibrutinib is about 12% on response rate at roughly similar follow-up. And what's most interesting is if you look at the deletion 17p subset, which are the most aggressive clones, these are the clones which arguably require the deepest level of constitutive BCL -- our BTK target engagement, they had virtually no difference between pirtobrutinib and ibrutinib.

I think their response rate was -- pirtobrutinib response was 80.6%, ibrutinib was 80%. And again, if you go and look at our data at roughly similar follow-up, we had a delta north of 20% in that population. So we feel very good about how zanubrutinib is performing in that population. And mechanistically, if you ask, well, how does that make sense? We feel that zanubrutinib really doesn't leave that much BTK engagement on the table. This is a drug that at trough is fully engaging the target. We've presented data and published data to the effective target engagement across all disease compartments and tissues at very, very high levels.

And pirtobrutinib, as you know, is a non-covalent inhibitor, which by default requires a thermodynamic equilibrium between on and off states, which is very different than covalent. And then if you think about the frontline setting, which, of course, was part of that trial, I think it's just too early to say much about that. And Aaron made -- alluded to this earlier, but in that trial, in the BRUIN 314 trial, only 1/3 of patients were frontline. The follow-up was, I think, 22.5 months. And we're talking about 18-month landmark PFS in which just over half the patients are really reaching that point.

And CLL is an indolent disease. It takes time for patients to progress. Ultimately, those data are really just a handful of events at this point. And we're going to have to wait for a much longer follow-up to see how those pan out against the bar of 74% at 6 years that zanubrutinib has set.

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John, thanks. This is maybe a good segue to talk about your BTK CDAC actually before we come back to sonrotoclax. But as we -- you obviously are running a head-to-head study against [indiscernible]. And so yes, maybe just stepping back, high level, how do you think about your BTK franchise strategy beyond BRUKINSA using or leveraging the BTK CDAC?

So the BTK CDAC is a very exciting molecule. It's a degrader. It's a fundamentally different mechanism. So there are a few key differences between the degraders and inhibitors. Number one is it's catalytic. One degrader can degrade several thousand copies of BTK protein. It's very different, of course, from the standard 1:1 stoichiometry that are associated with small molecule inhibitors. And then it also, by virtue of degrading the entire protein as opposed to binding solely to the kinase domain, it degrades the protein such that any scaffold function associated with that protein that is independent of the kinase domain is also obliterated effectively.

And there are mutations associated with zanubrutinib and also non-covalent inhibitors like pirtobrutinib that are in the kinase domain that abrogate kinase activity yet still result in BTK signaling. These are so-called kinase dead mutations. And they have implications from a durability of response, if you think longer term. And also those drugs are not active against those mutations. Our degrader retains activity against those mutations. And as a result of that, it seems, at least where we're going initially with the program is in the relapsed/refractory setting, again, intuitively, this makes the most sense initially given the profile of the molecule.

We have a pivotal -- potentially pivotal Phase II cohort that is fully enrolled and we will have data in the first half of next year, and we hope to be able to use those data to register the product, again, we'll see. That is in the relapsed/refractory CLL post-BTKi and post-BCL-2 setting. And we also have multiple Phase IIIs ongoing, one of which is versus investigator's choice, the second of which is head-to-head against pirtobrutinib. Again, we're confident in the profile of the molecule. We had an 84% response rate thus far in very heavily pretreated fifth-line patients, of which 80% of them have seen a BTKi and a BCL-2.

And in that data set, the 12-month landmark PFS was 79%. And when you look at -- when you look at, for example, the late-line pirtobrutinib BRUIN 321 study, they had slightly less pretreated population and a median PFS of 14 months. So we'll see how those data hold up in Phase III, but there's a reason why we're confident here. And I think KOLs have been very enthusiastic about this molecule because they're seeing responses in patients where they really don't have any other options.

Right. All right. So looking forward to that first registration data next year. What else will we learn at ASH about the BTK CDAC?

So at ASH, we're going to have several abstracts for the BTK CDAC. We'll have updated data across several B-cell malignancies, CLL, Waldenstrom's, et cetera. And we're looking forward to sharing some of those data in a month's time.

Great. And then yes, maybe then a couple of questions on sonrotoclax. You already mentioned its profile and areas of differentiation versus venetoclax, which is obviously established BCL-2 inhibitor in hematology. I think -- so this product is nearing disclosure of first registration data later this year, I believe, at ASH and MCL initially. And so maybe talk about how much more we will learn about its profile in MCL and how that will translate into the overall product offering as you think about it?

So of course, so at earnings, if you look at our earnings call, we had some data in the abstract on MCL. And maybe stepping back just a second. This is a product that received breakthrough designation in relapsed/refractory MCL. We plan to file globally based on those data later this year. And those data and longer follow-up will be presented at ASH in a month. And what's interesting about those data is when you look at them, again, this is a single-arm trial, so keep that in mind. When you look at them compared to historical benchmarks of venetoclax in the literature, you see trials of venetoclax in which venetoclax was used at 3x the approved dose.

And even despite the fact that it was triple the dose that is typically used of venetoclax, you see response rates comparable to what we're seeing and our PFS and duration of response outcomes are nearly double. And so again, in our view, when we look at the data that is emerging from that program as a single agent, we see the 14-fold increased potency, the greater therapeutic window really translating. And those are the data that you're going to see in a month and longer follow-up at ASH.

Okay. Great. And then we already talked about sonrotoclax's important role in your fixed duration regimen in CLL. But you also announced on the earnings call actually a Phase III study in multiple myeloma. And so stepping back, how do you think about the longer-term opportunity for sonrotoclax and specifically in multiple myeloma? So what's the size of that opportunity?

Yes. For multiple myeloma specifically, you're correct. We did announce that we will move forward to a Phase III later next year. Specifically, this is going to be in the translocation (11;14) population, which is about, give or take, 20% of multiple myeloma. This is going to be sonrotoclax as part of a triplet regimen with dara and dexamethasone. We acknowledge the competitiveness of the space. There are many, many, many options for patients with multiple myeloma, which is fantastic.

But a lot of the bispecifics, as you know, right now, are IV, and this would be a regimen that does not require infusions given subcutaneous daratumumab. That's point one. Point two, we saw early data from -- which we actually presented at R&D Day for venetoclax -- sorry, for sonrotoclax versus venetoclax in a combination with dexamethasone. And as you know, venetoclax in the CANOVA trial was close to reaching -- to being successful, but it didn't quite make it. And again, cross-trial comparisons, but we're seeing greater evidence of activity for sonrotoclax versus venetoclax in multiple myeloma, specifically in that translocation for (11;14) setting, which is underpinning our confidence to move forward with the pivotal trial.

Okay. Great. So obviously, between the 3 molecules, so BRUKINSA, sonrotoclax and the CDAC, you have really the CLL and hematology market in a broader sense under control and strong control. And so as we think about your solid tumor pipeline, the CDK4 inhibitor has kind of stands out as one of the more advanced programs. You did commit to a Phase III trial next year in first-line breast cancer. And so maybe just stepping back, talk about differentiation perhaps relative to Pfizer's atirmociclib.

Maybe I will just for the sake of the audience here, just remind everyone of what we disclosed on our earnings, and I'll come back and answer your question. So we decided to prioritize the first-line Phase III. And subsequently, we also decided to -- decide not to pursue a Phase III in the second-line setting, and let me just walk through the logic behind that decision.

So first and foremost, we're seeing some very encouraging data in the first-line setting for our CDK4 inhibitor. And then when you think about the second-line setting, this was always intended to be a transitional opportunity. The PFS of CDK4/6 inhibitors in the post-CDK4/6 setting is unfortunately only on the order of months, 6 months or so when you compare that to a couple of years in the first-line setting. And then on top of that, the second-line competitive landscape, as you all are aware, is extremely heterogeneous, and it has gotten even more competitive just in the past few months with recent data sets from other additional regimens.

And so when we step back and we looked at our data in the frontline setting, and we thought in the second line in 3, 4 years, if and when this would have made it to market in the second line, it was not likely to be an extremely impactful medicine in that setting. And so we decided to prioritize in the frontline setting. Now with respect to Pfizer, Pfizer presented some -- what we felt to be very interesting data at ESMO for their CDK4 inhibitor. They showed a 68% response rate, which is above the response rates that you would expect for a CDK4/6 inhibitor in the frontline setting.

And importantly, given they have longer follow-up, that response rate did appear to translate to a greater degree of PFS benefit than you would expect again with the CDK4/6 inhibitors in the frontline setting. They had 67% PFS at 24 months. What I can say about our molecule is that we're seeing a similarly high response rate as Pfizer. Obviously, we do not have the duration of follow-up yet to comment on durability, but we will definitely be presenting data for our CDK4 inhibitor in the frontline setting next year, primarily to give investigators confidence ahead of starting that Phase III in the first half of '26.

And then I just want to make one more final comment. This is a molecule that entered the clinic 40 months behind Pfizer. And they started their Phase III earlier this year. And so we really -- by virtue of the infrastructure that we have, it's incredibly valuable. We've been able to catch up materially in the clinic from quite behind to within roughly a year, give or take.

Great. Well, thanks, John and Aaron. Our time is up, unfortunately, so we have to wrap up here. I did have more questions about your pipeline, which has a lot of moving parts, a lot of molecules advancing, but we'll save that for next time. So thank you. Really appreciate the time.

Great. Thank you very much.

Good day, everyone. Welcome to BeOne Medicine's Q3 2025 Earnings Call Webcast. [Operator Instructions] After the speakers' remarks, there will be a question-and-answer session.

At this time, I would like to turn the call over to the company.

Hello and welcome. Thanks for joining us today. I'm Dan Maller, Head of Investor Relations at BeOne Medicines. Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentation on the Investor Relations section of our website, ir.beonemedicines.com.

I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most recent periodic report filed with the SEC.

Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation.

Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our Investor Relations website along with the earnings release. All information in this presentation is as of the date of this presentation, and we undertake no duty to update such information unless required by law.

Now turning to today's call as outlined on Slide 3. John Oyler, our Co-Founder, Chairman and CEO, will provide a business update; Aaron Rosenberg, CFO, will provide an update on our third quarter financial results and financial guidance; and Lai Wang, our Global Head of R&D, will discuss our R&D and pipeline progress. We will then open the call to questions. And joining the team for the Q&A portion of the call will be Xiaobin Wu, President and Chief Operating Officer; Matt Shaulis, our General Manager of North America; and Mark Lanasa, our Chief Medical Officer for solid tumors.

I'll now pass the call over to John. John?

Thanks, Dan, and thank you, everyone, for joining us today. The third quarter marked another strong quarter of execution. From a financial perspective, revenue reached $1.4 billion, which represents 41% year-on-year growth. GAAP earnings per ADS were $1.09, which represents growth of more than $2 over Q3 of last year. And we generated over $350 million of free cash flow during the quarter.

As Aaron will touch on, we strengthened our balance sheet and ended the quarter with over $4 billion in cash. BRUKINSA has continued its momentum with sustained U.S. leadership, and it's now the #1 BTK inhibitor globally. Sonro, our next-generation BCL2 inhibitor recently received FDA breakthrough designation in relapsed/refractory mantle cell lymphoma. And we're really excited about the totality of data emerging from that molecule, some of which we're going to highlight today.

BRUKINSA, Sonro and our BTK CDAC are the core elements of our leadership in B-cell malignancies, and they'll be on display next month at ASH where we'll present 47 abstracts from across our heme portfolio. The quarter also yielded multiple developments across our growing solid tumor pipeline, including clinical proof-of-concept for multiple early-stage assets, which Lai's going to discuss in more detail later.

So let me start with BRUKINSA, the backbone of our heme franchise. BRUKINSA continued to perform exceptionally well in the third quarter, growing 51% and exceeding $1 billion in quarterly global revenue for the first time. As a result and also for the first time, BRUKINSA is now the global value share leader amongst the growing BTK market. This, of course, is a major milestone for BRUKINSA and for our company.

As I discussed in detail on our Q2 earnings call, the commercial success of BRUKINSA is not by chance. It's the direct result of an overwhelming body of evidence that has accumulated over more than a decade. It's evidence that spans preclinical human pharmacokinetics, head-to-head clinical trials real-world data sets and patient physician preference in the market.

The evidence is remarkable for both its strength as well as its consistency, and this evidence continues to build with each new piece of data, both reconfirming and further strengthening our initial therapeutic hypothesis that BRUKINSA is the best BTK inhibitor.

At BeOne, we're relentlessly focused on our goal of discovering and developing innovative medicines that deliver long-term outcomes for patients. At ASH, we're presenting a 74% landmark PFS at 6 years for BRUKINSA in first-line CLL. This is from our Phase III SEQUOIA trial. We believe that these data have set the bar for what monotherapy BTK can and should be, what they should achieve in CLL.

With all the caveats of cross-trial comparisons, this is double digit better than what has been reported for other single-agent BTKis at 72 months. Interestingly, this level of sustained PFS at 6 years is in the same ballpark as other recent data from BTK van fixturation regimens at only 3 years.

Long-term follow-up from years 3 through 6 when patients are not on active therapy will be critically important to inform the future relevance of these regimens within the CLL treatment paradigm. And I think along those lines, what's also relevant about this year's ASH is what you're not seeing.

Given what I've just said about the importance of our long-term BRUKINSA data in CLL the absence of other long-term follow-up data from many other relevant CLL trials, such as AMPLIFY with the last data cut off April 30, 2024, CAPTIVATE and ELEVATE where data hasn't been reported for a couple of years.

Long-term data are the gold standard in CLL for a reason because CLL is an indolent disease, and it takes time to fully and truly understand how these regimens perform. BRUKINSA delivers the level of progression-free survival that patients and physicians should expect and should demand.

We believe in the promise of fixed duration, but we also feel that the current van-based options fall far short of that promise. In our view, the current options fail to satisfy the 4 key criteria that you see on this slide, depth of response, sustained PFS, safety and convenience. Specifically, we have concerns related to the low MRD negativity rates and sustained PFS for AV combinations, the cardiac safety, uveitis and general tolerability for IV combinations.

The long-term effects on the immune system and the related additional hospitalizations due to infections of obinutuzumab use and the overall treatment burden and feasibility of use with all of the van-based regimens. Our goal in fixed duration is simple. We aim to develop a more efficacious time-limited regimen that does not come with caveats or accommodations.

And based on the data we've generated to date, we believe that the combination of zanu and sonro is well on its way to achieving just that. Our confidence in ZS is based on the totality of clinical data to date, but there are a couple of key aspects in the data that we find exceptionally compelling.

Here, you can see the uMRD rates and the time to blood MRD from our Phase I trial. This was presented at our R&D Day in June, and we'll provide a further update on these curves at ASH. Of all the data our heme franchise is generating, these might be the most compelling to the KOLs that we meet.

So let me explain. First, the combination of zanu and sonro can drive very high rates of deep response. Secondly, and perhaps more impressingly, it does so exceptionally quickly with kinetics previously unseen in other trials of drugs targeting similar mechanisms.

This slide is so important that we're going to show it to you twice today, once now and once in live section. This is the type of deep response that we're looking for in a fixed duration regimen to give physicians and patients the confidence to stop therapy and to achieve positive long-term outcomes.

BeOne stands out as the only company with fully owned potentially best-in-class assets across the 3 foundational MOAs and CLL, BRUKINSA, sonro and our BTK CDAC. All 3 are anchored in differentiated design hypotheses and bolstered by an ever-growing body of evidence. All 3 of the potential for the broadest utility in the class. And all 3, whether as monotherapy or in combination, represent significant opportunities for patients, physicians and for our shareholders.

Together, BRUKINSA, sonro and our BTK CDA are driving the future treatment paradigm and the $12 billion and growing global CLL market. Before I close, I'd like to introduce what we're calling our development global super highway. For those of you that are newer to our story, BeOne was built different. Early on, we recognized the vast majority of the time and cost to develop and deliver a medicine was in clinical trials. We felt that such a critical component of the biopharma supply chain should be a core competency rather than something that is outsourced to a CRO.

We saw the synergies that were possible by vertically integrating manufacturing with an industry-leading clinical organization. And we know from experience how hard this can be for a small company. So fast forward 15 years, and we're proud to have built a global organization of nearly 6,000 colleagues across these 2 areas: clinical development and manufacturing. And in today's hypercompetitive costly and complicated era of drug development we really believe that this global super highway is unique to BeOne, and it's critical to generating superior returns on R&D investment.

To close, we're in the midst of an exciting milestone-rich period for both our heme franchise and our solid tumor pipeline. By the end of '26 we expect the initial global approval and launch of sonro and potentially pivotal data for our BTK CDAC. Our internal clinical team will be running more than 20 Phase III trials we anticipate more than 10 proof-of-concept data readouts and our research organization will advance around 10 new molecular entities into the clinic, 3 of which will be a heme and not just in CLL, but broadening our portfolio to help patients in other areas.

Now I'll pass it over to Aaron to provide the financial update.

Thanks, John. In the third quarter, we sustained business momentum across our product portfolio with another quarter of solid execution by our global commercial teams. Product revenue reached $1.4 billion in the second quarter, representing 40% year-over-year growth. BRUKINSA global revenues eclipsed $1 billion for the first time in a quarter growing 51% driven by strong performance across all geographies.

As John mentioned, BRUKINSA is now the leading BTK globally. In the U.S., we grew BRUKINSA volume by approximately 40% versus Q3 2024, driven by the quality and differentiation of our long-term clinical data across all patient types. The pricing dynamics in the United States were consistent with commentary provided last quarter with a mid-single-digit pricing benefit on a year-over-year basis.

Meanwhile, TEVIMBRA reported a 17% increase reflecting continued market leadership in China, albeit in an increasingly competitive market environment. This growth was supplemented by early contributions from launch markets.

Our in-licensed products also showed continued strength, growing 17% year-over-year, driven by growth of 31% from the Amgen in-licensed asset portfolio. We continue to see solid execution as we look at revenue from a geographic dimension. The U.S. remains our largest market, generating $743 million with year-over-year growth of 47%.

China revenue totaled $435 million, a 17% increase supported by TEVIMBRA and BRUKINSA market leadership and growth from our in-license assets.

Europe contributed $167 million, with 71% year-over growth as we continue our launch trajectory of BRUKINSA with increased share across all major markets. And rest of world markets grew 133% and driven by market expansions and new launches.

Now turning to the other components of our GAAP P&L. Gross margin improved to 86% from approximately 83% in the prior year. This improvement reflects the benefit from favorable product mix, price and product cost efficiencies, offset by period costs related to repositioning of our manufacturing capacity. Operating expenses grew by 11% and totaling $1.1 billion as we are investing with discipline to support our commercial growth and rapidly advance our innovative pipeline.

I thought it's worth noting that the Q3 2024 base for R&D has higher expenses for both business development milestones plus approximately $25 million in accelerated depreciation charges. Together, this has the effect of depressing the year-over-year growth rates in our Q3 2025 R&D expense, which you can observe to a degree on the non-GAAP P&L slide, which excludes depreciation.

We continue to invest assertively to advance our most promising development candidates. Income tax expense totaled $22 million for the quarter. And altogether, net income reached $125 million, representing diluted earnings per ADS of $1.09. Our non-GAAP P&L includes adjustments for typical items with a full reconciliation provided in the appendix.

Non-GAAP net income reached $304 million, reflecting an increase of $252 million compared to the previous year. This performance translates to diluted non-GAAP earnings per ADS of $2.65 for the third quarter.

The third quarter saw a notable progress in our priority of balance sheet strength as a competitive advantage. In August, we entered into a transaction to monetize our global IMDELLTRA royalty rights, generating $885 million in cash in the quarter while allowing us to participate in the potential upside with the asset. The Royalty Pharma agreement is accounted for as a liability, and therefore, we will continue to recognize the full IMDELLTRA royalty in other revenue as it is earned while simultaneously amortizing the financing liability and interest expense, please see our 10-Q for a full description of the accounting for this transaction.

And with our meaningful top line growth with margin expansion, we've seen a notable increase in free cash flow generation to $354 million in this quarter. Cash generation is the key metric of business sustainability, and we are very pleased with our progress on this dimension.

All in, Q3 ending cash and cash equivalents totaled $4.1 billion, an increase of $1.3 billion versus Q2. Moving to our 2025 financial guidance. Given our continued execution, we are updating our full year revenue guidance to be between $5.1 billion and $5.3 billion. Our gross margin guidance is unchanged, remaining in the mid- to high 80% range. And we are updating our operating expense guidance to be between $4.1 billion to $4.3 billion.

We remain committed to achieving positive GAAP operating income, and we expect to generate positive free cash flow for the year. Overall, we are pleased with our execution through the first 3 quarters of 2025, and we remain focused on full year delivery across all financial performance measures.

Now while early and staying away from providing detailed guidance, I'd like to provide some perspectives on 2026. As you consider your models for the fourth quarter of 2025 and into the first quarter of 2026, I thought it would be useful to remind you of the seasonality patterns in the U.S. of the BTK class. This includes factors such as typical inventory increases at the end of the year, followed by normal drawdowns in January.

Also, just like this year, Q1 2026 will have fewer shipment gains versus a typical 13-week quarter. This is simply the nature of the calendar, but it's something that should be considered in quarterly phasing. And while we remain committed to margin expansion across our planning horizon, the pace of improvement will be measured in the near term to ensure we are investing to maximize the value of our late-stage pipeline opportunities.

We look forward to providing our detailed 2026 guidance on our Q4 earnings call in February. And with that, it seems like an excellent time to pass it over to Lai who will share more progress about our pipeline.

Thank you, Aaron. Hi, everyone. Thanks for joining us today. Let me start with hematology. We have 50 abstracts, including 6 orals from our hematology portfolio have been accepted for presentation at ASH this year. This is a tremendous validation of the strength and the depth of our signs. I will highlight some of those key data later in my presentation.

Importantly, sonro has now received FDA breakthrough therapy designation for mental cell lymphoma. We're actively working on its first filing around the globe and our BTK integrated program has just started the Phase III head-to-head trial versus pirtobrutinib in the last refractory cell patients, a major step towards transforming the space.

On the solid tumor side, our momentum continues to build. We have achieved proof-of-concept for several innovative programs, including our CDK4 inhibitor, B7-H4 ADC, PRMT5 inhibitor under GPC3x41BB bispecifics. To be noted, most of these assets have been in the clinic for less than 18 months and some less than 1 year, this is the level of efficiency and the focus we aim to deliver across the portfolio.

For CDK4 we aim to initiate a Phase III trial in first-line BC in the first half of 2026. On the non- oncology side, our IRAK4 CDAC program achieved over 95%, IRAK4 [ protein ] degradation in healthy volunteers skin tissue, a clear PD proof-of-concept. We have already initiated a Phase II trial in rheumatoid arthritis.

Over the past few years, especially in the last 24 months, we have dramatically increased our output from the discovery engine. In that time, we have advanced 16 new molecule entities into the clinic, including 13 from our internal research team. Among them, all molecules have already achieved clinical proof-of-concept, supporting pivotal study plan.

This does not count our 4 degrade program, achieving tissue PD, POC. Across the portfolio, our programs have complete R&D-enabling studies in the medium of just 10 months, well ahead of industry benchmarks.

Even more impressively, in 2024 and 2025, we have completed over 170 dose escalation cohorts with a median time of only 7 weeks. This level of speed and the precision is what defines BeOne. Our ability to move fast, execute flawlessly under turn innovation into impact.

Moving on to our solid tumor portfolio. An area we are very excited about and where we feel increasingly confident in several programs advance towards registration. This confidence is built on strong evolving clinical data.

First, our CDK4 inhibitor program is moving forward quickly. We plan to initiate a Phase III trial in first-line hormone receptor positive breast cancer in the first half of 2026 driven by emerging strong efficacy and the safety data from our expansion cohorts. In addition, we depriotized the Phase III development in the second-line post-CDK4/6 setting due to the evolving competitive landscape.

In that context, we decided for competitive reasons to delay the disclosure of our late-line data since it is also relevant to our dose selection in frontline. Second, our B7-H4 ADC program has completed dose escalation, and we are now conducting dose optimization studies with particularly encouraging responses seen Gynecological and

Endometrial breast cancers.

Third, our PRMT5i Inhibitor stands out with potentially best-in-class features, including potency, selectivity and most importantly, brain penetration. Based on the emerging Phase I data, we are now accelerating this program into frontline lung and frontline pancreatic cancer.

And finally, our GPC3 x 4-1BB bispecific has delivered a pleasant spikes, while seeing very exciting signals as monotherapy in its first in-human study in heavily pretreated HCC tumors. Altogether, this is a portfolio that is maturing quickly and backed by early clinical momentum, and we are incredibly energized by what's ahead.

For our other solid tumor assets, we'll continue to execute and prioritize programs with the strongest potential. Our CEA ADC, EGFR x MET x MET Trispecific and the FGFR2b ADC programs are all showing encouraging early signals while continuing advancing the CDK2 Inhibitor, EGFR CDAC and the Pan-KRAS Inhibitor programs through Phase I dose aspiration studies.

At the same time, based on the current data and the broad competitive landscape, we have made the strategic decision to realign the B7-H3 ADC, and Pro-IL15 programs within the portfolio. This really reflects BeOne's disciplined development strategy, focusing our resources on programs with clear differentiation and advancing them quickly to the most important value inflection point clinical POC, where we can make database decisions.

This is how we continue to build a high-quality, high-velocity portfolio in solid tumors. Moving on to our hematology portfolio. Our sonro program is shaping up to be a potential best-in-class BCL2 inhibitor, offering greater efficacy improved safety and better convenience compared with the first-generation agents venetoclax.

We're now in the process of filing for approval in relapsed/refractory mantle cell lymphoma globally. And then we look forward to sharing good news very soon in this space. The most critical indication for sonro is CLL. We have completed enrollment in our Phase III trial comparing the ZS fixed duration regimen versus VO earlier this year.

In addition, we plan to launch another global Phase III study in the first half of 2026. Comparing ZS versus AV and mean to establish ZS as the best oral fixed duration regimen in treatment-naive CLL.

And finally, in 2026, we also plan to initiate a Phase III in second-line plus multiple myeloma exploring sonro-based triplet combination. Next, a quick update on the ASH presentation for sonro. What you see on this slide are 2 selected abstracts published early this week on sonro monotherpy, starting with mantle cell lymphoma in 103 relapsed/refractory patients who had [ power ] BTK inhibitor an anti-CD20 therapy.

So achieved an overall response rate of 53% with a medium progression-free survival of 6.5 months and a median duration of response of 15.8 months. These results look favorable compared to advanced historical data in a similar population even when [ Van ] was used at 3x of its clinical proven dose.

On the CRL side, the table on the right shows the data from a single arm study of 100 patients or post BTK in factor and post-chemoimmunotherapy. Here, sonro achieved a 76% over response rate with 19% compete responses. Both the efficacy and the safety profile look quite favorable relative to advanced previous published data in a similar population. Altogether, this results reinforced sonros strong potential to be the best-in-class BCL2 inhibitor in hematological malignancies.

In addition to the sonro monotherapy update, we are also presenting new data on the sonro combinations with Zanu under or with obinutuzumab in CLL at this year's ASH. For the ZS combination, we have more mature data as additional patients have gone through treatment. The 12 months uMRD rate has reached 92% and the most impressively with a median follow-up of 27 months to date, no patients have progressed in the 320-milligram cohort, which is truly remarkable.

For the ASH presentation, we have another data cut with additional months of follow-up showing consistent results. In terms of the safety, the profile continues to show a clear advantage compared to other fixed duration regimens. And in terms of convenience, we're very optimistic that for the vast majority of patients, only 1 clinical visit during the ramp up will be required for -- after [indiscernible].

This is a meaningful improvement for both patients and the physicians. What's most exciting about this combination is the kinetics of the uMRD achievements, which John showed you earlier. As shown on the left, the medium time to uMRD with the ZS combination was only around 4 months after starting the combo and importantly, this is independent of IGHV mutation status by about 1 year of combination therapy. That's the dashed line on the graph, the vast majority of patients achieved uMRD in contrast with the IV combination on the right, the medium time to uMRD is 16 months for IGHV mutated and 10 months for unmutated patients.

And at the 1-year mark of combo treatments, many still remain MRD positive. So overall, we believe that combining 2 potentially best-in-class agents, anu and sonro may provide the only true fixed duration options that delivers optimal efficacy safety and the convenience for patients with CLL in a reasonable time frame.

Now the update on our BTK CDAC, BGB-16673,16673 is the most advanced program of its kind in the clinic with clear best-In-class potential. We have initiated a head-to-head Phase III trial against the pirtobrutinib in the potentially pivotal Phase II study in [indiscernible] is expected to have a data readout in the first half of 2026.

We're also planning a fixed duration combination Phase III study with sonro in relapsed/refractory CLL and potentially pivotal II in Waldenström's Macroglobulinemia has been initiated. We will also show new BTK CDAC data at this year's ASH meeting. The table on that showed the CLL results published in the abstract. 16673 demonstrated an over response rate of 86.4% and with medium 18 months follow-up, the 12-month progression-free survival is now mature at 79%, a very favorable profile compared with pirtobrutinib in the similar patient population.

We also reported new data in Richter's transformation on the Waldenström's Macroglobulinemia in Richter's The OR was 52% with nearly 10% complete responses. In Waldenström's, we saw 83% ORR with a 26% VGPR risk. Altogether, this data further strengthens CDAC's position as a potentially best-in-class BTK degrader across multiple B-cell malignancies.

The robust clinical activity we observed is consistent with the preclinical data package with regard to the potency as shown on the left, we observed similar DC50 and DC90 values for 16673 and the [ Nurex ] molecule in head-to-head BTK-degraded assays in both human whole block cells and B-cells. And we believe 16673 holds a clear mechanistic advantage in terms of BTK mutation coverage as shown on the right, except for the A42AD mutation, 16673 can cover all other BTK mutants, whereas we observe the [ nurex ] molecule to 2 resistant hotspot at Methionine 477 and Glycerine 480 [ resumes ]. The broad mutation coverage of 1673 further reinforces its best-in-class potential.

And its ability to deliver potentially more durable responses for patients. Together, sonro and 16673 highlighted the depths, quality and the momentum of our hematology portfolio advancing rapidly towards multiple late-stage milestones and the transformation opportunities in the years ahead.

Finally, I'd like to share a few key milestones we are tracking for the remainder of this year and into 2026, focusing on the ones I have not mentioned earlier.

First, for BRUKINSA, the Phase III in term analysis readout for the MAMRO study in treatment-naive mantle cell lymphoma has been delayed from the second half of this year to the first half of next year due to the slower-than-anticipated event rate.

In addition, we are anticipating accelerated approval for sonrotoclax in relapse/refractory mantle cell lymphoma and the CRO in China early next year. Important milestones as we continue to broaden access for patients globally.

Turning to our early stage pipeline. We're anticipating POCs for CDAC before the year-end and the other assets in 2026. We look forward to sharing more data in future updates. And with that, I will turn the call back to John.

Thanks, Lai. We'll now open the call to Q&A. [Operator Instructions] Operator, please go ahead.

[Operator Instructions] Our first question will come from Yaron Werber with Cowen and Company.

Hopefully, you can hear me.

Yes.

Congrats, really nice quarter. I'm going to violate the rule right away. Just 2 quick questions. Number one, BRUKINSA's the global leader. You're obviously a little bit behind in Europe in terms of when you launched any sense and when new territories are coming in to accelerate that?

And then secondly, Life for the CDAC data in the first half next year in CLL for the potentially support accelerated approval, can you give us a sense of what to expect there? And sort of how mature is the PFS is going to be?

Right. So Xiaobin, do you want to start?

Yes. In Europe, we grow for BRUKINSA are tremendously, so close to 70%. And we notified in Europe in some country like Germany, Austria, AMPLIFY launched. And we don't see much excitement among the [indiscernible] and the company may actively switch the mono acala to AMPLIFY. But so far, we have not -- we see some prescription, but not extremely a lot prescription.

Therefore, the total acala in Europe, if you see the number, is flattening.

So regarding to the CDAC data, and this is a single-arm study, so likely to be based on the ORR as well as the DOL. So depending on the first discussion with the agency, as usually, it will be probably about 12 months after the last patient.

Our next question comes from Reni Benjamin with Citizens Bank.

Congratulations on another amazing quarter. Would love to just focus on the earlier stage pipeline a little bit. You had mentioned proof-of-concept data. Can you maybe provide a little bit more color as to what you're seeing with some of these other assets? And should we be thinking that all these would likely progress to Phase III trials moving forward?

And if I can sneak one in, is there a teaser you could provide regarding the 10 new molecular entities that you're filing next year? Is there a novel target that you're most excited about?

We wish that science worked in a way where everything worked. But Lai, why don't you answer that question?

I'll probably refer to Mark because he is in the frontline for all this data, Mark?

Thank you, Lai. Thank you, [ Reni ] what I would say is that for all of our early programs, we established very clear criteria of what success looks like based upon the preclinical data what are we looking for in terms of PK, PD, safety and ultimately, efficacy? If you think back to the slide that Lai showed where he talked about where the different programs stand. I think you can think about that as some of those programs are meeting all of those criteria, the 4 of CDK4, PRMT5, B7-H4, GPC3, and therefore, we're actively planning acceleration to Phase III studies and program growth. Others, we continue to wait for data. And we believe that we'll have the data to make the final determination for both of the programs in the first half of '26.

Yes. Then in terms of the new [ molecular ] entities we are going to bring to clinic next year. I'm going to use the GPC3 4-1BB as an example. To be honest, among the program we took into the clinic last year, that certainly was not the most exciting one for us based on the preclinical data. But certainly, we are very pleased with what we have seen in the clinic today. So I'm not going to say which one is the most exciting one for us in the next year, but we're certainly looking forward to bring more. Just want to emphasize one more thing. What you have seen from BeOne is really just the beginning, what you can see from our really prolific discovery engine.

Next question comes from Andrew Berens with Leerink Partners.

Let me give my congratulations on the progress and execution for the quarter. I think with Aaron's question, you answered one of the ones I had because Astra in their earnings release today did highlight the fixed duration AMPLIFY regimen getting traction in Europe, but it sounds like you guys have not seen a lot of that yet.

So I just wanted to confirm that that's what you said. And then a question on the PRMT5 program. It's still expected by year-end. Just wondering, I know you mentioned the first-line PDAC and non-small cell lung cancer opportunity. Just wondering how you think of combination partners for those settings?

Yes. I confirm and the -- so Ocala market share and also the revenue in the last 3 months are pretty stable in Germany and not increasing -- of course, with AMPLIFY approval and the fixed duration of AMPLIFY will be added to the respective guideline. This may give some plus for [ Ocala ]. But overall, in Europe and also in Germany, the [ Ocala ] total data flattening.

Mark, do you want to take the second part?

So we, as you heard, are very excited about our PRMT5 molecule. That's only been in the clinic since January of this year. But given its high potency and CNS penetration, we're now seeing objective responses across multiple tumor types, including both lung and pancreatic cancer as well as additional tumor types. And critically, given its high selectivity, we're also seeing a very favorable safety profile that we think will enable combinations, which will be key to unlocking the potential of this mechanism.

And therefore, we're advancing into frontline to combine with current standards of care. We do not yet have the data, but it is our expectation that we'll be able to combine with chemotherapy and PD-1 in non-small cell lung cancer and standard of care chemotherapy in frontline pancreatic cancer, and we'll look for similar development opportunities in early lines of other tumor types with frequent MTAP deletion.

Okay. Any belief that maybe combining with some of the selective agents might work in certain mutations like RAS mutations.

So we are very interested in RAS biology. Our pan-KRAS molecule is advancing through Phase I. We discussed at R&D Day a commitment to bring multiple additional RAS targeting molecules into the clinic. So certainly, in pancreatic cancer, for example, we will ultimately look to combine PRMT5 with KRAS. So again, the aspiration given potency and selectivity is that we should be able to combine with whatever is the appropriate additional therapies for that patient given the disease state and any other concurrent mutations.

Our next question comes from Yigal Nochomovitz with Citigroup.

Okay. Great. This one is for Lai or Mark. Maybe. Could you give a little more detail on the design of the CDK4, Phase III in terms of what you can say at this point about the control arm, the size of the study, anything on the powering? And also what are the doses that are the final contenders for that study?

Please go ahead, Mark.

So at R&D Day, we talked about the 3 dose levels that are being explored in our expansion phase, 240, 400 and 600. We've completed enrollment of our frontline cohorts. And we're very excited with the data as they're coming in.

We are seeing a high response rate that we think will justify as initiation of a Phase III study the core hypothesis with the molecule is that having a more selective CDK4 inhibitor will be superior to currently available CDK4/6 inhibitors.

And therefore, we're intending a head-to-head study we're still waiting for data to make final decisions around study size and powering, but we certainly should be able to share those details in the near future as we move towards a Phase III study start by the end of the first half of next year.

Okay. And then I think Lai mentioned the new Phase III ZS versus AV. I was just wondering regarding the rationale around that. I was under the impression you kind of already knew the conclusion there that ZS was better? So I'm just curious as to the rationale for that additional investment to further prove that point.

Please go ahead.

Yes. Thank you for the question, and we agree with your comments. But we felt this is important to establish ZS as really the best oral fixed duration regimen. So we picked the one which likely will be approved soon by FDA, the AV regimen. We do have a lot of confidence in term for this particular study.

Yes. I think if I just elaborate a little bit on that, we encourage everyone to look frequently at the CLL data, especially the long-term data that we've presented but still people will say, well, there's no head-to-head study against [ Ocala ] versus [indiscernible].

And still, people will discount the body and wealth of information that's there. And I think when you look at the data and you talk to the top KOLs, I think at this point, with this long-term data, it's very clear.

But nonetheless, there's always someone who says there's not direct head-to-head. And I think this commercially is helpful, and it's helpful to bridge that information gap help educate people more quickly. I mean just when we're looking at that space, the long-term data, it's meaningfully different with all the cross trial comparison.

As we said, it's double-digit different. look at the PFS, look at the OS data. It's impressive, but we still get that comment in a small portion of the population around the globe. So we just think, it's important to do this so we can ensure that everyone is getting the best medicine and the best regimen. So we're committed to doing it.

Our next question comes from Leonid Timashev with RBC.

I just want to ask maybe on some of the commercial dynamics you're seeing outside of the early line setting in CLL and maybe more in the relapsed/refractory setting is how is BRUKINSA share holding up or growing there? And then ultimately, how do you expect the mix of a degrader BRUKINSA and covalent inhibitors to play in the future there?

Sure. Matt, please.

Sure, happy to address that. Yes, we continue to see strong new patient start share across the lines of therapy, including in that relapse setting. And then as we've discussed in the past, we're really confident in our overall CLL franchise leadership strategy.

You made reference to the multiple mechanisms that are in our portfolio. And as you've heard from John, we continue to have confidence in our BTK mono due to our head-to-head superiority with another BTK and our best-in-class profile. Including PFS, safety and tolerability in the long-term setting that John mentioned.

We also see an opportunity for therapy that will include zanu plus sonro. We've spoken before about the requirements for therapy there. And we're confident in a really strong MRD PFS safety and tolerability profile, but also in the convenience that sonro can bring to that regimen.

So of course, we see the future opportunity for fixed duration with zanu plus sonro. But right now, we're confident in monotherapy. Of course, when it comes to the degrader we see a clear opportunity there in later lines of therapy. I'm sure you're familiar with resistance mutations that can happen in those earlier lines, and we have the confidence to do a head-to-head superiority study for the degrader versus pure dose. So we see a strong opportunity across patient types in the cross lines of therapy in CLL.

Our next question comes from Sean Laaman with Morgan Stanley.

Just to go back on the CDK4 inhibitor, just to maybe throw some meat on the bones around the decision not to pursue later lines and to go for first line. And then also just to confirm, are we still going to see some data at San Antonio and what do you hope to present at that forum?

Thank you very much, Sean. Yes. So again, what we're seeing in our expansion cohorts is a very strong emerging response rate. We are waiting for data maturity. Now in the context of the strength of that data and also importantly, the context of emerging data externally, so there are a number of new agents that are leading to both fragmentation in the second-line as well as an increasing bar for success in second-line.

We always view the second-line opportunity as a transitional opportunity for this molecule and the key study as the frontline study. So given this external dynamic and our strong internal data, we made the decision to deprioritize second-line and to accelerate frontline.

And again, we're very much looking forward to that study. Currently, we then subsequently made the decision that we would not share the second-line data this year San Antonio. We think those data are relevant to our dose level selection for Phase III in frontline and we, therefore, will not have data for this molecule at the San Antonio, but look forward to sharing data at a future venue that will -- should we say substantiate our plans for the Phase III study in frontline.

Great. And one quick follow-up just on zani plus sonro versus [V plus O]. So Phase IIIs are recruited earlier this year. What's sort of the signpost pathway or the map going forward in terms of future announcements around that trial?

Lai, do you want to answer that, please?

Yes. So to me, in that particular study is a PFS events-driven studies, as you can imagine, with the control arm using the vial, it's really good therapy as well. So it would take a little bit of time to get into the PFS readout at the same time, we are also monitoring the uMRD rate, this will be something we can probably take an earlier look at.

Our next question comes from Jess Fye with JPMorgan.

I have one on the EGFR targeted assets. I guess what in particular makes you say that the EGFR cMET product goes in the promising bucket, whereas the EGFR CDAC is in the still exploring bucket. Is that based on clinical data? Or if not, can you just elaborate on kind of how you segment of those.

Sure, Mark. Please go ahead.

Sure. Thank you, Jess. So we have a number of different EGFR targeted therapies that are moving forward. And as I mentioned earlier, for each program based upon the preclinical evidence, we have expectations of what we would like to see for the molecule initially in terms of PK and safety, but ultimately in terms of efficacy. So what we're seeing from the EGFR MET-MET Trispecific, though it's very early days in dose escalation is that we are seeing clinically meaningful responses with that agent.

With the EGFR degrader, we continue through dose escalation. We've had some tumor regressions. We're happy with the PK and the safety profile. We simply need more data maturity. It's important to highlight that these are 2 totally different mechanisms of action, and therefore, our expectations for what we would expect from each molecule are somewhat different.

Our next question comes from Clara Dong with Jefferies.

Can you hear me?

Yes.

Congrats on the quarter. So you talked about the seasonality for the entire BTKi class. So just wonder how the seasonality dynamics differ across key regions in the U.S., Europe and the rest of the world as well. And then just looking at the time line for sonro and the BTK CDAC entering the market, sonro expected to file for MCL in the U.S. this year and BTK CDAC could have a pivotal readout next year in CRL.

So is this the right understanding that potentially BTK CDAC that can be approved first in CLL in the U.S.? And how do you anticipate this influencing physician sequencing strategy across B-cell malignancies special in CLL?

So Aaron, going to lock.

Great. Thanks for the questions, Clara. So as I said in my prepared remarks, I just wanted to reinforce as you think about your models, the seasonality patterns, this is really a focus in the U.S. where we typically do see inventory builds across the sector in the fourth quarter and then that unwinds to a degree in the first quarter. And then we did reference back to the same calendar issues that we experienced in '25 also in '26.

Globally, you see that to a lesser effect in our business in China, Q4 is typically a relatively lighter quarter by comparison. But given the magnitude and import in terms of percentage of revenue, for BRUKINSA in the U.S., we thought it was really important to highlight as you think about rolling over your models from '25 to '26.

So I can hand it over to Lai.

Aaron, you're correct. In terms of in the U.S. as well as probably use out of that -- CDAC is likely to get the CLL approval probably ahead of the sonro, but that's not the case in China. In China, we already filed the [ someone ] for the CLL, which we're also anticipating approval early next year.

In terms of sequence of the therapy, we view that CDAC can provide a really broad coverage in terms of patients who had BTK inhibitor. As shown actually in one of the slide in today's presentation, this really covers pretty much everything except maybe one mutation. So we do believe this is probably at this moment based the level evidence is positioned very well in the later line therapies after the COVID and BTK inhibitor.

Our next question comes from Michael Schmidt with Guggenheim Partners.

I just had another bigger picture question around the CLL market. As you noted in the slides, I mean it sounds like the AMPLIFY regimen has moderate uptake. But fixed duration treatment will clearly be part of the CLL treatment landscape longer term, including your own combination. And so I was just wondering how you think about how that might impact the overall size of the CLL market, the BTK inhibitor market longer term?

And then just a clarification on seasonality, Aaron. I know you made some comments around inventory in stocking at the end of the year. But then when I look at guidance, it seems like the top line the higher end, the top end of the range for revenue could be achieved with almost only flat Q-on-Q growth. And so was just wondering if there's anything else going on in 4Q that we should be aware of?

So maybe I'll start with a quick answer around that. As I laid out earlier in this long-term PFS really matters. You have 6 years of follow-up for data matters. These are cancer patients and you don't want progression there's no area outside of CLL I've seen where people talk about, let's take a regimen where you give up years of milestone PFS.

You just don't see that. Whether it's van-based fixturation treatments or other BTKs or [Porto], really all options beside chemo, they look pretty decent at 2 to 3 years. And there just isn't enough time to understand the durability and the outcome for patients. BRUKINSA consistently shows best long-term patient outcomes in CLL.

It's why it's the standard of care, and it's why it's the global leader. The more follow-up we show as we're doing at ASH, the more differentiated it looks. The 6-year data in CLL in first-line and second-line and in all high-risk subgroups, the story is the same, the best long-term outcomes for patients. It's 6 years follow-up, 74% PFS rate for BRUKINSA in first-line CLL.

When you COVID-adjust this at 77%, our OS is 84%, 88% COVID-adjusted. In ELEVATE TN, Acalus PFS is 62%, and their OS is 76% at the same time period. In second-line and deletion 17p, it's the same story. Unparalleled median PFS from Alpine and our SEQUOIA Deletion 17P data shows that BRUKINSA works very well in high-risk patients. It's just not the case with the other options.

And we're still reporting our follow-up data because it tells the story. Where is the other data? Where is the long-term data from ELEVATE? Where is it from CAPTIVATE. Where is it from AMPLIFY. It's very noticeable, it's not being reported. And with respect to [Porto] it's 18 months of follow-up in second-line CLL it's not even close to being long enough. And as we've mentioned, 2 to 3 years, you just can't differentiate yet.

And I think from that perspective, we're extremely confident in both the short term. And when we talk about long term, the really exciting thing is this desire to have fixed duration treatments. It's a great thing if you can get there. And so far, it does look like SC is going to be unlike anything we've seen yet. It's too early to be sure. There's not enough long-term follow-up data for that either, but the early data looks noticeably different than anything we've seen before. So we're really, really excited about that.

Now maybe I'll jump to Aaron to answer some of the other parts of that question.

Yes, thanks. Obviously, there's tremendous opportunity across the franchise as we think about where we're participating today in a $12 billion in growing market, whether you look at it from either a BTK space or an overall CLL space. To your question on the guidance, we did reinforce the seasonality really to make sure we support dialing in your modeling in that regard, given the history. We feel really confident on our execution over the course of the year.

As you referenced, we've taken up the bottom of our range from where we started we started the year at 4.9% to 5.3%, and now we're at 5.1% to 5.3%, showing increased confidence and really the great execution from our global teams. As you said, if you annualize the current quarter run rate and you think about the next quarter, we feel that the range that we provided is certainly within our expectations. The import of the seasonality common is really specific to the United States, and we want to make sure that, that perspective is really incorporate. Thank you.

There are no further questions at this time. I will turn the call over to John Oyler for closing remarks.

All right. Thank you all. I would like to point out that a few weeks ago, BeOne celebrated our 15th anniversary as a company. It's very hard to believe that in this relatively short period of time we've been able to become one of the leading oncology companies in the world.

I'd really like to think that this is because, as you heard today, were driven by scientific excellence, exceptional speed, and a relentless drive to provide the best long-term outcomes for patients. And on behalf of everyone here at BeOne, I'd really like to thank the broader oncology community including the patients, their families, the clinicians, our employees and all of you who have been with us for the journey.

We truly believe that together, we are how the world stops cancer, and we're just getting started. So thank you again for your time today and your thoughtful questions. Have a great day.