Nuvation Bio Inc - Ordinary Shares - Class A Aktie

Hello, and welcome to Nuvation Bio's Third Quarter 2026 Financial Results and Business Update Call. Today's call is being recorded, and a replay will be available on the company's website. [Operator Instructions]. Now I'd like to turn the call over to J. R. DeVita, Vice President of Corporate Development and Investor Relations at Nuvation Bio. Please go ahead.

Thank you, and good afternoon, everyone. Earlier today, we issued a press release summarizing our financial results for the quarter ending September 30, 2026, and provided a business update. The press release is available on the Investors section of our website at nuvationbio.com. Today's call includes forward-looking statements including statements about the therapeutic and commercial potential of [indiscernible] and savusitinib; our development plans for taletrectinib, satusitinib and our drug-drug conjugate platform, along with our plans for future updates from these programs. The components of our anticipated product revenue, our expected milestone payments and spending patterns and our cash runway and profitability potential. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements.

For a full discussion of these risks and uncertainties, please review our quarterly report on Form 10-Q, which we filed with the U.S. Securities and Exchange Commission today. Joining me on today's call are our Founder, President and Chief Executive Officer; Dr. David Hung, our Chief Commercial Officer, Colleen Sjogren, and our Chief Financial Officer, Philippe Sauvage. Now I'll turn the call over to Dr. David Hung. David, please go ahead.

Thanks, J.R. Good afternoon, everyone, and thank you all for joining us. Today, I'm pleased to discuss the progress we made across our business in the third quarter. We generated $45 million in overall revenue driven by another quarter of strong pros growth. Net U.S. and IBTROZI product revenue was $27.5 million, which represented 18% growth from the last quarter. Approximately 160 new patients started treatment with IBTROZI, about 65% of which were in the first-line setting. The commercial signals that matter most to our long-term thesis remains encouraging. 15 months into our U.S. launch, we continue to both build a growing base of patients on therapy and strengthen our position in the Rosslyn market.

IBTROZI has reached an all-time high in its share of active patients receiving a ROS1 TKI and continues to lead in first-line new patient starts with greater than 60% market share as of the end of the quarter. Our revenue growth reflects an expanding active treatment base driven by an increasing proportion of first-line patients that we believe can stay on therapy for yearsas seen in our trust clinical speeds. IQVIA claims data for the third quarter demonstrated a 15% decline in total new patient starts across the ROS1 TKI market. This is further evidenced by a lower volume of ROS1 positive testing alerts from our laboratory data partners.

We believe these observations suggest that at least part of the softness in our first-line new patient starts is a reflection of the overall flow of newly identified and treated patients rather than a loss of gross competitive position. Despite the market dynamics described. As of the end of the quarter, we maintained our strong position as the leading ROS1 TKI in total active patients across all lines of therapy combined. ROS-positive lung cancer is an ultra-rare disease, and the number of new patients entering treatment can fluctuate from quarter-to-quarter.

We do not believe 1 quarter provides sufficient data to establish an identifiable demand trend nor draw clear conclusions. We are monitoring market activity and treatment patterns closely while maintaining our focus on the drivers we can influence identifying patients earlier, educating physicians about appropriate testing, supporting biomarker informed treatment decisions and an increasing appropriate use of targeted therapy. We also are encouraged by how IBTROZI's lodge compares with historical targeted lung cancer launches, particularly given the small ROS1 population and fragmented prescriber base. While we realize comparisons are nuanced due to differences in size of patient populations, cost of therapy and initially approved lines of therapy.

We believe this is helpful to put IBTROZI's launch in context. For example, [indiscernible] into the launches of Lebrina and Asensa for ALK-positive lung cancer. U.S. net revenues per SEC filings and financial reports were $25 million and $36 million, respectively. As you know, IBTROZI has already reached similar levels of sales in a more competitive market despite rosin incidents being approximately half that of ALK. It is key to remember that the ALK-positive lung cancer market was not developed overnight, it took time for testing patterns, positioning confidence durability on treatment and long-term data to align behind the agents that ultimately became market leaders today.

Most fundamentally, our confidence begins with the clinical profile. In TKI-naive patients in Trust 1, IBTROZI demonstrated a 90% objective response rate, or ORR, 50 months of median duration of response, or DOR, and 50 months of median progression-free survival, or PFS, is tolerability profile, including the unique absence of the CNS warning and precaution in the label, is another critical point of differentiation among brain-penetrant ROS1 PKIs. And remember, these metrics are supported by a median patient follow-up of 51 months in the TRUST 1 study. We believe these attributes can support physician confidence, sustained first-line adoption and meaningful time on therapy. This clinical profile is also one of the reasons we chose to develop a toy in the adjuvant setting. While we're encouraged that enrollment is fully on track in this first of its kind study for ROS1.

If approved, this indicates you could expand the patient population IBTROZI is able to address and the data from [indiscernible] study in RET-positive non-small cell lung cancer has given us even more confidence that we could reach a meaningful result in Ross on sooner than we initially thought. Taken together, the results reinforce our view that we are building a durable commercial franchise and that those has become the standard of care in ROS1-positive lung cancer. Quarterly new patient activity will not always move in a straight line, but our competitive positioning, growing active patient base and ability to reach more eligible patients provide a strong foundation for the years ahead. Moving to south lucitanib.

We remain very excited about this program and its potential to become a key value driver for innovation bile as we move to 2027 and beyond. In August, the FDA granted fast track designation to sacrusitinib for the treatment of IDH1 mutant glioma. We view this as supportive external validation of both the unmet need in this disease and the potential development path for sapucitinib. Fast Track designation is intended to facilitate development and expedite review of therapies that may address serious conditions with unmet medical need and we are pleased to have this designation as we continue to advance the program.

As a reminder, in July, we announced updated long-term results from the Phase II J201 study in 27 patients with chemotherapy and radiotherapy naive, grade 2 IDH1 mutant glioma. With a median follow-up of 39 months, the centrally assessed ORR increased to 52% from 44% at 28 months of median follow-up, median PFS had not yet been reached and the 36-month PFS rate was 79%. Responses in the study have continued to deepen and no new safety signals were observed with additional follow-up. We will present more detailed data beyond these top line results at the Society for Neuro-Oncology Annual Meeting next week. As a result of this encouraging data set, we recently announced an enhanced development plan that allows us to address two key goals.

First, our four studies together address all grades and risk groups within the broad IDH1 mutant glioma landscape. Second, two of these studies focus on patient groups with high unmet needs and no alternative treatment options and evaluate ORR as a primary endpoint, which will allow us to generate data quickly. In fact, these two studies in patients with Grade III oligodendroglioma and in patients who have progressed following treatment with vorasitinib also analyzed tumor growth rate or GR, as a secondary endpoint, which may provide an even earlier signal of efficacy. This is a key difference from our other two pivotal randomized studies, which evaluate PFS as a primary endpoint and will not generate data until 2029 or later.

As a reminder, these pivotal studies include SYGMA, which is evaluating [indiscernible] in patients with high-grade and high-risk astrocytoma and a separate study in patients with Grade 2 IDH1 mutant glioma. Enrollment in the SYGMA study, including the exploratory cohort is on track and we expect to be enrolling patients in all 4 studies in the coming months. We plan to provide more specific updates on enrollment and clarity around timing of data readouts next year. Finally, we also remain on track to provide an update on our drug conjugate, or DDC platform by the end of the year. This update will include additional detail on how we plan to move the program forward and into the clinic. We are excited by the progress of this program and look forward to sharing more information soon.

Overall, the third quarter reinforced the long-term opportunity in front of us. IMROZ is now a commercial leader with a growing active patient base that is driven by an increasing number of new first-line patients and their long duration of treatment. Saflucitinib continues to advance as a meaningful second franchise with potential data next year, and our DTC platform can contribute to future pipeline growth. With that, I'll turn the call over to Colleen to provide a more detailed update on IBTROZI commercial launch.

Thank you, David, and good afternoon, everyone. IBTROZI continues to strengthen its leadership in the ROS1 market with a launch trajectory that stands out against historical benchmarks. Just 5 months after launch, we have achieved approximately twice the cumulative patient starts of earlier generation ROS1 TKI launches at comparable points in their commercialization based on our internal data and adjusted claims estimates. This is particularly meaningful in an ultra-rare disease with a broad and fragmented prescriber base.

We believe this performance is a testament to both ptosis differentiated clinical profile and the strength of an experienced commercial team that knows how to successfully launch targeted oncology therapies. In the third quarter, U.S. net product revenue grew 18% sequentially to approximately $27.5 million despite an observed decline of about 15% in new patient starts across the overall ROS1 TKI market. This quarterly decline was observed in 2 distinct data sets. IQVIA data and the number of ROS1 NGS testing alerts from our contracted lab partners. This is the kind of fluctuation sometimes observed in ultrarare disease, and we do not believe is indicative of any trend.

In fact, it builds confidence that we continue to grow our active patient base and our sales in a down market. This growth was broad-based across treatment settings, reflecting deepening physician confidence, expanding adoption and sustained demand for those -- our commercial execution continues to translate into significant market leadership. And this quarter, we achieved an important milestone. If Toz is now the leading ROS1 TKI in total active patients across all lines of therapy combined, this based on IQVIA claims data. This is not simply a measure of new patient starts. It represents our share of all patients actively receiving a ROS1 TKI including those who have initiated therapy years ago on earlier generations of ROS1 TKIs.

Having achieved this leadership position just over a year post approval in a market with established therapies is particularly significant and reinforces both the strength of IBTROZI clinical profile and the success of our commercial execution. We are also continuing to strengthen our first-line position. We established IBTROZI as the market leader in total active first-line patients through the end of the quarter and today, our share of first-line new patient starts is more than 60%. As David discussed, IBTROZI's compelling efficacy, exceptional durability and generally favorable tolerability profile continue to differentiate it in the first-line setting.

Based on multiple advisory board meetings and one-on-one engagements, physicians continue to point to the strength of our clinical data supporting our belief that IBTROZI's durability is a benchmark against which other ROS1 therapies will be measured, especially given our mature patient follow-up. While our trust clinical studies were much longer than NETosis time in the market, to date, we have observed a clear similarity between duration of therapy in the real world and durability in our clinical trials. This is further evidence of why we believe IBTROZI can benefit patients for years. As the launch continues to mature, we are seeing a natural evolution in the ROS1 patient population. At launch, there was a pool of patients receiving earlier generation ROS1 inhibitors who were candidates to switch therapies due to disease progression or tolerability.

We have successfully captured many of these patients. As a result, the pool of patients immediately available to switch has become smaller and future growth will increasingly be driven by newly diagnosed patients. We believe this dynamic, combined with our entrenched commercial leadership provides a strong foundation for sustained long-term growth. And while new treatment options are entering the market, our leadership remains strong as intros continues to be the only brain-penetrant treatment option without a CNS warning and precaution in its label. To date, we have not observed a material impact on IBTROZI's overall active patient share with recent market entrants, and our data suggests that early uptake of a new competitor is largely concentrated in later lines of therapy with no off-label use in TKI-naive patients.

Beyond our growing market leadership, we are also encouraged by the opportunity to expand the overall ROS1 TKI market. Claims data show that the number of patients actively receiving a ROS1 TKI increased materially year-over-year following IBTROZI's launch, even with the market pullback this past quarter. We believe this growth demonstrates the potential to expand the population of receiving a ROS1/TKI. And we see an even more substantial opportunity ahead through earlier identification of ROS1 fusions and increased adoption of targeted therapies in place of chemotherapy with or without immunotherapy.

However, we see two key barriers remaining along the testing to treatment journey. First, limited awareness that DNA-based testing alone may miss ROS1 fusions. And second, the urgency to initiate treatment before molecular testing results are available. potentially leading patients to receive chemotherapy or immunotherapy instead of a targeted therapy. We have focused commercial initiatives underway to help drive the shift in testing and treatment decision behavior, which we believe are key sources of long-term growth for TRUs. For example, through our quality-based initiatives, we are addressing critical gaps in patient care from significantly improving NGS testing rates at key community oncology practices to ensuring patients receive optimal care with appropriate targeted therapies.

We are also assessing testing lab alert data to prioritize relevant physician outreach and advancing network collaborations to strengthen molecular testing and treatment decisions. Additionally, we are also investing in field training, coordinated omnichannel marketing and AI-enabled approaches to make HCP engagements more targeted and timely. We know this may take time, but patients deserve it. And our focus is always on increasing the rate of diagnosis and displacing inadequate treatment options. At the institutional level, we continue to strengthen access and pathway positioning. For example, one major community pathway recently reinforced the position of IBTROZI as its primary first and second-line ROS1 TKI treatment choice, along with focused contracting initiatives and tailored strategies across academic centers, IDNs and community practices, this reduces practical barriers to access.

These efforts require close appropriate coordination among sales, market access, marketing and medical and I'm incredibly proud of how our experienced teams are executing cross-functionally. What gives me confidence in the long-term success of IBTROZI is the combination of strong clinical differentiation, an established and growing market position and a commercial team that understands both the opportunities and the work required to capture them. We have built a strong foundation over the first 15 months and we remain focused on translating that leadership into sustainable long-term growth and bringing the potential benefits of Aptos to more appropriate patients.

With that, I'm going to turn the call over to Philippe.

Thanks, Colleen, and good afternoon, everyone. For detailed third quarter 2026 financial results, please refer to our earnings press release, which is available on our website. I will highlight a few key points from the quarter. For the third quarter of 2026, total revenue was $45 million, including $27.5 million in IPTV net U.S. product revenue and $17.5 million in collaboration and license revenue. For the first 9 months of 2026, we generated $159.9 million in total revenue. This included $69.2 million pros net U.S. product revenue and $90.7 million in collaboration and license revenue. The commercial dynamics David and Colleen discussed are consistent with our view of how this market would and will develop as behaviors change.

The later line pretreated ROS1 population represented an important but finite opportunity early in the launch. The long-term growth driver now becomes first-line adoption and the accumulation of patients who can remain on therapy for multiple years. David mentioned the trajectory of precedent launches in the ALK-positive lung cancer space. These precedents tell us a few things. First and foremost, that it throws these launches in line with prior rail lung oncology launches on a population-adjusted basis. but also that it takes time for the first-line patients on therapy to build a durable revenue base. This is why we continue to be excited by ptosis potential.

Our access strategy continues to be effective. Gross to net deductions were approximately 30% in the third quarter. We expect gross to net to remain generally stable as our payer mix and contracting mature. The remainder of our revenue was generated through collaboration and license agreements. We continue to receive royalty revenue from open biologics in China and [ Nippon Keeco ] in Japan. So China and Japan launches are progressing ahead of our expectations, and we continue to view our ex U.S. partnerships as a scoring component of the broader to the opportunity. In fact, $7.7 million of our total revenue for the quarter was driven by milestone and royalty payments from these partnerships. RECONNECT We are also working closely with ASI for Europe and other select territories. We expect potential approval in Europe in the first half of next year, which will trigger an approximately $30 million milestone payments to evasion buyer.

On the expense side, we continue to invest in the business and our programs, resulting in total operating expenses of $75.2 million for the quarter. R&D expenses were $32.7 million for the quarter and $98.4 million for the first 9 months of 2026, primarily reflecting investments in the trust and satellite clinical development programs as well as preparation for future development activities. SG&A expenses were $42.6 million for the quarter and $123.5 million for the first 9 months of 2026, primarily driven by support for the commercialization of IBTROZI. While we always expect small quarter-on-quarter fluctuations in our spend, we do not expect material changes to our general spending patterns for the remainder of the year as the rise of R&D spend on saprucidanib is compensated by gradual reduction of the [indiscernible] trust program over time.

It is also exciting to highlight that for the first time, Its is now in the quarterly revenue run rate related to launch-related expenses that represents a self-sustaining commercial program on a stand-alone basis. Our goal has always been for IBTROZI to be a driver of future profitability and we view this as a first step on the journey of IBTROZI being able to finance all of our spending activity.

Turning to the balance sheet. We had cash, cash equivalents and marketable securities of $663.4 million as of September 30, 2026, which now includes all proceeds from our convertible debt offering this summer. This solid cash position gives us the confidence to continue investing in our future, driven by our pipeline of exciting assets. Importantly, our approach to capital allocation has not changed. We remain disciplined, we will continue investing the IBTROZI, advancing [indiscernible] and progressing our DDC platform for a position of strength. We also continue to evaluate business development opportunities only where we see the potential to generate compelling returns and create long-term shareholder value. Based on our internal revenue projection and the current operating plan for all of our programs, we continue to believe we have solution capital to reach profitability. I'll now turn it back to David for closing remarks.

Thanks, Philippe. This quarter really enforces what we are building at Innovation Bio, a commercial program with the potential to redefine the treatment of advanced ROS1-positive lung cancer A second program that continues to gain momentum in IDH1 and glioma and a pipeline platform that we believe can support future growth. We recognize that changing treatment behavior in target oncology takes time. But we are confident in the fundamentals. IBTROZI has a differentiated label, a growing active patient base and the durability and tolerability profile, we believe are necessary to support long-term adoption.

At the same time, safucitinib is advancing through a comprehensive development plan in an area of significant unmet need. I am proud of the progress our team continues to make and grateful to our employees, investigators, partners and shareholders and to the patients and families who place their trust in us. I'll now ask the operator to open the line for questions.

[Operator Instructions]. Your first question comes from the line of Farzin Haque with Jefferies. Please go ahead.

First on Glioma, are you providing any color on the enrollment for the 2 cohorts, the [indiscernible] the post [indiscernible] patients? And when we could potentially get the ORR readout in 2027?

We haven't yet provided color on that, but we will probably be doing that in the future time.

Got it. And then on IBTROZI, the October sales are looking in line with prior months. But with the new patient starts holding up and the first-line patient base is accumulating, how should we think about the 4Q revenues despite the broader ROS1 market decline that you're seeing? Is 108 million consensus the right area to think about for the year?

Yes. I think there's lumpiness in this last quarter. So I think that we don't really look at that as a trend of any store. So we anticipate growth continuing around the same work as we've seen in the past.

Your next question comes from the line of Gregory Renza with Truist Securities. Please go ahead.

It's Anish on for Greg. Congrats on the progress this quarter. We wanted to know within the first-line opportunity, how are you seeing IBTROZI compete with repotrectinib what is driving physician choice? And is the bigger remaining opportunity taking share from other TKIs or earlier ROS 1 testing and conversion from chemo/IO?

Okay. Well, that's a lot of questions. But I think we're doing very well against repo. As you know, we are not only a market leader, but we are also -- in the first year of our loss, we've sold twice as much drug as all the ROS1 agents combined. So we've done extremely well against our competitors. We think the market is going to grow by a couple of ways. Number one, we do believe that we will take share from other TKIs given. If you look at our efficacy, which is not -- has not been matched our safety profile, has been mentioned, we are the only on TKI that penetrates the brain that does not have a CMS aware of precaution.

So that's unique. So we think we will continue to pick markets but from other TKIs, but we also do think that we will grow the market because good drugs grow markets. And we saw that happening with ALK. We saw that with GFR and we think that's going to happen in ROS1. We do anticipate increasing testing for ROS1, but we also anticipate other changes in practice that are now supported by NCCN guidelines, namely reduction of IO/chemo use and using a precision RAS1TKI for precision patient like RAS1. So we do think that, that will continue to grow the market. Colleen?

Yes. I want to add on to that, too. Thanks for the question. It's a good one. So when you look at IBTROZI right now, what is really remarkable looking at the team's achievement truly right now has the largest number of patients actively received in a ROS1 TKI. Now that's across all lines of therapy combined. And to your question, that's including patients who started in prior periods on therapies available for years. So this is distinct just from being #1 in new star. So reaching this position in just 15 months after launch, that reflects both new patient adoption and patients continue in treatment. So we think that's really important.

And I'd like to just address quickly what you said about testing. We see this as one of the most meaningful opportunities. So when we look at the two care gaps that matter most, we're looking at this idea that DNA-only testing can definitely miss some of these ROS1 fusions. And then the other part of it is these treatment decisions beginning sometimes before molecular testing results are even back and available. So we're hyper focused on improving comprehensive testing, and that's including appropriate RNA-based methods. We're also very focused on helping practices incorporate molecular results into their treatment decisions. So these changes do take time. We know that. This team has been an ultra-rare disease before but they definitely can improve care and expand the appropriate targeted treatment for these patients.

And I want to add one more comment to Colleen's comments. So if you look at the duration of response in the [indiscernible], it's 50 months. That's like repo track them, their DOR around 36 months. So that's a pretty significant difference. And how long pages will be on therapy. That contributes to more patients being on therapy. But on top of that, I mentioned that we are the only as on TKM without a CNS warnings precautions. As you look at our median-time of follow-up with the cross data so far, it's 51 months. We're not talking about 14 months of follow we've had well over 4 years of follow-up, and you know that adverse events accumulate with time.

In spite of a 15 1-month follow-up, we have right now, no CDS works the cost in our label. We have a very, very low incidence of adverse events, we think that, that, combined with the efficacy leads to a growing pool of patients on therapy, which will contribute to the revenue stacking that we've talked about from day 1. So we do think that a number of patients [indiscernible] will continue to grow, especially because of our long duration of response and are really excellent tolerability.

Your next question comes from the line [indiscernible].

Great. Congrats on the quarter I had a couple of questions. One for IBTROZI. Maybe it would be helpful to walk through in the U.S., the nuances between the community and the academic setting, other any differences there? And then as your partners prepare for a launch in China and in Japan, in that market, are there anything that then you would call out as differences that may help the launch and adoption? I'm just trying to think of the comparison to the U.S. And then I have a follow-up on [indiscernible].

Sure. So in the community, we do see lower rates of testing than in many academic centers. So I think that will improve over time. But I would say that community is still not getting as much testing done as a emissions are. On top of that, we do think that there is probably more I/O chemo use in the community setting than there is in academia. So I think those are two of the most important differences. When we look at China and Japan, those launches have actually exceeded our expectations. And part of that's because testing is actually remarkably high in China and Japan. And in China, you get the trouble for not ordering NGS on lung cancer patient in 2026. I wish I could say that for the U.S., that's not the case. But I would say that the testing rates in China and Japan are excellent and probably contribute to the reason that those launch have actually exceeded our expectations.

Okay. And then just on SAP with the expansion of the SYGMA study. Maybe just talk a little bit about what that means for the standard of care across the different European countries? I'm just trying to think of variations in the standard of care among the different new European countries and what that could do to some of your comps or maybe enrollment kind of time lines?

Yes. I don't think it's going to really change in one of the countries. The things that all the patients have to have failed to get on to SYGMA study are all pretty standard I don't think that's going to continue to do any real variation. I think that this is a pretty uniform patient population we anticipated being pretty standard across all the countries. We are trying to find countries where there are different standards of care in which LoRa is not available to do a study against placebo because that's not possible in countries that do have more. But I would say for the sign signal countries, the standards of care are pretty standardized across all of them, and we don't anticipate any real problems from a clinical trial standpoint.

Your next question comes from the line of Li Watsek with Cantor Fitzgerald.

Maybe just on SAS readout, what should the endpoints could we potentially get in 2027? And what would be impressive outcomes either [indiscernible] for settings? And then on those just wondering what the reason might be behind the sequential decline of the new patient starts for the overall market?

Okay. Let me answer your first question first. So with regard to [indiscernible] readout, we've previously said that we expect at least 20 patients to be enrolled this year in the grade 3 [indiscernible] on the study. So that means by June of 2027, we will have somewhere between 6- and 9-month follow-up on at least those 20 patients or more be enrolled more than that. So in general, if you look at how long it takes to get a response on saclasitinib, we would say those responses, we see are generally in the range of 6 -- between 6 months and 12 months. So we would expect a number of those patients to have objective responses. We are also initiating these postmorocitinib study.

This study is different because there are a lot of patients now who have been put on [indiscernible] in the thousands. And we know from the [indiscernible] that about 1/4 of them progress on [indiscernible] within about a year. So given the fact that [indiscernible] is now pushing almost 2 years since launch, we would expect there to be well over 1,000 patients that would be available that will be progressing on IBTROZI, and we believe that it will be very easy to identify patients progressing on [indiscernible] because or progressing clearly the opportunity to see responses there is even greater.

We believe that the [ BARDA beat ] is in the range of 20%. We know from Chimerix, as an example, their approval was based on 50 patients in their trial with 11 responses, about a 22% response rate. We know that other glioma trials have been in the range of about 70, 75 patients or so. So we think that's somewhere in the neighborhood of 50 patients at a 20% response rate gives you a data set that would be pretty compelling to FDA in an unmet need and certainly grade 3 [indiscernible] 2 indications where there is absolutely nothing available to these patients. So we think that's a wide-open opportunity.

You want me to take the -- Li, so your second question on Atos and the slowdown. So a couple of things. In my experience and the team's experience, this is really the volatility that you expect in an ultra-rare market, even when we look across the other TKIs in the lung space, you saw a sharp decline in EGFR and ALK Q1 and then it bounces back. We can never attribute sort of a slowdown to one single cause but the evidence that we do see here points in one direction. So the IQVIA data shows lower overall market status. We talked about that 15% pullback that we see -- and that aligns naturally with what we saw in our lab partner alerts move the same way. So approximately a 25% decline there.

So the good news in a market that's pulling back, it true you still maintain more than 60% share of first-line new patient starts. So while reaching, by the way, the leading position in total active ROS1 TKI patients, so this is very consistent with the smaller market flow than a broad deterioration in our competitive position. So additional quarters will show. And we expect that, that will show that the market volume will also normalize.

And Li, just because we've heard some confusion over our clinical trials and what endpoints are being used and when the readouts. Well, let me just reiterate that for everyone. So there's core to -- the SYGMA study is a PFS readout. That's going to be long. That's going to read out in 2029 or so. And against vorisitinib, that's going to also be a PFS readout. However, two of our studies are response rate studies. The grade 3 [indiscernible] is a response rate study, which we believe we will have data on starting probably mid next year. and the post baricitinib study is a response-based study, which we will also start to have responses to 2027. So we would expect that.

So while we cannot tell you exactly when the response will occur we feel very confident given our data that we will see responses that we think that [indiscernible] selling will be the beginning of a number of response that will observe hopeful borrowing pacing for those indications.

Your next question comes from the line of Leon Timashev with RBC Capital Markets. Please go ahead.

This is Vander on for Leo. So I know you touched on a little bit a bit of this already. But I guess when looking at the post more setting, are there any precedents or comps that you can point to that would be helpful when we think about reusing a mechanism while moving down in treatment line kind of how we can think about framing responses there. SP1 As the question why we believe that we will have responses in the [indiscernible]?

Okay. I mean, first of all, if you look at our response rate, it's significantly higher than [indiscernible] more than double [indiscernible] response rate. So clearly, we are -- we have -- we just have low responses. But number two, if you look at the kinds of patients we're treating we have responses in sicker, more advanced types of glioma than [indiscernible]. And it's always hard to treat the more advanced, the harder ones than the easier one. So given the fact that we have high-grade responses when [indiscernible] and given the fact that we had more than double the low-grade response to [indiscernible] and given the fact that there's always some overlap in the spectrum that we almost have between low and high grade, we would certainly expect to have responses in those more failures.

I don't think our data are pretty compelling in that regard. On top of that, we've made the point previously that our adverse events are different. Our Vora's primary adopts liver [indiscernible]. Ours are immune type reactions, things that we believe indicate increased immune activity things like [indiscernible] our slightest rash paramos. These are things that we believe are consistent with an immune mechanism. And if you look at our responses that we've seen so far in all of our studies, as I mentioned, it can take 6 to 12 months of the response, that sounds an awful long like immuno-oncology. If you look at our response we get them, they're really durable.

If you look at our GVM, that patient's tumor has been gone for 3.5 years, high grade, [indiscernible] gone for 3.5 years. Those are immune type reactors that we think completely differentiate us more. So just given our efficacy at we see so far and the kinds of adverse event we've seen and the durability of our responses, we would certainly anticipate that we will see response [indiscernible].

Your next question comes from the line of Priyanka Grover with JPMorgan. Please go ahead.

So on the persistence trends on the front line, second line, what have you seen throughout the quarter? Basically, are discontinuation rates still tracking with what was shown in the clinical trials?

Priyanka, so when we look -- yes, so when we look at treatment-related adverse events in the first-line and second-line TKI naive, we are tracking very closely. So when you look at launch through September, our TRAEs are tracking very closely to what we saw in our trust trials. So that's been consistent since launch.

And generally speaking [indiscernible], we have not seen anything different from what we've seen in the clinical trial in terms of patients staying on therapy, to time with cell therapy and all of these things. Not anything different so far. Obviously, the clinical trial, we had more than 50 months integration. Here, we've launched only 15 months. So we cannot say for the future, but it's clear that so far, we've seen tracking it exactly to the clinical trial track. So really no difference there. It is very reassuring to the long-term potential of that market, of course.

And one thing maybe I'll add on to that, Priyanka. So keep in mind that many of the patients who started early in our [indiscernible], they had received prior ROS1 therapies. So in progression, that more heavily pretreated population has been an important driver of where we saw those discontinuations. But to Philippe's point, you monitor discontinuations by not only line of therapy, but cause, so not just in aggregate, and our adverse event-related discontinuations have, in fact, remained low and consistent with the trials.

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

This is Steven on for Yaron. One from us on [indiscernible]. Are we inferring correctly that you might expect the grade 3 oligodendromo study to be the faster readout versus the [indiscernible] and then maybe a follow-up on the tumor growth rate, how would FDA acceptance of that endpoint change the timing on the path to market? And could we potentially hear an update around the growth rate before the ORR data come out?

SP1 So I don't know which really faster. I think that we feel pretty confident that the all of the study will only be positive because we've seen great responses there. I think post [indiscernible], we also, as I mentioned, we have so much higher -- more than double the objective response rate in [indiscernible] the low-grade setting and have significant high-grade response for [indiscernible]. So I just think the spectrum of activity is so different between stat and right. I feel bullish on that study as well. I can't tell you which will read out faster. I think that the Voro study should accrue faster because there's more patients, but we started accruing the Grade 3 [indiscernible] study months ago.

So that, again, will they really be different, I don't know. Tumor growth rate, we think it's a really important endpoint. Now it's not accepted yet by FDA, but I think it makes the point that you can't have a response where that's growing, you can't shrink without paging is slow and that's just a no-brainer. So when we change the tumor growth rate from positive to negative, it's hard to ignore. And we're going to assemble data to show how well that correlates with ultimate response. But we do think that when you change the tumor that's growing with a positive flow to one that has a negative flow.

Certainly, the patient is going to feel a lot better about that as this is doctor, and I would imagine so with the FDA. Now whether or not they'll accept it at this point, we have no idea, we're not assuming that. We're still assuming they'll take response rate, but we will present those data with our objective responses to form a package. I think will be important in the future because I think that is where the CO had because I do think that you can't get a response without a change in the tumor growth. And maybe another point to keep in mind. We're not talking enters that often. We're not talking about the blind study. So you can see response rate over time. And doesn't necessarily mean you have to wait for a certain time to read out that we would do for PFS.

This is response rate that we are monitoring over time. So as we accumulate patients in both of those studies, we will have a better view of the response rate, and we will know where the slope is taking us to David's point about the tumor port, which will give a lot of confidence to us that if the tape of that curve is spending we will eventually get to the kind of response we are hoping for, and that's really important to you.

Your next question comes from the line of Michael Yee with UBS. Please go ahead.

This is Matt on for Mike. Congrats on a nice quarter. Could you talk maybe for the Grade 2 low-grade low-risk study? Do you expect the control arm of that study to perform similarly to the original RORO study? Are there anything in the patient population to think about that might not be the same? Any thoughts there would be great.

I do think there would be [indiscernible] so we're not inventing any new wheels here. We're just trying to do a better drug to get the same deal to get better results. We expect the trial to be very similar.

Your next question comes from the line of Mayank Mamtani with B. Riley. Please go ahead.

[indiscernible] on for Mayank. Congrats on the share gain this quarter. So you had a slide show in comparing [indiscernible], both of which grew about fold from your third quarter as first frontline patients accumulated. What can you confident that IBTROZI closely follows that same curve? And also on [indiscernible], for next week, what should we focus on for the 4 SLO posters? n

Yes. So as we had mentioned, if you look at the sales in the first 5 quarters of [indiscernible] they are in the range of $26 million to $30-something million. And we're smack that in that range despite the fact that loss incidence is half about. So in spite of big half the incidents, we're still generating about the same amount of sales. So we think that's pretty good. And they still grew that market fivefold more beyond that. And we think that given our trajectory we should, we're comparing quite favorably to the out launches. So we think that we're actually doing pretty well.

And the other thing which is very reassuring that Colleen was mentioning earlier, right, is that this has been, to your point, a very steady and important growth over time, but not necessarily like every quarter higher on new patient to. Colleen was mentioning that earlier. If you look at the new patients starting out, was down 19% versus Q1. So you do see in that gray space some fluctuation. But despite those fluctuations, the trend is clearly up in that space and has been up for a very long time. Because of the extremely long duration of our response and the very high celebrity of rosy, we believe we're going to see exactly the same thing, which is a general trend going up and going up for a very long time. Even if you could have the fluctuation of new patients to one part of the net, those things happen.

Let me make another point. So if you look at the DOR of at least we elected it's much, much shorter than our 5-month DOR and [indiscernible] didn't at the time, did not even know that the Crown data will ultimately give them a 7-year PFS. But if you look at our duration, you're not going to even see that per year. So we're only 15 months -- 15 months out. you're not even going to see the stacking from its for another full stacking for another 3-plus years, right? So the fact that we're already matching the launches at half the epidemiology incidents and we haven't even gotten to the stacking suggest to us that we're going to do really well.

Got it. And for next week for the SNO posters, what should we focus on?

SP1 We haven't -- you're going to see more data on gaps and durability of responses. We can't give you a lot more color than that, but you're going to see more detail on the depth and durability of the responses that we've presented before.

Your next question comes from the line of Robert Burns with H.C. Wainwright. Please go ahead.

Two questions for me, if I may. So obviously, we saw updated data for -- from the ARRIS 1 trial at ESMO this year, and GSK is planning to file an sNDA in the coming months. or is it same in the frontline setting. So considering that as well as the launch dynamics that you're announcing within the frontline setting for TROI, I wanted to get your thoughts on the potential impact of zidezamtinib's potential approval in the frontline setting on IBTROZI future revenue potential in the front line.

And then switching over to Vora. Obviously, considering that fact that we're going to see -- we're going to see data from the Phase II trials in 2027, which could potentially support an FDA approval. I want to get your thoughts as to how you're thinking about the build out -- whether you'll have to build out your commercial team further to launch it in the CNS indications that you're pursuing in 2028.

Let me take the first question, and I'll turn it to Cole for a second. So the bottom line is we have a 5-month DOR in the first-line setting. We have not seen anything from the date on what their duration of response will be in the first-line setting. So I would just say that it's going to be pretty hard to beat a 90% response rate in the 5-month DOR. As we've mentioned, except for [indiscernible]. There are no drugs in the industry of oncology that have been able to better a 15-month DOR at those. So I would say that we don't know how their label will look. When their second line label came out, it there were some surprises. Zagato had CNS worries in Pecos, which no one had expected. If you look at their adverse events, even now, 42% peripheral edema, something that's very noticeable to patients.

CNS warning precautions, shortness of breath, 4% grade 3 shortness of breath. These are things that I think are going to make it more challenging to continue using drug in the first line setting where you're -- if you want to get to a 15-month DOR, you're going to have to have a pretty tolerable drug with 1 month of follow-up, we've shown extremely tolerable profile for IBTROZI. But after only 14 months of follow-on presidential, as I mentioned, they already are up to 42% [indiscernible] and toxicity plus all the other things I've mentioned. So I think the data will come out when the data come out. And right now, we think that we are at the bottom beat, and I think it's going to be hard to match. Colleen, I'll let you turn.

Yes, sure. I'll add a little bit on to that. I mean, first of all, we expect competition to evolve. And I just want to reemphasize, when you look at the accomplishments of what my team has done across cross-functional marketing, market access, sales, medical affairs, when you look what they have accomplished in 15 months as of fourth entry into the ROS1 market. It's just remarkable. And what brings us a lot of confidence in the future is that KOLs so are our top thought leaders consistently cite our durability and our data maturity as key differentiators.

So as David said, with many describing are approximately 50 months median duration of response, supported then by our 51 months [indiscernible] follow-up. It just has created a benchmark for them. So combined with our favorable tolerability profile, this just reinforces physician confidence, and I would say particularly in the first-line setting. So we will continue competing what I believe is most important is on the totality of evidence and on our execution rather than assuming any market share is permanent. We are ready for competition, and we feel well positioned.

And Robert, to your structure point about launching in glioma Obviously, there are lots of things that we will not have to do. Like we could leverage fully our commercial organization as it is. The only difference is different calling points. So we potentially need to add some reps. But when you think about day 1 at about 17 reps. So it's not -- we're not talking about a huge team. Glioma created a certain number of centers, which is rather limited because obviously, it's spring cancer you don't treat that everywhere. So we are thinking about relatively limited commercial team that will be able to fully exploit all of the synergy we've had by being already a fully commercial organization when you think about net OpEx management, all that we have to support Salesforce today, all market access, et cetera. All of this will be leveraged. So it's an addition because different calling points, but a relatively small addition.

Your next question comes from the line of Silvan Tuerakcn with Citizens JMP. Please go ahead.

SP-25 This is Josh Harman on for Silvan Perkin. Congrats on the update today. Maybe just on the variability in the ROS1 diagnosis how consistent has that, I guess, 3,000 annual diagnoses been year-over-year? And is the variability is it year-to-year? Or is it more quarter-to-quarter, I guess? And then additionally, maybe could you speak to some of the relevant updates in glioma at ESMO?

Okay. So let me be clear, we were never talking about any data suggests that the epidemiology is on. There is a large amount of literature in the support roughly 2% incidence of non-small so long cash being going positive. What we were talking about just that where you have a rare indication like Glass quarter-to-quarter, there could be lumpiness. The thing is going to change. We've seen this -- if you look at Elk scripts, they varied as much in just recently, I believe that 1 of the quarters recently was showed a 15% reduction in outstrip in the quarter. We've seen that in other orphan indications. So we don't believe that the overall epidemiology [indiscernible]. We just believe that from quarter-to-quarter, when you have a rare indication, you may see some lumpiness and you may have quarters are down quarters that are out there.

But overall, it will equilibrate to roughly 2% of all lung cancer. New patients properly identify can situate from 1 quarter to the next. And that's what happened, as we said in our [indiscernible] everywhere really. But the trend in the epitogystands, which, to your point, means that it's a quarter-to-quarter fluctuation, another year of change.

Yes. I don't think there's anything in [indiscernible] really changed. In fact, it really further highlights how special [indiscernible] is because there were actually no data for any agent that had on results that are compelling, in our opinion, this happens. So nothing that we can identify in the landscape. We do think that [indiscernible] is the most polishing drug being decaled and so we are excited about the program.

To add to that, another point we made in the past is that because we are going to develop safe market for voice now available, it's going to be very, very hard for anyone in the future to develop anything in IDH1 written glioma without comparing to an active comparator, which will be either us or rating at that time. So not only we've not seen very much the development going on in that space. But any future development in that space will be much more difficult because we'll have to compare to an active comparator, and we know it's much harder to do and much longer.

Your last question comes from the line of Boris Peaker with Jones Research.

Just two questions. On IBTROZI, could you comment on the gross to net adjustments this quarter and how that is trending? And the second question on the SYGMA trial. I'm just curious in post-chemo radiation, sometimes you see pseudoprogression, which could complicate the modified no assessment. So I'm just curious what steps are you or the centralized blinded independent committee taken to adjudicate for progression versus maybe treatment-related inflammation or pseudoprogression.

I will start with the GTN. So pretty much stable this quarter like it has been in past quarter. As I mentioned in previous calls, so next time you're going to see [indiscernible] I'm sorry, can you hear me? Yes. So next time, we're going to see an evolution of our GTN will be at the time of our next price increase because of inflation impact and things of that nature. But it's been very stable throughout the year. And we think we really stabilized around this 30% gross to net. That's where we are, and that we believe we're going to spend through the end of the year. And I'll let David comment on the second question.

This study is being compared against placebo with a blind independent committee review. So I don't I think that there will be significant differences between the two populations, but the comparator is placebo. So I think that's the control. And I don't know how the comment on that. It's a controlled study. We think that's...

I'm just worried that even on a placebo, but the radiation itself could cost due to progression?

Well, but there's both -- there should be in both arms, right? The difference will be the drug. And just given the results we've seen so far in our SAP studies, we think the drug will be a significant difference.

There are no further questions at this time. I will now turn the call back to David for closing remarks.

Well, we want to thank you all for your support, and we look forward to updating you on our next call. Thanks so much.

This concludes today's call. Thank you for attending. You may now disconnect.

Hello, everyone. Welcome to the Day 2 of the Cantor Healthcare Conference. My name is Li Watsek, a biotech analyst here at Cantor. It's my great pleasure to welcome our next company, Nuvation Bio, for a fireside chat. And with me today is David, CEO; and Philippe, CFO. Thank you for joining me.

Maybe, David, I will turn it over to you to give us sort of a 10,000-foot view of the story before we get into the pipeline.

Great. Thanks, Li. Thanks for having us. So Nuvation Bio, I think we're on really solid footing. We launched IBTROZI, our ROS1 inhibitor, a little over a year ago. I think that with now all competitors' data out in the open, I think it's pretty clear that IBTROZI is the best drug in class. If you look at our efficacy, 90% response rate, 50-month duration of response in the first-line setting, that's actually never been matched by any drug in any indication in oncology. So I think we're clearly the best ROS1 drug.

Our tolerability, again, with an overall discontinuation rate of 6.5%, discontinuations for any of our top 6 adverse events at 1 in 337 patients, again, extremely tolerable drug. The reason that this opportunity is so unique and underappreciated is that very few drugs in oncology have durations of response that are even close to 50 months. Because of the 50-month duration of response, that leads to revenue stacking that you generally just don't see.

So even though the epidemiology tells you that there are 3,000 ROS1 patients newly diagnosed in the first-line setting every year, if we were just to multiply that times the current drug price, that would be $1 billion a year. And for every year thereafter up to 4-plus years, you would expect an additional $1 billion, so $2 billion in the second year, $3 billion in the third year, $4 billion in the fourth year. So that's where you can see the revenue stacking leads to a significant number. And that's with the epidemiology based on DNA testing, which is 30% less sensitive than RNA testing. So when RNA testing becomes standard of care, you can even see that potential $4 billion market exceed $5 billion.

So where are we with relation to that? As I said, 3,000 new patients a year by DNA testing, that's 250 patients per month. If you look at the number of first-line patients in our first quarter of launch, it was 70. Second quarter, it was 80. Third quarter, it was 100. Fourth quarter, it was 140. So if you just look at where we are right now at 140, that's almost 50 patients a month. The market is 250 patients per month by the epidemiology. So after a year, we're already 1/4 -- 1/5 of the way to capturing the entire pie.

And we think that with other new changes like the guidelines, NCCN Guidelines changing to now contraindicate IO, that will further increase adoption of ROS1 agents. And then with a general increase in testing that will further increase the uptake of drugs like IBTROZI. So I think we're doing extremely well on that launch, and we look forward to updating you with every quarter that we announce our sales for the quarter.

Safusidenib is our IDH1 drug for gliomas. I would say that, that program is really exciting because we just recently announced 3-year follow-up data with that program. And if you look at our only competitor in the space, which is vorasidenib, if you look at safusidenib's non-progression rate of 79% at 3 years, so only 21% progression at 3 years, we would say that, that is -- that's just not been observed before in gliomas.

Our response rate at 3 years has increased from 44% to 52%, again, not observed before. So I would say that program looks extremely promising. We're going after all 4 pieces of the glioma pie, so low-risk low-grade, high-risk low-grade, low-risk high-grade and high-risk high-grade. We have 4 clinical trials that are targeting all 4 pieces of those -- of that pie.

The SYGMA trial is a PFS study that won't read out to 2029. We have a study against placebo that will also be a PFS trial that will read out in 2029. But we have 2 other trials that have response rate endpoints that could read out significantly sooner. One is the Grade 3 oligodendroglioma trial. Because these patients all have measurable disease, we will be using response rate as the primary endpoint. If we look at Chimerix, which got their drug approved in DIPG on the basis of 11 responses out of 50 patients, we think something around a 20% response rate is potentially approvable.

And then we're doing another study, which is in post-vora failures. These are patients who failed vorasidenib, and if we show responses with safusidenib in those patients, we think that's really exciting because now these patients have no other treatment options today, and we believe that would allow us to capture the entire vorasidenib market.

Again, Servier has treated more than 6,000 patients since launch. We know that the progression rate for vorasidenib at 1 year is about 23%. So about 1/4 of those should have failed by now. And we need -- we think we need to get something like 50 patients and show roughly 10 responses to potentially have an approvable package. So we're pretty excited about that.

Our drug-drug conjugate platform is our 2 small-molecule conjugate platform, which is kind of like an ADC without the A. We're using 2 small-molecule drugs. We're going to announce an update on that in the second half of the year.

From a cash standpoint, we have $700 million on the balance sheet. So we're very comfortable, far more than we need to get to profitability. And with that, I think we're feeling very comfortable where we are.

Yes. That's a great overview, David.

Let's start with the IBTROZI launch. As you mentioned in your Q2, you had a very nice frontline patient mix in terms of percentage. So it's about 85%, right, in new patient starts. How should we think about the long-term growth trajectory from here as you guys shift more towards the front line?

Yes. So that's a great question. So we -- as I mentioned, we started with 30% of our patients in frontline to 40%, now up 85% in the frontline setting. And with that, we've still only captured right now 20% of the theoretical 3,000 patients per year in the frontline setting.

So where else are we going to get it from? First of all, we're already the market leader among our competitors, but there's still more to be had. There's still some repo sales. There's still some crizotinib sales. We hope to eventually cannibalize all of that.

Number two, in spite of NCCN guidelines, we know that especially in some community centers, IO chemo is still being used, in some centers as much as 40%. So we think that as we -- as NCCN guidelines kick in and people start to really realize there's a many year difference in survival between IO chemo and a ROS1 agent, we think that we will start to convert that IO chemo use to ROS1 use, and that's going to also potentially even double our sales.

And then on top of that, we know testing rates, while they're high in the academic centers, in some community centers, it can be as low as 30% to 40%. So we have a potential to even double sales based on this improvement of testing rates in the community. So we're at 50 patients now. If we were to double from IO chemo, that would take us to 100. If we were to double that from testing that, it could take us to 200. And that would be closer to the 250 theoretical patients that are massively available in the frontline setting.

So we are going to continue to just educate physicians on the vast difference in outcome between IO chemo and our ROS1 agent. We'll continue to take market share, we believe, from current ROS1 -- other current ROS1 agents, and testing in general has increased because many precision oncology tests now have turned lung cancer into one of the most treatable cancers on the planet if you know you have one of these mutations.

Another point I want to raise is that if you look at the selpercatinib RET study with LIBRETTO-432 study, that hazard ratio of 0.17 is one of the most robust hazard ratios ever seen in this adjuvant study, which means that you're going to need to look for RET-mutated lung cancer earlier because you can reduce the risk of death 83%. So that's going to be a rising tide that lifts all boats. When you look -- you don't look just for RET, you look for everything. So things like that will also move the testing far more forward and increase overall testing. So we think that those things will continue to accelerate our discovery of first-line patients and treatment of those patients.

And then on the point of physician guidance, I know it takes some time to change physician behavior as to some physicians using IO chemos. But beyond just education, what other things can you guys do to sort of facilitate that transition into using a ROS1 agent? And is it more of a problem in the community or the academic...

It's definitely more of an issue in the community. I think most academic centers are pretty comfortable using precision oncology agents for precision mutations. I think that in many community centers, many of them still give a lot of IO chemo, and that's kind of their default thinking. I do think that we're not leaving it entirely to the hands of the physicians. We're educating them, but we also have very close connections with patient advocacy groups.

We're making sure that our digital marketing campaign also reaches patients broadly because this is a rare disease, and digital marketing is extremely efficient in reaching a broad swath of patients. So we're not just targeting physicians. We're targeting physicians. We're targeting advocacy groups. We're targeting patients. And so I think all of that together has already resulted in us capturing already 20% of the maximum ROS1 market in just a year, and we think that will continue to grow.

And we're also targeting organizations themselves. We have partnership with multiple organizations around the U.S. to just look at what they do, what is their practice, how does that evolve, how many ROS1 patients are they treating with the TKI. And we just show to them the gap between where they are and where they should be from a patient pool perspective. And this is extremely powerful because nobody can challenge the fact it's better to give a targeted agent than IO chemo.

So those organizations, especially in the community, have been consolidating, aggregating, and there are organizations that are really trying to push best practices into practices everywhere. And those partnerships have been extremely useful to change behavior. In some cases, we've doubled the number of patients. In some cases, we've tripled the number of patients. So this is really also another way to say, "Hey, look at what's going on in your organization compared to what is best for patients and how can we help you to reach that kind of level".

Okay. And then we know GSK is going to perhaps get their frontline label for their ROS1 agent. It's already approved in second line plus. How do you think this market share dynamic will play out next year once you get the frontline label?

So I think that we saw the Jideytro label last month. And I think that it's pretty clear that it wasn't what was anticipated. So we really had always touted Jideytro as a CNS-sparing ROS1 agent. Not only was it not CNS-sparing, but they actually received a CNS warnings and precautions, which makes now IBTROZI the only ROS1 agent without a CNS warnings or precautions.

If you look at the incidence of Jideytro CNS toxicity, it was 25% already even though their follow-up period is 1/4 of ours. And we know that with longer follow-up, you get more adverse events. So at already 25% with just 1/4 of our follow-up, we would expect that to increase significantly, potentially even up to repo or beyond repo. So we don't think that's going to make it easy to use.

On top of that, other adverse events that weren't even anticipated, 22% to 25% incidence of pancreatitis, 38% peripheral edema, these are things that make a drug very cumbersome. Our most common adverse event is liver function test abnormalities, but that's invisible to patients. They don't even know they have it. But when you have CNS tox and swelling and pancreatitis, you know you have something wrong. So we just don't see -- we think that's going to make it difficult in the -- especially in the frontline setting to be on drug for a long time.

And given the fact that we are now the only ROS1 agent without a CNS warnings or precautions, we think that gives us now a huge advantage on the safety side. And with our unprecedented efficacy, I would say that we don't think we actually have a close competitor.

If you look at just the efficacy in the second-line setting with Jideytro, 48% intracranial response rate versus our 66% response rate, again, not close. So I think that we're feeling extremely comfortable with where we are. We expect to take market share continually away from our competitors. We -- our biggest competitor is actually IO chemo and testing. So that's where we're really focused. But I think compared to other competitors, I think we are extremely strongly positioned.

Yes. And we also haven't seen any long-term data...

That's correct. There's no significant frontline data presented for it -- for that agent. So I think we -- and I don't know how you'd get 90% response rate and 50-month DOR. It's going to be very, very challenging to even match that much of a speed. So I think we're very comfortable with where IBTROZI's profile sits. And we think that right now, the way we're going to get to the 100% is to change prescription behavior with IO chemo and increase testing, but that's where we need to be. But we're already 1/5 of the way there after just a year.

I mean, right now, you have a pretty nice 2-year head start. What else can you do to accelerate the entrenchment in the frontline setting?

I think the biggest thing we can do to enhance entrenchment is just to give physicians experience with the drug. And there was one criticism with AnHeart is that they didn't have a lot of U.S. experience. Now, we've had a year of U.S. experience and physicians who use IBTROZI love IBTROZI.

So I would say that the thing that has entrenched IBTROZI use more than anything else is physician experience with it. And so we've now seen many patients -- many physicians represcribe IBTROZI because of their good experience with the drug. And I think that, that will only continue to accelerate given the fact that if you look at other alternative options, there isn't anything close.

Maybe switching to safusidenib, your IDH1 inhibitor for glioma. I think this is a very compelling opportunity. What are investors missing about saf?

I don't think they're really missing anything necessarily except that when you look at 2 of our trials reading out in 2029, it's just hard to get a lot of investors excited about such a far-term readout. So I think -- I'm not sure they're missing it. I think they just -- it doesn't attract their attention because those are farther away. What they might not appreciate is how quickly the other 2 trials could potentially read out. So those are response rate trials. We've already said that we're going to have 40 patients enrolled in the Grade 3 oligo study by next year. And what we don't know is how long it will take to see responses.

Our shortest responses have been as soon as 2 weeks. Our later response could take a year or longer. So we don't know of those 40 patients how many responses we'll see by next year, but it's conceivable that we'll see enough to be of interest to FDA to start our discussions.

The other thing that we are going -- we've already discussed with FDA, and we'll continue to pursue is when you have a tumor that's growing, its slope is positive. When you look at a response, by definition, slope is negative, it's tumor shrinking. But there's a lot of difference between a positive slope and a formal RANO response.

We would argue that any time a tumor flattens out its growth curve or goes down, even if it hasn't had a formal 50% reduction in volume, that's a benefit to a patient. To my knowledge as an oncologist, no one ever died of a tumor that hasn't grown. So we would argue that there is real clinical benefit to slowing down the growth rate even before a patient hits a formal response, which is a relatively arbitrary criteria. If they're not growing their tumor or even shrinking it slightly, it's hard to argue that's not a benefit to a patient.

In fact, what's interesting, if you look at our 3-year data, 79% of our patients have not progressed. But many of those patients at 3 years weren't responders. They just didn't progress, but they're still alive and still on drug. So it really supports my point that you don't necessarily have to have a response to have clinical benefit. So one thing we're going to talk to FDA about is once we get some response rate data, we're going to present our tumor growth rate data and show how tumor growth rate changes can precede response by a long time, months or even years. And we believe that there's still real clinical utility of that.

And what's also interesting is that vorasidenib has also presented tumor growth rate data as well, showing that change in tumor growth rate often -- and by definition, precede response. You can't go from a positive slope to a response without change your tumor growth rate. By definition, it has to change. So the 2 drugs that are being developed in IDH1 glioma, both have shown TGR changes. We think that, that's a very interesting endpoint, and we would love to see if FDA would consider adopting that endpoint as an approval endpoint. But we'll have that discussion and see what happens.

Okay. And how do you explain that safu shows better results in the higher-grade glioma than vora? Do you think it's just...

Well, first of all, I would say safu shows better results in high and low-grade. So in the initial INDIGO set, the response rate for vorasidenib was 11%. In our initial data set with Daiichi, it was 44%. So it was a pretty big difference. In the INDIGO study, vora's response rate in high grade was 0%. Ours in our first study was 17%. So I would say we were better in both high grade and low grade.

These 2 drugs are not equivalent. While they both are IDH1 inhibitors, if you look at our adverse events compared to vora's, 5 of our top 7 adverse events are immune adverse events, like vitiligo, rash, arthralgia. Vorasidenib has none of those effects. Their primary AE is liver function test abnormalities. We believe that safusidenib does have an immune component independent of its IDH1 activity. And we've actually started to characterize that in our preclinical work. So we don't think the drugs are equivalent.

When we look at the time to onset of response with safu, it sometimes takes months or even a year. When we get responses, they can last for multiple years. We have GBM that has disappeared for 3.5 years. It looks like an IO agent. So we think that safusidenib in addition to being an IDH1 inhibitor is also potentially a novel IO agent. And we don't think these drugs are in any way equivalent, and we believe the clinical data support that.

I think that's such an interesting finding that safu will have this immune-like effect. Do you think it's on target or off target? Do you guys have any...

So we do have some data on that. We're not talking about that because clearly, we're using that data to analog our next molecule, so...

But I think, Li, to your previous question about what our investors are missing, it's really important to understand that with our development plan, we are not only going after the vora market, but we are going after the whole glioma market. It's really a development plan with high grade, low grade, high risk, low risk. Everything is in there with steps, obviously, with first results in maybe by 2027 and then '29, like David said, it's really capturing the whole opportunity. And I think it's something that investors have a hard time to reconcile because vora has been doing so well already, and so...

So I guess just on that point, obviously, you're running 4 different trials looking at 4 buckets of patients. How would you rank the probability of success? Which one is more derisked?

Well, I mean, I actually believe that all have a great chance of success just based on our data. If you look at the SYGMA study, I mean, we're -- as I mentioned, just the study we just published at 3 years, we had a 52% response rate and 79% of patients had not progressed at 3 years. There is no drug today that can show those kind of data. So I would say that looks pretty good to me.

If you look at the -- our INDIGO type study with safu against placebo in places where vora isn't approved, vora got approved. Our response rate is higher, our PFS is longer. I think that looks pretty good. If you look at the post-vora failure study, we -- given the difference in activity, especially in some of our -- so if you look at higher risk Grade 2s and lower risk Grade 3s, it's a spectrum. It's a lot of overlap.

So the fact that we've seen such dramatic effects in that Grade 2, Grade 3 interface, we think that the chance that we'll show activity after vora is very high. And then, in the Grade 3 oligo, and we had 17% response rate in recurrent high grade, Grade 3 is easier than that, lower risk, we're close to 20% on the high-grade recurrent disease. You would expect to meet that bar in a lower risk, lower-grade disease. So I think that -- we feel that we have a really good chance at all of them.

I guess for the post-vora study, do you have any direct clinical evidence showing that you have activity after vora? Have you treated any patients in the sort of post...

We don't have that direct comparison. But what I will say is that if you look at vora's -- the INDIGO study, which are mainly low-risk, low-grade patients, we certainly have high-risk low-grade patients and low-risk high-grade patients in which we've seen responses. So the fact that vora did not have those responses and we have them strongly suggests to us that there's going to be a spectrum of patients where there's that overlap. They didn't have those responses, and we had those responses. So I'm going to guess this drug will work there because we're seeing responses in an overlap population that they did not have a response.

When do you think you will be able to finish enrollment for this cohort? Will you need 40, 50 patients?

So we've said that we're going to have 40 patients in the Grade 3 oligo study done by '27. And clearly, we think that the number of patients the FDA will need for approval is 50. So if we really start to see responses, we're going to increase that to 50. And then, we haven't given a number for the timing or the timing of the post-vora study. I would say that all 4 studies -- I mean, the studies that have started are all on track. There's a lot of enthusiasm for the molecule. The patients are out there.

So -- I mean, if we look at the post-vora study, Servier has treated over 6,000 patients since launch. We know from the INDIGO study, 23% progressed at 1 year. So about 1/4 of those 6,000 patients probably either have progressed already or close to progressing. Out of the 1,500 patients, we need 50, and we need to show responses in 10. So we don't think it's going to be really hard to find those patients.

Yes. It seems like you still have plenty of patients out there. And for the ex-U.S., phase III study in Grade 2 disease, has the FDA confirmed with you that the ex-U.S. data can support U.S. approval?

No, we haven't discussed our FDA correspondence publicly, but everyone realizes that you can't do that study where there's vora. It's just prohibitive. So we will have plenty of other data sets. In addition to that study, we're going to have the SYGMA study. We're going to have the Grade 3 oligo study. We're going to have post-vora study, and we're going to have safety database on many, many, many patients. So we believe that, that trial is well positioned.

And some of those studies will be heavily skewed towards the U.S. If you think about the post-vora study, that will be a lot of U.S. patients because that's where there are the most vora patients, obviously.

I think the other thing to keep in mind that we are pointing out to investors is that because of the difficulty to do any head-to-head trial in that space, it's going to be extremely difficult for anybody else to come after us too, which means that by doing this kind of -- we are probably the last company, if you want, that can do ex-U.S. versus placebo, low-grade glioma study. After us, it's going to be practically impossible, which means that it's really kind of make the market for us too for a long time.

Even in the U.S., I think that safu could be the last IDH1 molecule approved because how do you go head-to-head against that, it's just virtually impossible.

And lastly, maybe just touch on business development, what would be sort of the sweet spot for you guys in terms of bringing new assets?

We like -- we want later stage. We'd love to have something that fills the gap between now and the '29 safu approval. But we want something that is great ROI, compelling data, important unmet need, something like the AnHeart deal. That was a great deal for us.

That's a great deal. Yes.

And so we'll be very disciplined. We do have a fair amount of cash, but we want to make sure that we spend it wisely. And so we're going to be very disciplined. There's a lot of stuff out there right now, and I think that there's going to be a lot of opportunities.

And we didn't have time to spend a lot of time on this. But obviously, with the DDC platform, we also have an early-stage pipeline. So it's not like we're in a company that has nothing after. If you want, at some point we do have something after. We have an early-stage pipeline. We have safu, which is more advanced. We have IBTROZI, which is already on the market. So if we can find something compelling to David's point, we will do it, of course, but it's not something we absolutely have to do, right?

Okay. Great. It looks like we're out of time. David and Philippe, thank you very much for the time today.

Thanks so much, Li.

Thank you, Li.

Actually, Citi's done a biotech conference, I think for 20 years after Labor Day and last year, we moved from Boston to New York, but I think we're sort of rebranding it sort of Back to School, but it's been happening for a long time.

So we're thrilled to have Nuvation Bio. So we have David Hung, Founder, President and CEO, with us; Philippe Sauvage, CFO. And thanks, guys, for joining us.

Thanks for having us.

Yes. So I don't know, David, do you want to kick it off just with any sort of high-level stuff before we get into any details.

Yes. I think it's been a really great year for us. As you know, IBTROZI was -- got FDA approval a little over a year ago. We've had a little over a year of launch and IBTROZI has been a very strong launch. We are already the number one ROS1 TKI today on the market. I think that the uptick of IBTROZI is consistent with what we believe is a best-in-class profile, an unmatched duration of response of over 4 years, a very tolerable safety profile with extremely low discontinuation rate. And I think that a very strong CNS control for a disease that gets to the brain a lot.

So I think that the launch of IBTROZI has gone really well. And I think that it will continue to go well, considering the fact that now we don't see any real competitors on our horizon, given the most recent label, zidesamtinib, which I think is challenging. Again, with CNS oriented precautions, which we don't have adverse events, again, we don't have. And frankly, efficacy that doesn't match our metrics. So I think that we are in a good position there.

Safusidenib, you saw the 3-year data. I would say that data is pretty unprecedented 52% response rate at 3 years, 79% non-progression at 3 years. That's just not been seen in glioma high or low grade glioma, by the way. So we feel very comfortable there. We're in a number of pivotal studies for safu, and are just in the process of getting those trials enrolled and hopefully completed soon. So I think we're in a comfortable position there.

We -- our cash with the shoe now is about $700 million. So we are comfortable on cash. We have -- we have plenty to get us through to profitability, as we've said. We have internal programs with our DDC platform that we're going to be updating the Street on later this year. But I would say, all in all, it's been a pretty strong year for us. And we're in a pretty comfortable position.

Awesome. Okay. Well, Dave, let's start with the IBTROZI. So the part of the kind of the long term is to get more patients taking IBTROZI in first line. And those patients would have a super long duration of therapy when that happens. Maybe give us kind of where you are now, where you think you could be, not guidance, but call it a year or 2 from now?

Yes. So about 85% of our patients right now are first-line patients, which is pretty good. And as I said, we are the leading ROS1 TKI among our competitors. But our biggest challenge isn't really so much our competitors as just the practice in -- especially in the community. Right now, even with ROS1 disease, there's still a lot of IO chemo being given more than it should be. There's a huge difference in outcome with IO chemo versus precision oncology agent like ROS1 TKI and there are multiple publications showing that even if you were to switch patients to a ROS1 agent after just 35 days on IO chemo, your survival never catches up.

And in spite of that, we still see significant amount of IO chemo use. So that we're trying to change and we're all over NCCN trying to make sure that those guidelines are really adopted. The NCCN actually contraindicates IO for ROS1 disease and yet, it's still done. So we're trying to really make sure we educate physicians on that point.

What do you think the tipping point is for that? Just NCCN is obviously a good...

Yes. The NCCN guidelines changed about 1.5 years ago. So it's -- nothing happens quickly in clinical practice, but I think that we are at that point where I do think that ROS1 TKIs are being appreciated more than IO chemo, at least, so we've had a very concerted effort at multiple community centers, some of the larger aggregators to review their IO chemo use compared to their ROS1. And when we educated them, we were actually able in one center to double their ROS1 TKI use another center to triple their use.

So education does work, but it's a little bit of a center-by-center education program. Now some of these centers are very large so that if you hit one center, you can capture many patients in many states. So it's worth doing, and we are doing that. So one big competitor for us is IO chemo I think that's where we have a lot of improvement to have.

The second thing that we need to improve is just testing in general. Even if you look at other precision oncology cancers like ALK or EGFR even 10 years out, even those cancers are being tested for 100%. And so we've seen that in academic centers, ROS1 testing is close to 100%. But in community centers, some of the lower centers can have testing rates as low as 30% or 40%. So that's another major educational effort. And I think that now there are so many precision oncology agents that gradually will increase, that's a rising tide that should float all boats.

I think that the recent selpercatinib data in RET showing the incredibly robust hazard ratio, 0.17 in the adjuvant setting compels even earlier testing for RET. And as a result, it should compel testing for all lung cancer mutations. You can't just look for 1 patient. So you're going to look for all of them.

So I think there are a number of tailwinds that should help us. But right now, I would say those are our biggest challenges.

Is there some level of evidence from testing that you feel like would be a real momentum driver? I mean it seems you're totally right. There's tons of testing across the oncology landscape, right, for biomarkers, et cetera. But is there -- can you build awareness through that? Is there more work to do, I guess, is the question?

I think there's always more work to do. I mean, testing in 2026 should be 100%. There's such a huge difference in outcome for patients if they get a precision agent versus IO chemo. So it's a no-brainer clinically, and yet, it just hasn't done. So I think that we are seeing increasing in testing rates. If you look at selpercatinib sales, they're increasing. If you look at ALK and EGFR, they've all increased over the years, too. So I think that -- it will get there. And I suspect that ROS1 just really in the same position as those other agents.

So I feel confident that we'll get there. I do also think that testing itself is getting better automated. It's a lot less cumbersome now to get an NGS test result back because in many centers, they're actually automatically flagged, they're actually pooled. They're actually consolidated and highlighted and put to the front of your chart. So there are a number of things that make using NGS a little bit easier.

And I think that those things will improve the uptake of precision oncology agents in general.

And maybe just at a high level, where are we sort of OUS with regard to these drivers versus the U.S.?

We're partner with Eisai. So Eisai is going to be covering Europe. I think there are a lot of the same issues in Europe, I think, but those agents -- the other precision oncology agents sell well in Europe. It's still -- so I think that we still say -- we probably face less of the issues of IO chemo in Europe than we've seen in the United States. But I think that testing in general can still improve everywhere. But I would say that in Europe, we feel pretty confident that we're in good hands with Eisai on that.

Yes. Okay. And then...

By the way, you mentioned, if you look at Japan and China, by the way, testing rates are really high. There's very little IO chemo use. It's perhaps that's related to financial incentives for IO chemo that don't exist in China and maybe less so in Japan. So we do see extremely high testing rates and the use of the appropriate agents there. So there are differences around the world. And I think the U.S. is one of the more challenging areas, but we feel that we have easily the best agent out there. Our growth has been good, and our adoption seems to be on track. So we still do feel confident about it.

Okay. And I guess the -- one of the final questions on IBTROZI. Just the TAM. Talk a little bit about the kind of the peak opportunity as you see it, maybe U.S. And then through Eisai, the rest of the world?

So the epidemiology -- and we've actually confirmed the epidemiology internally by reviewing electronic medical records across multiple large aggregators. And one -- in one such study, we took over 39,000 medical records of patients who advanced non-small cell lung cancer and looked at the number of ROS1 diagnosis that they had among those 39,000 patients. So we find exactly 2.1%.

So the literature says 2%. We found 2.1%. So the market is there. So if you look at the number of non-small cell lung cancer patients and take 2%, that's about 3,000 patients per year. So if you multiply that times the drug price, which is about $350,000 a year. That's about $1 billion for every year of new patients. But because of our 4-year plus stacking, that $1 billion in the first year should go to $2 billion in the second year, $3 billion and $4 billion in the fourth year, a little over in the fourth year. And that's with DNA testing.

If RNA can detect about 30% more than that, which it should, that could be conceivably $5 billion plus if you can get all 3,000. That's a theoretical maximum. You're not going to ever get 100% of that, but we do think that the market is large. It should be well over $1 billion. If we just look at the current epidemiology and multiply that times current drug price and our duration of response.

Perfect. Any other IBTROZI questions?

Okay. Just I guess the last one is the duration of therapy is -- are there lessons to be learned maybe in the real world today versus the clinical practice? Maybe if you see people discontinue, what is the reason in the real world and maybe your long-term kind of view on matching the PFS...

So -- the reason that we're so bullish on the future of IBTROZI is that so far in our -- over a year since launch, we have not seen any surprises. Our patients on IBTROZI seem to be staying on is exactly as long as we would expect from our clinical trial so far. So no surprises.

I think that one of the reasons that our drug is taken for as long as it is, not only is it highly efficacious. But if you look at our 6 most common adverse events out of our 337 patients, only 1 patient discontinued drug for any of the top 6 AEs. Even though LFT elevations are our most common AE, LFT elevations are clinically invisible. People don't know they have it.

So for the most part, I would say that, we've been very encouraged by how long patients are taking drug. And as they get more and more used to it in managing some of the more common adverse events, that should continue. So we do feel that what we're seeing in the real world is good, and we're pleased with it. And now compared to our competitors who have far more challenging tolerability issues that are much more clinically apparent than things like LFT elevations, we feel that our advantage will just be consolidated going forward. We think it's going to be pretty hard to beat a 50-month DOR and we're already years ahead of many of our competitors and it's just to going to be really hard to beat that.

And how do you beat a 90% response rate? No drugs in history have had. A 50-month DOR and a 90% response rate. So we feel comfortable on the efficacy front. We're probably never going to get beat. And on the safety side, patients are taking it because the discontinuation rate is pretty low. So we're -- we feel pretty good about this launch.

In your discussions with investors, IBTROZI to safu to the rest of the -- to the platform technology, what would you say is the distribution? Are most people focused more on safu?

I think that people are mainly focused on IBTROZI. Safu is something that I don't think people have really spent a lot of time. I think because of our -- when we announced that our first pivotal readout would be 2029. I think that was just too far out for anyone to give it any attention.

2039, the most...

Minus [indiscernible]. So since we announced our first pivotal study, we actually have announced several other studies that are now enrolling patients and looking at response rate, not PFS as end points. And the advantage of response rates is that they can happen much sooner. We know that at least for a couple of other glioma drugs, you look at Chimerix for Day One. Both of those companies have glioma drugs that have been approved only on response rate.

So we know that's an approval endpoint. If you look at the Chimerix approval for their glioma drug, it was based on 50 patients and a 22% response rate. That was 11 responses out of 50 patients. That's not a lot. So we are enrolling multiple studies now covering all 4 types of glioma from low risk, low grade to high risk, high grade. And we think that, at least in the studies that have response rates as end points, the readouts are going to be considerably earlier than 2029.

And now I think as a result of that, we're getting a little bit more attention.

I guess let's talk a little bit more about Safu in detail. Could you walk us through maybe for those who are still ramping on the story, the development programs that you're evaluating the product in?

So if you look at the only competitor we have in IDH1 glioma, it's vorasidenib. And if you look at their INDIGO study, which is the study upon which they received approval in their Phase III study, vorasidenib had 11% response rate in low-grade glioma and a 0% response rate in high-grade glioma.

When we announced our Daiichi data, we showed that if you look at in low-grade glioma, safus response was 44%. And in high-grade, it was 17%. But 1/3 of that 6% were complete responses, which means the tumor disappears. We had a GBM patient whose tumor disappeared for 3.5 years, another high-grade oligo that's been gone for about 2 years.

So very, very, very robust responses. If you look at progression rates in the vorasidenib trial in INDIGO, at 1 year, there was a 23% progression, we had 4%. And in the INDIGO study at 2 years, they had 41% progression and we had 12%. So again, pretty big. Now we both vorasidenib and safu both announced recently a 3-year follow-up. And at 3 years, if you look at the non-progression rate for the safu arm now, it's 79% at 3 years out. So it is really -- that's just not really been seen before. So that's a very, very durable response for a brain tumor that has had no therapy really until vorasidenib.

If you look at our adverse event profile, 8% or -- 7% of our -- only 7% drug discontinuation due to drug-related adverse events, which is pretty well tolerated. So I would say that, that efficacy and that tolerability, we feel is going to be a winner for us. This is a huge market because even though the actual number of patients with glioma is about the same as ROS1, low-grade glioma patients can live for 20 years plus without drug. And even high-grade patients can live 4 to 7 years. So we're talking about the worst glioma patients still having a potential DOR longer than IBTROZI in first line. And the low-grade glioma was having a potential DOR 5x of IBTROZI if that materializes, that would be one of the largest commercial opportunities ever seen in oncology.

So I said that IBTROZI, if you look at the TAM there with RNA testing, it could be $5 billion a year maximum TAM. Well, in low-grade glioma, it could be 5x that because it's just 5x longer DOR, right? So if you look at vorasidenib pricing, they're priced at $40,000 a month, so 30% higher than IBTROZI. So just looking at that, that makes the TAM of this opportunity dwarf ROS1. And we think ROS1 is already big.

Are there lessons learned from the Servier launch? I know we don't have a lot of visibility on that. But from a commercial setting, right, like can you look at that to have a proxy for awareness? Can you look at your clinical plan maybe to try to pull the trigger a little earlier? I know you mentioned response rates...

Right. So we can only glean Servier sales from Royalty Pharma's royalties. But when we look at the Royalty Pharma royalties in the last quarter, vorasidenib is on about a $2 billion a year run rate after only 18 months on the market. So it's done great. It's the only glioma drug approved. So it's done great and the market is there. And there are no conflicting practices like IO chemo or something because no one does that for brain tumors.

So I think the vora launch has taught us that the market is exactly what we think it is. It's there. It's for -- there for the taking. We think that -- I mentioned that at 1 year vorasidenib's progression rate is 23%, which means that in the 18 months since launch, they -- as of last quarter, they had treated over 5,500 patients, which means 1/4 of those have already progressed or are progressing. That's well over 1,000 patients, 1,250 patients that are already progressing and in need of another agent. So that market is there. So we think that safu will fulfill that need.

I guess what sort of KOL feedback are you receiving regarding safu and the opportunity there?

We received shockingly positive KOL feedback. Most of these KOLs don't -- are reluctant to call a drug better than another without a head-to-head trial. And almost every KOL you've spoken to say, yes, your drug is better than vora. So that's something we don't see very often. We just had a major KOL, one of the large institutions here make that comment to us. So I think the data are hard to compare because, as I said, when you have almost 80% of your patients still on drug at 3 years, there isn't anything close to that.

So I would say that our KOLs love this drug. I mean our trials are enrolling exactly on track because people like the drug.

Great. Yes. You mentioned data 2029. Can you maybe walk through the trial design? And maybe what we can see?

Yes. So this is a maintenance study for -- it's called the SIGMA trial, and it's -- take patients who fail standard of care therapies, and it's against a standard of care, and it's a progression-free survival endpoint. So that will just -- it's a slow when you wait for events to look for progression. You have to wait for progression and you have a drug that has a really long time to progression, it's going to take a while. So we think that, that study will read out in '29. Shouldn't be long within that. It's been on track for enrollment. But I think that what's maybe more exciting to investors and also in some ways to us because we want to get this drug out as quickly as we can.

We're looking at a number of studies, populations that are amenable to an end point that's a little sooner to read out. So one example of that would be Grade 3 oligodendroglioma. Almost all of these patients have measurable disease, unlike the SIGMA patients who don't always have measurable disease. All the Grade 3 oligos have measurable disease, which means that they have a tumor that can be assessed for size and response when you treat it. So that should be a response rate that we can see.

We have another study, which is maybe even more exciting, which is the post-vorasidenib trial. These patients, as I said, 1/4 of them will fail vora in the first year. Once they fail, they don't really have a lot of options. And we can show responses after vora failure. And we know these tumors are there because they're growing because, they're failing, right? So they're actually growing. Safu can shrink those tumors, I think that will have a huge halo effect on people's perception of the drug to work where something has failed, I think, always makes a drug look superior.

So I think that if we can show changes in response compared to vora, I think that's going to be a very positive trial for us.

The second thing that I mentioned on last quarter earnings call, is that we're also looking at something called tumor growth rate because -- when tumors are growing, their slope is positive. When tumors are shrinking their slope is negative. You cannot go from a positive slope to a negative slope without changing your slope. I mean -- so that has to reflect the change in tumor growth rates. So we've actually now looked at our data and have shown that in every one of our cases where people -- patients respond to therapies, there is a change in tumor growth rate.

The growth rate slows and then it goes from positive to negative. And we think that's clinically meaningful. Now the FDA doesn't currently accept that as approval endpoint. But we -- as we accumulate more and more data, we intend to continue to pursue that conversation with them because I don't think anyone's going to argue that a growing tumor is less good for a patient than a shrinking tumor. And that's reflected by the TGR, tumor growth rate. So response rate is still a gold standard endpoint, but we think tumor growth rate can and should be another endpoint to consider, and that would be even sooner to read out than response rate.

Quick question on the development plan. Is there a switch study maybe to do over the long term? I know obviously, you're going after patients that are refractory and that's a tangible population. But do you think, eventually, you could do something to that degree or maybe an earlier line, what are the challenges, I guess, of having vorasidenib as the standard of care today?

Yes, I do think that -- it's interesting that even today, we're getting a lot of calls from low-grade patients who are contemplating vora but would rather be on safu. And they're asking if they're eligible for our trials because they've seen the data and they think the data are better. So we do think that if we show responses in any of these populations, SIGMA, the Grade 3 oligo, the post-vora study, we think that, that would be compelling for patients to receive it earlier and earlier because as good as Vora is, their data doesn't really compare to safu. And I think that our hope would be that patients don't even switch. They just start safu, no matter what they have because I think it's probably the better drug if they have low-grade or high-grade disease.

Geoff, what's important to keep in mind is that, of course, we are talking about several trials, but they hope, at the end, accumulate to build a whole glioma population, right? You have the low-grade glioma. We're doing that ex U.S. in places where you have no access to vora. So that puts us into approval there and to be used exactly in the same place where vora can be. But then with the post-vora, evidence of further efficacy is a Grade 3 oligodendroglioma, evidence of further efficacy and with a high-grade glioma evidence that we work even when vora doesn't.

And I think when you sum all of that together, it becomes pretty clear that if we are successful for all those trials, we are going to grab the whole market. Because why would you pick something which is less efficacious, especially for something like brain tumor.

Great. Yes. I guess, could we talk a little bit more about the global opportunity. I guess, how is awareness ex U.S.? And just how are you looking to expand?

This is a disease, which is obviously everywhere in the world and everybody will treat it. So I think from the point we are making earlier with taletrectinib, it's a very different proposal because to some extent, ROS1 can be missed. This will not be missed. And this will be only in centers that are very strong, doing brain cancers. You don't do that everywhere, right? So I think in terms of promotion, a number of places we need to go and to where it works, it's a very easier to some extent, population to reach, if that's your question.

Then vorasidenib today is in the U.S. I think they just got a pricing in Japan, which was relatively high, which is good news for the value that we put in that market. They are in negotiation in Europe. We will develop something for the whole world, just like we did.

Yes. As Philippe said, it's really hard to miss a brain tumor because the brain is confined by a rigid skull. You can't grow without causing so much pressure that you get clinical symptoms. So no one misses a brain tumor. It's diagnosis is pretty quickly. So I think that, that the market is there. We've already seen the vora uptake. They're selling a ton of drug, they have extremely high uptake. And in fact, they're even getting uptake in patients who are even on their label, a testament to how desperate these patients are and how much they need some therapy.

So we can show what we hope to show in these populations. And we think that we -- safu could and should take the entire glioma market.

Great. I guess any other safu or we can move over to DDC. Great. Yes. Let's talk a little bit about the DDC platform. Maybe could you walk us through the technology here and how it could be differentiated?

So the idea behind the DDC is -- so we certainly all know about ADCs, but the problem with ADCs is the A part is really big. So it doesn't allow that molecule to cross cell membranes very well. Many of those ADCs have to be cleaved to release their warhead. When they release the warhead, that warhead is no longer actually targeted. It can diffuse elsewhere. You get interstitial pneumonitis, you can get lots of systemic side effects.

So the idea behind a DDC is making the targeter or and the warhead both small molecules or combining 2 warheads. You can mix and match your payloads in multiple ways. But because they're all small molecules, they're in order of magnitude smaller than ADCs and now readily can access intracellular compartments and go into the cell and get into the tumor. So we think there are real advantages there.

When we started our program a year ago, we had a candidate that we took into the clinic and when we got into humans, we learned a lot of things about how these -- this is a first-in-man study. So when we learned a lot of things about how 1511 worked when we were in patients. And while we actually did see responses. It wasn't perfect. We learned things that we thought we could improve and our idea is that if we take a program into the clinic, our hope is to take it into pivotal studies, but if we're going to commit $100 million plus to a pivotal study, we want to make sure that molecules as fine-tuned as we can make it.

So we decided to do that. We decided to redesign some of our molecules with some of the considerations that we learned from our first study. And we've been doing that. And so hopefully, later this year, we'll be announcing an update to that program.

And just to be very clear, this is really hard to do, right? Don't take it the wrong way. Because it's very easy to combine 2 molecules to make something that doesn't do anything at all. That's relatively easy. But to combine 2 molecules to make sure that it retains both properties that made those molecules very successful one way or another in oncology. That's a hard part. And that's why we've been really building a lot of understanding of the way that works, and that gives us a potential of having really this strong platform where we can come up with more and more molecules in that space.

And if you can combine them and on top of that, make them synergetic, then it's really the holy grail because what we see in ROS1 or IDH1 are disease that are driven by a single mutation to some extent, very strongly by a single mutation. So that's easy. But that's unusual in cancer. In most cases, you have several processes going on at the same time. But you can combine your agents, make them synergetic so that you're blocking several parts of -- the several processes going on, then you can hope to have the same kind of super long efficacy we've seen in ROS1 and IDH1. And that's the promise of our DDC platform.

Philippe is right. It took us 5 years to figure out the chemistry. It's really, really tough. But when we do see activity, and we managed to make a molecule active on both ends, we see activities and we see profiles that we don't see with any other agent. So it is exciting, but it's been challenging.

I guess final question. When you think about Nuvation, looking to next year, maybe talk about what you think the most compelling part of the story would be? Is it the commercial adoption? Is it potential data?

So next year, I think there are a couple of things we'd like to see. Number one is IBTROZI really starts to take off with the first line in revenue stacking. We think that we are clearly going to be the leader in that area. So we're excited to see that finally take hold and testing increase and IO chemo use go down.

We think safu should have some -- we're going to start to see some data from our trials next year. So it's hard to know when. Our shortest time, the response in a safu is a response in 2 weeks, but our longest time is over a year. So that's why we can't really tell you when we think we're going to see those responses. But we know we do see responses and when we start to get those, I think that's going to be super exciting because as soon as we see any significant responses, we're going to be going to FDA and ask them, what do you need to approve this drug. As I said, Chimerix had 11 responders to get approved. So it's not a lot of patients.

And then hopefully, we'll have DDCs chugging along, and we'll still have a ton of cash. And we're also looking out always for exciting business development opportunities. And so that's something else that we also keep focusing on.

Thanks, guys.

Thanks so much, Geoff.

Thank you, everyone.

Hello, and welcome to Nuvation Bio's Second Quarter 2026 Financial Results and Business Update Call. Today's call is being recorded, and a replay will be available on the company's website. [Operator Instructions]

Now I'd like to turn the call over to J.R. DeVita, Vice President of Corporate Development and Investor Relations at Nuvation Bio. Please go ahead.

Thank you, and good morning, everyone. Earlier today, we issued a press release summarizing our financial results for the quarter ending June 30, 2026, and provided a business update. The press release is available on the Investors section of our website at nuvationbio.com.

Today's call includes forward-looking statements including statements about the therapeutic and commercial potential of IBTROZI and safusidenib, our development plans for safusidenib and our drug-drug conjugate platform, along with our plans for future updates from these programs, the components of our anticipated product revenue, expected milestone payments and our cash runway. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our quarterly report on Form 10-Q, which we filed with the U.S. Securities and Exchange Commission today.

Joining me on today's call are our Founder, President and Chief Executive Officer, Dr. David Hung; our Chief Commercial Officer, Colleen Sjogren; and our Chief Financial Officer, Philippe Sauvage.

Now I'll turn the call over to Dr. David Hung. David, please go ahead.

Thanks, J.R. Good morning, everyone, and thank you all for joining us. I'm excited to discuss the continued progress we made across our business in the second quarter. IBTROZI delivered another strong quarter, with net revenue growing 25% to $23.2 million, in line with the median estimate from our 10 covering analysts. Approximately 160 new patients started treatment with IBTROZI in the quarter, but importantly, about 85% of these starts were in the first-line setting, our highest percentage since launch only 12 months ago. While we believe that revenue is the metric that best reflects the health and trajectory of the business, we felt it was helpful to again provide new patient starts this quarter to give more color on positively shifting launch dynamics.

I'd also like to provide you with 3 specific points of context to further frame our view of the launch today. First, we are executing on our commercial plan well, and we are now the ROS1 TKI market leader in both first-line and overall new patient starts. Second, we are expanding the ROS1 market beyond how it has been viewed historically, with the majority of IBTROZI's growth coming from the first-line setting. And third, the promise of IBTROZI's clinical differentiation is being realized in the real world.

Now I'll spend some time walking through these points in more detail. We are very encouraged that the number of first-line patients starting IBTROZI continues to robustly grow. In fact, we saw growth in first-line new patient starts of approximately 30% from the prior quarter. The remainder of our new patient starts were within the TKI pretreated population, which we believe is lower than previous quarters because we have now created so many of these more advanced patients in the 12 months since our FDA approval. We expect the first-line patients to become the main driver of long-term growth due to the much longer duration of treatment in the first-line setting, and we see this dynamic happening in real time. As Colleen will discuss, we are thrilled that IBTROZI is now the #1 choice for newly diagnosed advanced or metastatic ROS1-positive noncancer patients.

The profile of IBTROZI is exceptional. In TKI-naive patients in TRUST-I, IBTROZI demonstrated an objective response rate or ORR of 90%, and both a median duration of response or DOR and median progression-free survival, or PFS, of [ 50 ] months, a response and durability profile, that to our knowledge, has not been shown by any approved therapies in any solid tumor oncology indication. When a drug combines this level of efficacy and durability with a generally favorable tolerability profile, there is the potential for patients to remain on treatment for years. As more patients start in IBTROZI, the prevalence patient pool grows, while the population is simultaneously expanded by new incident patients per year. As the dynamic shifts to more patients staying on drug longer rather than patients coming off of drug more rapidly, we believe the IBTROZI's launch begins to look more and more like a chronic disease drug launch than a typical cancer drug launch.

Short durations of response are common for many oncology agents measured in months rather than years. This short duration of response does not generally allow these agents to appreciably grow the number of patients treated year-over-year. Celgene's blockbuster [indiscernible], with a nearly 3-year DLR in multiple myeloma, is an example of an oncology agent that was able to grow its treated population year-over-year due to its durability.

The clinical data set our expectations high, and we are pleased that commercially, we are meeting them. Adverse event-driven discontinuations remain low, while discontinuations that we do observe continue to be concentrated in later-line patients with greater disease burden and exposure to multiple prior therapies. The increasing proportion of first-line patients gives us significant confidence in the long-term trajectory of IBTROZI.

Feedback from both our field organization and leading thoracic oncologists has remained positive and highly consistent. At the American Society of Clinical Oncology or ASCO Annual Meeting, reception from the medical community exceeded our expectations. There is genuine conviction in IBTROZI's clinical profile, recognition of the impact we are having on patients and a growing appreciation that the durability data we are generating puts IBTROZI in a category of its own in ROS1. Many oncologists drew a parallel between IBTROZI's more than 4-year DOR to [ lorlatinib's ] recent and impressive long-term CROWN data and how it has changed the treatment paradigm in ALK-positive lung cancer. We believe the growing maturity of the IBTROZI data is having a similar effect on physician prescribing decisions in ROS1 positive disease.

Also at ASCO, we presented new patient-reported outcomes from the TRUST-II study that further characterized what patients experienced while receiving IBTROZI. At the first assessment, 88% of patients reported improved or stable global health and quality of life scores. And importantly, positive function improved or remained stable over the course of treatment. It is notable that IBTROZI is the only brain penetrant ROS1 TKI today that carries no warning for CNS adverse reactions, a direct result of the outstanding clinical safety data set. This stands in contrast to the 3 other brain penetrate ROS1 TKIs on the market, including last month's newly approved ROS1 TKI, where CNS warnings are part of all of their labels.

Importantly, CNS adverse events, which may include cognitive impairment, directly affect how people living with the disease think, communicate and function in their daily lives. And for someone who would hope to be on therapy for years, that is not a small thing. The commercial trends position feedback, quality of life findings and longer-term efficacy data, taken together, continue to reinforce our belief that IBTROZI is becoming the standard of care in advanced ROS1-positive lung cancer.

Turning to safusidenib. We are equally excited about the progress we are making toward developing a comprehensive treatment option across the broad spectrum of IDH1 mutant glioma. We recently announced updated long-term results in the Phase II J201 study in 27 patients with chemotherapy and radiotherapy naive grade 2 IDH1 mutant glioma. With a median follow-up of 39 months, essentially assessed ORR increased to 52% from 44% at 28 months of median follow-up. Median PFS had not yet been reached, and the 36-month PFS rate was 79%. Responses in this study have continued to deepen and no new safety signals were observed with additional follow-up.

While we realize the limitations of cross-trial comparisons due to differences in study design, patient populations, endpoints and sample size, we believe these results can be viewed favorably against the latest update from the INDIGO study of vorasidenib, in which with median follow-up of 42 months, the ORR was 21% and the PFS rate at 36 months was 52%. These updated data continue to reinforce safusidenib's differentiated profile and compelled us to expand our clinical development plan.

As we have previously discussed, we think about the IDH1 mutant global market in 4 broad segments: Group A, high-grade high-risk disease; Group B, high-grade low-risk disease; Group C, low-grade high-risk disease; and Group D low-grade low-risk disease. This is a helpful slide that shows great subgroups are being addressed by our 4 clinical studies.

Our existing Phase III SIGMA study evaluates safusidenib in Group's A and C as maintenance therapy for patients with high-risk IDH1-mutant astrocytoma following standard of care. A separate exploratory cohort is evaluating safusidenib in Group B, enrolling patients with Grade 3 [ olldendroglioma ] following surgery and before chemotherapy and radiation. Together, those portions of the program address 3 of the 4 segments of the glioma opportunity.

We recently announced 2 additional studies that extend the program into the remaining Group D, the low-grade low-risk disease segment, which will also present an important new treatment sequencing opportunity. The first new Group D study, [ G307 ], is the randomized Phase III trial that will evaluate safusidenib in the 140 patients with newly diagnosed Grade 2 IDH1 mutant glioma, who have not yet received chemotherapy or radiation. The study will be conducted outside the United States and regions where vorasidenib is not yet approved or accessible, and its primary endpoint will be PFS. This study also gives us a direct opportunity to evaluate safusidenib in the low-grade low-risk setting for vorasidenib FDA approved. And upon completion and assuming the study is successful, we plan to engage with FDA to discuss the potential for an NDA submission on the basis of these results.

The second new Group D study, G209, is a Phase II trial that will enroll up to 40 patients in the United States with Grade 2 or Grade 3 IDH1 mutant glioma, whose disease has progressed following treatment with vorasidenib, but are not in need of immediate treatment with chemotherapy or radiation. The primary endpoint is ORR. And this study will also likely capture patients from Group C and B, given the broad population being treated commercially with vorasidenib.

This is an increasingly relevant real-world treatment study. As more patients receive vorasidenib, physicians and patients will need an effective option when the disease eventually progresses, particularly one that may allow patients to further delay chemotherapy or radiation, which can present significant long-term side effects for these younger patients in the prime of their lives. We believe demonstrating activity following vorasidenib could further strengthen safusidenib's potential across the low-grade market and provide these patients with a critical option.

While our 2 Phase III studies, SIGMA and G307, have PFS as their primary endpoint with data expected in 2029, we now also have 2 exploratory studies, which use ORR as the primary endpoint, the grade 3 oligodendroglioma cohort and the G209 study post-vorasidenib. In these studies, we are now also evaluating tumor growth rate or TGR as a potentially even earlier signal of efficacy. In our safusidenib data, we've observed favorable TGR changes prior to formal renal responses in all responders. While TGR is not yet a validated regulatory endpoint, it may be an earlier surrogate market with the potential to identify those patients who are likely to go on to achieve measurable response or clinical benefit. We look forward to generating data that we may be able to share externally.

Taken together, SIGMA and the Grade 3 oligodendroglioma exploratory cohort G307 and G209, allow us to efficiently evaluate safusidenib across all grades and risk groups within the IDH1 glioma landscape, in both before and after treatment with vorasidenib. That is what we mean when we say we're pursuing the full lean opportunity.

We also remain on track to provide an update on our drug-drug conjugate, or DDC platform by the end of the year. That update will include additional detail on our clinical development plan.

Finally, in June, we completed an opportunistic approximately 5x oversubscribed convertible debt financing, which provided both an attractive opportunity to retire higher cost debt and add further strategic flexibility, including for business development. Philippe will discuss the transaction in greater detail.

With that, I'll turn the call over to Colleen.

Thank you, David, and hello, everyone. Four quarters in, and our commercial team continues to raise the bar. Our cumulative new patient starts have significantly outpaced prior ROS1 launches, and we continue to pull ahead of both repotrectinib and entrectinib combined. That is a direct reflection of physician confidence in IBTROZI's clinical profile and the relentless focus of our commercial organization.

What I want to highlight today though is that the growth we are seeing this quarter goes beyond the numbers. It is the composition of that growth and what it signals about the long-term opportunity that makes me most optimistic about where we are headed. IBTROZI is now the most prescribed ROS1 TKI across all lines of therapy in 2026 based on IQVIA claims data from January to May. And importantly, data show doctors are now choosing IBTROZI for new patients over 50% of the time in the first-line setting. This reflects the medical community's growing confidence in IBTROZI and conviction that its clinical profile, specifically long-term durability and manageable safety, makes it the right choice in the first-line TKI naive setting.

That conviction is translating into something more meaningful than just market share, namely market sequencing. The treating community has increasingly designated IBTROZI as the standard of care in the first-line setting, with other currently approved therapies viewed as options that follow IBTROZI in the treatment paradigm. And we expect that trend will only continue to build.

We believe that IBTROZI's profile in the TKI-naive setting is unmatched, a confirmed 90% overall response rate and a median duration of response of 50 months. Equally important is IBTROZI's differentiated safety profile compared to other CNS penetrant ROS1 inhibitors, both in adverse events, as well as warnings and precautions. As previously mentioned, IBTROZI is today the only brain-penetrant ROS1 TKI to not have CNS warnings and precautions in its label.

Durability over time combined with tolerability is what defines the value of a therapy in oncology. And that is where IBTROZI's data stand out. For a physician making a first-line treatment decision for a newly diagnosed patient, that distinction is not a footnote, it is a defining factor. What makes this even more meaningful is the directional shift we are seeing within our own new patient starts, which totaled approximately 160 for the quarter. Importantly, approximately 85% of these 160 new patient starts were from the first-line setting compared with approximately 30% first-line use in patients starting IBTROZI at launch less than a year ago. In practical terms, the center of gravity of our business is moving towards patients who are beginning their ROS1 journey for the first time. And our first-line new patient starts are at their highest point ever, growing approximately 30% over the prior quarter.

Our patient starts in the later line setting are slowing due to IBTROZI's successful capture over the past year of many of the TKI pretreated patients who on earlier generation ROS1 TKIs, had either progressed or failed for tolerability. For first-line patients, starting on IBTROZI means the potential for 4-plus years of durable response. That is the long-term value of this clinical profile fully realized, and it is where our commercial team has been deliberately and systematically driving prescriber behavior since day one.

As David mentioned, net revenue grew 25% quarter-over-quarter, and that growth is not concentrated in any one provider segment. It is happening across every practice setting. This reflects the medical community's deep belief in IBTROZI's clinical profile, our ability to remove barriers and treatment decisions, favorable market access positioning and our commitment to getting patients on therapy quickly.

Integrated delivery networks, or IDNs, large integrated health systems that span hospitals, outpatient clinics and physician practices have become a meaningful and accelerating contributor to demand. Community demand has notably grown since launch, and academic accounts continued to demonstrate strong and expanding adoption of IBTROZI, contributing to 50% of our business. When growth is broad-based across academic, community and IDN setting simultaneously, it reflects institutional confidence in IBTROZI's profile, and that is exactly what we are seeing.

One of the most encouraging trends this quarter is that the ROS1 lung cancer market itself is growing. And I want to put that in context for a moment. ROS1 inhibitors have been available for nearly a decade, and we came to market as the fourth option in this class. Based on IQVIA claims, the number of patients receiving any ROS1 TKI in the first-line setting grew almost 20% from our launch through May 2026 compared to the same period a year earlier. In other words, more newly diagnosed ROS1-positive patients are being treated with the TKI today than ever before.

While this growth is encouraging, on top of that expanded pool of patients receiving a ROS1 TKI, there are still substantial numbers of ROS1-positive patients receiving chemotherapy and/or immunotherapy in the first-line setting, even though this regimen is no longer recommended by NCCN guidelines. We would expect these patients receiving IO and/or chemo to over time be treated with IBTROZI. Changing this entrenched market behavior takes time. But the trend is moving in the right direction, and we believe IBTROZI is a meaningful driver of this initial shift. That said, we continue to execute focused initiatives to disrupt the habitual tendency towards chemotherapy and I/O in the community setting, and ensure that every ROS1 positive patient and their physicians have the information they need to make a treatment decision that is consistent with current treatment guidelines.

We strongly believe every patient with a ROS1 fusion deserves the opportunity to benefit from the prolonged durability and high response rate IBTROZI has demonstrated in the first-line setting. And partnering with the community to make that happen remains one of our most important priorities. Ultimately, everything we do comes back to patients living with and impacted by this disease. When I think about what potentially 4-plus years of response actually means for somebody who has just been told they have ROS1-positive lung cancer, that is what motivates us the most here at team Nuvation.

Our purpose is reflected in every metric we track. This quarter demonstrates continued execution from a team that understands how to win in targeted oncology. First-line market share leadership in new patient starts, demand growing across every setting and a real-world tolerability profile and duration of use that mirrors our clinical data. The foundation we are building, cohort by cohort, physician by physician, is what we believe will drive the long-term revenue opportunity David described earlier.

Now I'd like to turn it over to Philippe.

Thanks, Colleen, and good morning, everyone. For detailed second quarter 2026 financial results, please refer to our earnings press release, which is available on our website.

We'll highlight a few key points from the quarter. In the second quarter, we generated $31.7 million in total revenue, which was greater than the median estimate of our 10 covering analysts. This included $23.2 million in IBTROZI net U.S. product revenue, which, as David mentioned, was in line with the median estimate of our 10 covering analysts, and $8.5 million in collaboration and license revenue. For the first 6 months of 2026, total revenue was $114.9 million, including $41.7 million in IBTROZI net U.S. product revenue.

As David and Colleen mentioned, our IBTROZI net revenue grew 25% from the first quarter. This was mainly driven by both growth in first-line new patient starts and an increasing percentage of first-line patients picking up or active patients on therapy. We believe these trends will support the long-term potential of IBTROZI because we expect these patients will stay on therapy for years.

From the outset, we understood that the pretreated ROS1 population represented a finite opportunity, and that later line patient accrual will naturally diminish over time as we successfully shifted our focus towards the first-line setting. It has happened a bit faster than we expected, which is a testament to the impressive pace of our launch and our successful capture of the TKI [indiscernible] population.

Our access strategy continues to be effective, with broad coverage to label across commercial, Medicare and Medicaid plans. Gross to net deductions were stable at around 30% in the second quarter. We expect this to continue to remain generally stable as our payer mix and contracting mature.

The remainder of our revenue was generated through collaboration and license agreements. We continue to receive royalty revenue from [ Innovent ] Biologics in China and [indiscernible] in Japan, and we remain eligible to receive approximately $30 million from Eisai upon the potential approval of IBTROZI in Europe next year.

We continue to invest in the business and our programs, resulting in total operating expenses of $73.3 million for the quarter. R&D expenses were $30.7 million for the quarter, and $65.7 million for the first 6 months of 2026, primarily reflecting investment in the TRUST and safusidenib clinical development programs, including SIGMA, and preparation for the 2 newly announced studies. SG&A expenses were $42.6 million for the quarter and $80.9 million for the first 6 months of 2026, primarily driven by support from the commercialization of IBTROZI. We do not expect changes to our general spending patterns for the remainder of the year.

Turning to the balance sheet. We had cash, cash equivalents and marketable securities of $661 million as of June 30. As David mentioned, we recently completed an offering of 0.75% convertible senior notes due 2032, which resulted in total proceeds of approximately $279.1 million net of fees and related reimbursements. Our cash balance at quarter end includes $242.6 million of these net proceeds as $36.5 million was secured from exercise of the overallotment option which occurred after quarter close. We were thrilled that the transaction was approximately 5x oversubscribed, and we [ upsize ] the original offering amount. This deal was entirely opportunistic as we believe we have sufficient capital to reach profitability prior to the offering.

As we approached the June 30 deadline under our term loan agreement with Sagard, we had the option to draw an additional $50 million at a minimum interest rate of 10%. We determined that it made more financial sense to access the convertible market at a 0.75% coupon, elect not to draw the additional $50 million and pay the approximately $58.7 million for the voluntary prepayment of the $50 million already outstanding under the term loan along with accrued and unpaid interest, fees, costs and expenses. As a result, the transaction materially lowers our cash interest expense, and we expect to build less interest under the new notes that we would have paid even without drawing the extra $50 million under the Sagard facility. We still retain the synthetic royalty interest financing we closed with Sagard last year.

Of course, we are sensitive to the implied dilution for our shareholders, which is why we also entered into capped call transactions designed to reduce potential dilution upon conversion of the notes. So capped call has an initial cap price of $10.458 per share, representing an 80% premium to the closing share price at the time of the offering. After costs associated with the capped call, repaying the term loan and covering transaction expenses, the remaining proceeds further strengthened our balance sheet and provide additional flexibility for general corporate purposes. This transaction does not change our approach to business development. We will remain disciplined and will pursue only opportunities that we believe can generate compelling returns and meaningfully increase long-term shareholder value. Additional capital simply gives us greater flexibility and the ability to be more competitive if and when we identify the right opportunity.

Overall, our capital position enables us to support the continued growth of IBTROZI, execute the expanded global development plan for safusidenib, advance our DDC platform and evaluate additional strategic opportunities from a position of strength. Based on our current operating plan and revenue trajectory, we continue to believe we have sufficient capital to reach profitability and fund the anticipated launch of safusidenib.

I'll now turn it back to David for closing remarks.

Thanks, Philippe. This quarter reinforces what we are building at Nuvation Bio. We believe we have the commercial program with the potential to turn advanced ROS1-positive lung cancer into a disease that patients can live with for years, a second program positioned to address the broad spectrum of IDH1 mutant glioma and the financial strength to advance both opportunities with urgency and discipline. We also continue to work towards enhancing our pipeline further with our DDC platform.

I'm proud of the progress our team continues to make and grateful to our employees, investigators, partners and shareholders, and the patients and families who place their trust in us.

I'll now ask the operator to open the line for questions.

[Operator Instructions] Your first question comes from the line of Farzin Haque with Jefferies.

Congrats on the progress. Maybe related to IBTROZI, like what is your read on the GSK's delayed repricing at roughly 8% higher than IBTROZI? They also have like the CNSAs and pancreatic talks on the label. That was a bit surprising to us, but the label does not explicitly state that they excluded concomitant driver mutation. To what extent do these level differences increment your commercial message?

Farzin, so I'll let Philippe answer the question on pricing, but I'll get to the other one. If we look at the label that we saw with zidesamtinib, I think probably the biggest surprise to us was the CNS warnings and precautions. Zidesamtinib, since its inception, has always been touted as a CNS sparing TTI for ROS1. And I think we were surprised to see that if you look at the label, a 25% incidence of CNS adverse reactions that include dizziness and ataxia cognitive impairment, psychiatric disorders, seizure. These are things that I don't think we expected. We had not seen that previously. And as I said in the script, that now places zidesamtinib in the same bucket as repotrectinib and entrectinib as the brain penetrant ROS1 TKIs that all have CNS warnings and precautions, and that makes IBTROZI now the only ROS1 TKI without CNS warnings and precaution.

The other thing that we were, I think, a bit surprised by, if you look at the other adverse events like a 38% rate of edema, 25% rate of peripheral neuropathy, 22% amylase and 25% lipase elevations, which are indicative of pancreatic toxicity, 15% rate of shortness of breath. Not only were we surprised by the magnitude of these findings, but that's after only a very short follow-up period. We're talking about a follow-up period as a quarter of what we had with IBTROZI. And we know that adverse events are linearly correlated with [indiscernible] follow-up.

So when we look at all these numbers, with one quarter of our follow-up period, we would expect, since they're linear, that would be that -- when the follow-up reaches the [indiscernible] of IBTROZI's follow-up, we would expect these AEs to potentially quadruple. So I think we were surprised by that we don't see anything in the label that we find a threat to IBTROZI. If we just look at the efficacy numbers with the caveat of [indiscernible] comparison of course. But in the second-line setting, the ORR for zidesamtinib was 49%. In our JCL pool data, it was 56%. And maybe the most important, if you look at the intracranial response rate, this is the main way that these patients progress, and that's what limits survival more than anything. Zidesamtinib's intracranial ORR was 48%, ours was 66%.

So we just don't see anything in the efficacy side or the safety side that we feel as a threat, and we will maintain -- we believe that we are the best-in-class ROS1. I think that our adoption is consistent with that. We've seen raw enthusiasm for IBTROZI across all segments. As you know, when we started our launch, 75% of our customers are academic, 25% community. Now it's 50-50. So we have broad support across really all segments. And I think that really speaks to our label. We just don't see anyone on the horizon that we think is going to be a threat to our label and our profile.

Philippe, I'll let you answer the pricing question.

Farzin, thanks for your question. Yes, just like you, I guess, my reaction was very much about this is a pricing strategy for a later line drug, which kind of makes sense considering we are a first-line drug and they are not. It's a later line approval. We made at the time of a launch, as you remember, a very different strategy of being slightly lower than [ repotrectinib ] because we really wanted to have broad access for line-agnostic therapies. [indiscernible] GSK went to a different direction with a higher price, which is more aligned with the later line drug strategy. I don't have any more insight than that, but that was the first thing that came to my mind.

And the other thing, Farzin, which I didn't -- I was talking about second-line characteristics. Our first-line data is -- we don't even know what [indiscernible] first line data are because we have a 90% response rate and a 50-month duration of response. There hasn't been any drug ever in oncology that has matched that. So we think the chance of that being matched or better by another drug is possibly pretty remote. So we just don't -- and no matter how you look at it, if they're follow-up in the second line is a quarter of ours, you can imagine that the amount of time they're behind us in the first line is even well beyond that, years beyond -- behind where we are.

So we don't see competition in the second-line setting. We -- we know that their priority approval was for a third-line setting. We think these patients need a third line drug. We're delighted to see another option for those patients. But in the second-line setting, we still believe that our safety and tolerability as well as efficacy are superior, and we do think in the first-line setting, there's nothing to even -- begin to compare with our data because there is none. So we feel very confident now that we -- the last cards on the table, I think we feel very confident of our position in ROS1.

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

Great. Congrats on the quarter in progress. David, maybe just to follow up on the GSK approval and launch. You talked about some of the -- maybe the surprises and just the positioning with IBTROZI now against the latest entrant. I'm just curious with respect to the early approval earlier than the anticipated PDUFA, how has that sort of informed and maybe altered the tactical plan with Colleen and the team just given that it has come to market sooner than expected?

And then just secondly, maybe as a follow-up and looking longer term, as you contextualize this market, in that theoretical fashion, the longer-term patient stacking opportunity into the launch. How has the 1 year under our belts really help to maybe alter or provide some headwinds or tailwinds to some of the patient stacking theoretical data that you've provided to us about the multiyear stacking opportunity for IBTROZI.

Let me start, and then I'll turn to Colleen. So with regard to an earlier approval than the September 18 PDUFA day, I don't think that has any significance for us at all. In fact, frankly, for us, it's always been a little bit of a mystery of what we were competing against, and it was actually helpful for us to see the label early. And as I said, that surprised us. We did not expect to see a tolerability profile as challenging as we did see in their label. So for us to know that sooner, it was actually helpful to us. It didn't change at all our [indiscernible] strategy. I'll let Colleen address that.

But the most important thing on this call is that we've said all along from day 1, even though we've -- of course, the prevalence pool of pretreated patients is larger than the incidence tool. When we started a year ago, they were somewhere between 1,000 and 1,500 prevalence patients. We've now marched through most of those patients, which is why we've actually depleted that role. And if you look at new patient starts diminishing somewhat because we've actually went through that pool a lot faster than we ever thought we would, which is a testament to the strong profile, safety and efficacy of IBTROZI, but we've always said this is a first-line market. And the fact that we are now 85% first-line patients, that's -- we're pretty pleased about that.

And I think that we would expect -- I think I said on the last quarter call, that this was going to be a biphasic NPS number. You start with a pool, you start treating through it, that number is going to diminish and then you're going to grow the market. As Colleen already said, we've already grown the market, 20% in the total loss on TKI number since our launch, and we would expect a number of drivers to continue to grow that. Number one, when good drums are available, more people use the markets grow, number one.

Number two, we know that testing is going to increase. That's a general trend in the entire industry, not just for us, but for all precision oncology. We know that's going to happen.

Number three, within testing, even if you have a positive test, we still know that [indiscernible] is still being used a lot more than it should be. But remember that the NCCN guidelines that contraindicated IL only came out on January 7 of last year. So that's about 1.5 years ago. So even though IL chemo has been used for years and years in ROS1, it's not the right therapy. NCCN finally came out with the right position to contraindicated, but the physician change in behavior is not immediate. That's happening. That will continue to switch. We will continue to see -- even with testing, what we call effective testing so that we will switch from not much having a -- while some patients that's diagnosed but then goes on IL, now those patients who are diagnosed will get on the appropriate ROS1 TKI, and we don't think there is a ROS1 drug better than IBTROZI in that regard.

And then the last point is that as we shift from DNA to RNA testing, we will also see about -- hopefully a 30% or so increase in the number of diagnosis as RNA is about 30% more sense than DNA in identifying ROS1 infusions.

Colleen, I'll turn it back to you.

Yes. I think that you've just asked one of the most important questions in the launch right now and asking about sort of this first line shift in revenue stacking. I'm actually glad you asked it. So when we look at the earlier line patients and looking at earlier line patients responded at higher rates, they obviously tolerate our therapy better. They're staying on treatment significantly longer. And when we look at IBTROZI specifically, when we talk about demonstrating a median duration of response of 50 months in the TKI-naive patients, and then we compare that to the later line patients where disease progression, they've been on many prior different therapies and that's really their primary driver of discontinuation. So when we look at each sort of successive cohort of first-line patients and they begin their therapy and they remain on therapy. That's what creates for us this compounding base of active patients. So that's what's building our revenue over time.

So when you look at the 25% of sequential growth for the revenue that we've delivered this quarter while managing the natural transition away from these later-line patients, that's early evidence of the dynamic beginning to play out. So David mentioned this, too, but we really are starting to build a chronic disease model, and the shift in patient mix is really the foundation of that.

And Greg, maybe to add one thing to Colleen's point and your question about the timing of launch. What is really important to note, as you noted yourself, is that all late-line patient pool has already been displayed from all perspective, all those patients have been -- have had an opportunity to use IBTROZI prior to the launch of zidesamtinib, which is again is a testament to the speed and the impact of Colleen's team to really make sure that all those patients could benefit from IBTROZI.

As of now, when you look ahead, as we've always said, this is a first-line story. And let me just remind you again, doesn't have a [ first line ] indication now. So all these later line patients have already, from our perspective, had an opportunity to use IBTROZI prior to the zidesamtinib launch, which I think is really, really important for us.

Your next question comes from the line of Mayank Mamtani with B. Riley Securities.

Congrats on a strong quarter. I was just curious against the roughly 750 newly diagnosed frontline patients. There's still a lot of capture rate you can grow here going. And David, I was just curious, any testing initiatives you're involved with directly and how can we see this penetration kind of move up? I know you talked about some IO plus chemo trend, but just the underlying testing, how that can grow? That was question one. And I do have a follow-up on the [indiscernible].

Mayank, let me start and I'll turn it to Colleen. So when we started off in our launch, we made the comment that if you look at the academic setting testing, which are nearly 100%, and they are. But if you look at community centers, depending on the community center, while some can have pretty high testing rates in the 80% plus range, there are some that have testing rates with 50% or even lower. So we've actually met with many of the larger community oncology aggregators who have low testing rates and embarked upon projects. To point out to them their testing rates, and interestingly, many of them were surprised at their own testing rates. They actually internally had thought they were higher, but they weren't. And by raising that awareness, we were able to, in several centers, more than double their testing rate just so far, and we think that that's something we're going to continue to do. So we're trying to point that out.

The other thing we're trying to point out to these same centers is that some of them have much higher I/O chemo use than they would have actually thought. When you talked to the management, they think it's low. We actually look to the data in the electronic medical records, they're actually much higher, again, a surprise to even their own institution, and we've been putting that out to them as well, and that's also [indiscernible].

Colleen?

Yes. So Mayank, thank you for that question because it's really insightful. And it's a real dynamic across targeted therapies in lung cancer. And I want to be very clear, we're not dismissive of it. So despite NCCN and ASCO guidelines specifically recommending against chemo with or without the use of I-O and in recommending targeted therapies such as IBTROZI for our ROS1-positive patients, it's that habitual prescribing pattern in the community that persists.

So you asked about what we're looking to do. So we have several targeted specific initiatives to disrupt this cycle specifically and have direct partnerships with community practices, we have patient identification programs and different tools that are making it easier for physicians to identify and flag these mutations, and make sure that the mutational status is flagged before defaulting and making a treatment decision in that first line.

So -- and as David mentioned, on the testing side, obviously, pushing and advocating for the RNA-based testing. We know in the publications that it shows to have a significantly improved detection rate upwards of 30%. So we -- as I said, insightful question, we see it across lung cancer, but we are addressing it head on, and we believe that we are making extremely good positive progress for these patients.

I had one more thing, which Colleen alluded to, if you can hear me, Mayank -- which Colleen alluded to, which I think is really important that -- the point you're making is so important for patients. But it goes beyond ROS1. Like many targeted oncology, there is still a lot of efforts to do. And if you were at ASCO like we were, you saw the big push from our colleagues at Pfizer for -- in [indiscernible] because those problem exists there as well. It's really something that we all have collectively to do for patients in the U.S., make sure everybody important, understand the importance of testing, being properly tested and identifying good mutation.

Let me make one other point. I've said that good drugs grow markets. And if you look at IO-chemo and the PFS for IO chemo, which has just been used for a decade or for forever, the PFS of IO chemo is but a year or less. So if you look at one of the first early ROS1 TKI [indiscernible], well, their PFS is 16 months. One could argue that 16 months is not that different than 12 months. So back then, when that was your option, how compelling it was to necessarily use ROS1 TKI over IO chemo. Was it the same level? It was just not a compelling argument. And you could make the argument, but it was closer.

Now when [indiscernible] came out with a 36-month PFS, 34 months duration of response, that significantly changed the bar. And that was really when the NCCN changed their guidelines. It was really based on the repo data. But now with IBTROZI a 50-month DLR, it's virtually impossible to make that clinical argument. Now you're talking about years of life difference. So the necessity for testing just got greater because you can do more about it. And so this is what I meant when I said good drugs change markets, and that's what we're already seeing now. And we go into these centers, those who used to use a [indiscernible] get to the brain and track pretty short PFS. They get it. And now things are changing. It's not overnight. But this is why when I say good drugs grow markets, they do, and we're already seeing that.

Just very quickly on the G209 glioma, obviously, a lot of investor interest there in expanded program. Just very curious to hear the post-ora cohort you've added? And maybe just talk to a little bit about your expectation on the data there itself and how big the population you intend to have exposure there were maybe engaging with regulators that make sense.

So if you -- if you look at [ Servier ] statement in the last quarter about how new patients on [ vora ], they said at over 5,500 patients were on vora, not let that number even higher with the latest quarter. And if you look at the initial INDIGO study, 23% of those patients progressed at 1 year. So since [indiscernible] has now been out for over 1.5 years, we would expect about 1/4 of those patients to be feeling or already have it failed. So that's -- we're talking about 1,250 plus patients who have probably already failed lora -- or are failing vora.

And so that speaks to 2 things. Number one, it speaks to how large your unmet need is. If you look at the duration of response of vora, even though it is the best thing in glioma, currently, the duration of response is not 80% 3 years like we've seen in our J201 study. So there is a need for a longer and more effective therapy, and that's what we're developing safusidenib.

So we do think that speaks to the importance of the unmet need of this market, but it also speaks to the feasibility of enrolling that study because there are so many patients that were failing vora. We've said before, if you look at the precedent of other companies in the space, Chimerix got approved on a 22% response rate of 50 patients. So that would basically be 11 patients out of 50 to get a response. So I don't know if that's the number, agenda in 77 patients, but some were within, let's say, [ 50 and 80 ] patients. [ 40 % ] of that is somewhere between maybe 10 to 15 patients. That's what we're looking for, for a response rate that we think could allow us to take a package to FDA, to start discussing what the regulatory approval strategy could be. We think that's not only exciting, but not that far away.

And on top of that, we made -- I made a comment in the script about this new endpoint tumor growth rate. So before tumors shrink, it's got a slowdown. It doesn't just go from growing to shrinking, it plateaus and then -- so the slope is positive, then it becomes more neutral and then it becomes negative, right? So by definition, you have to go through a TG -- you have to change your tumor growth rate before you can get a response. And in all of our responders in the [indiscernible] study, we saw a shift in the slope of TGR.

So we can tell when patients are slowing down and when -- and we believe that depending on the rate of slowing and the magnitude of slowing, we can predict who are still -- or likely want to have response. So that's potentially even earlier readout than ORR in seeing if [ safu ] has activity. So we think that's another important point. And in fact, even though it's not currently a regulatory endpoint, in many ways, I think it's legitimate. A tumor that's slowing down and then shrinking is probably pretty important to a patient. So if it isn't a current regulatory end point, in our opinion, it should be considered, and that's a discussion we intend to have with FDA.

Your next question comes from the line of Michael Yee with UBS.

This is Matt on for Mike. Congrats on a nice quarter. Maybe one more on the IDH1. I just wanted to ask kind of what gives you confidence that the FDA would be amenable to filing in low-grade using the OUS data? Do you think you would need to supplement with some U.S. data? Or I guess I'm asking how do you think that's going to play out in that low-grade setting around that placebo-controlled study?

Well, the most compelling argument is that once they feel more, there's nothing. So there is no option. I think that there's no evidence that the biology of IDH1 reasonably almost different across geographies or ethnicities. And once they feel [indiscernible], they're in really, really tough position. So I just -- I find it hard to imagine why anyone who wouldn't want to give patients that option. They have nothing left there. If you're talking about trying to go for radiation or chemo, which is single-digit response rates. And by the way, that isn't benign. There's only so much radiation you give any brain. At some point, you're killing regular brain in addition to your tumor. You just can't do that.

So -- and on top of that, our studies actually do have sites in Western countries. So we're not -- there will be areas where we can enroll these patients even in the U.S. or Western countries and so we are looking at real-world evidence approaches here. So it's not going to just be only remote scale. Countries that don't have applicability to Western patients.

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

Great. Maybe just a question, as a follow-up, David. The study in the vora failures, how fast do you think you can enroll that? And then for FDA -- an accelerated approval, should we sort of expect that you need to have a 12-month sort of DOR or is 6 months sort of the bogey? And are we still thinking about the sort of 40 to 50 patients is the right bogey that would be amenable to filing?

We think that, that 50 to 77 patient number is in the ballpark. We won't know until we've done it because we have to take the data to FDA and they said they want to see it. But if you look at the 2 present, they've actually approved 2 drugs based on one of the 50-patient study, one in the 77 patient study. So they've done it before. We think that's a reasonable ballpark. Could it be slightly bigger, I guess it could be. I'm not sure why it would be because there is nothing for these patients.

In terms of response rate, as I said, Chimerix was 22%. We think that's -- given the fact there's nothing there and chemo is what, 8% or less response rate. I think -- I just think that, that -- we think it's going to be in that ballpark. So I can't say that we know that to be true. But from our proliferate discussions, I think that's probably clearly in the ballpark. On duration, we think 6-month DOR.

So that's what we have so far. Of course, they have said they want to see the data, but from their discussions with the FDA so far, we think in the range of 40 to 50 patients, 6-month DLR, efficacy greater than 20%. We think that is -- that would warrant a really serious discussion on approval.

The next question comes from the line of David Nierengarten with Wedbush Securities.

Just one on the dynamics of the kind of dispersion amongst prescribers. Just when you are in the field, is there any pushback or accounts that prefer to use other ROS1 agents or have been using other ROS1 agents in the front line? And as a follow-up to that idea, are there -- are you more successful in getting the accounts who have been in second line to move to their frontline setting in new patients or -- are there some remainders who are using other approved agents?

Yes. David, so what I can tell you, let's first look at just sort of channels you asked about traction in the different channels. So we're definitely seeing a broad-based simultaneous growth across all 3 of the settings. And why that matters is when growth is just concentrated as you know, in one1 segment, that's where it's kind of fragile, and you get concerned. So when it's happening everywhere at once, which is what we're seeing, it's really reflecting genuine real institutional confidence. So the academic accounts, they still represent about 50%, as David said, of our business, and they continue to demonstrate strong adoption across many of the leading cancer centers. So we're seeing that strength continue.

And then what's really great is community demand has grown notably since launch. So we're really seeing traction picking up there. When we look at sort of the IDN accounts, they now are also meaningful and accelerating contributor to our demand. So again, all 3 combined signals such a healthy growth and trajectory for our launch.

So -- and we talk about this a lot, but that combination does reflect both the clinical belief in IBTROZI's profile and the work that my team is doing to ensure that these physicians have the access support and all the information they need to prescribe. So when we see sort of that base growing in the way that it is collectively across all 3 channels, it gives us incredible confidence.

To your other question, when you're asking about converting, when we look at that 160 of last quarter and talk about the importance of the composition, 85% of those 160 are now in that first-line TKI naive setting. So we're seeing success there, too. And our team is doing a great job conveying our message there.

And David, just to keep that in mind because it's so important for the confidence in the drug. Quarter-on-quarter for first-line patients, you're talking about 30% growth. So the confidence is broad for the first-line patients, 30% growth quarter-on-quarter on first-line patients. So it's really important to keep in mind.

Your next question comes from the line of Silvan Tuerkcan with Citizens Bank.

This is Josh on for Silvan. Congrats on the progress here. Yes, I mean, I guess, you already touched a little bit on the revenue stacking. But I guess as you look to build on these strong results, do you have any insights you can share on repeat prescriptions and how that sort of -- is tracking with the impressively low discontinuation rate that you saw in TRUST-I and TRUST-II?

And can you also just reiterate the status of the EU application, which I think was validated in March maybe? So is the expectation for a standard review time in the EU and the milestone following thereafter?

What I can tell you is that we had -- we met with a ton of KOLs at ASCO. And like any drug, you don't know until you know. And when KOLs have used IBTROZI, we have found that when they do get another loss location, having used IBTROZI, they're very, very likely to re-prescribe it. In fact, we've seen that a ton. So we've seen such appreciation for the durability in particular as well as tolerability, but most physicians make their treatment decisions based on durability. It's hard to argue for anything else. So when patients have used IBTROZI and find it as tolerable as it is, given the DLR, we see a ton of re-prescriptions for new patients. And I think that's the -- what we're most heartened by.

Philippe, do you want to comment on the Eisai?

Yes. We messaged to your point about that prior. We expect first, an approval in the first half of next year. We said probably late Q1, early Q2, maybe through the first half of next year. And that will trigger, as we said, a $30 million milestone from Eisai. It's a standard review, but everything is progressing very well, and we have no concern from now.

And Josh, just one more addition to that. You talked about discontinuation. So obviously, that obviously is also an indication of repeat prescriptions and refills. So when you look at our adverse event-driven discontinuations, they do remain low, and they remain in line with our clinical trial data. So the direction of this dynamic is exactly where we want it to be. And so I think that, that just speaks to, again, the persistence of the patients staying on therapy.

Your next question comes from the line of Boris Peaker with Jones Research.

Great. Let me add my congratulations on the progress. Just a question on ROS1 testing. So you've mentioned that community settings, some are not aggressive at testing. I'm just curious, is it just lack of awareness or are there maybe some other incentives was why they don't bother with testing? Are there any logistics hurdles or reimbursement pushback that they are dealing with? Curious what you observed there.

It's really hard to know. I would say -- I think a fair amount of it is still just lack of awareness. We don't have complete visibility to all of the incentives that drive behavior within any practice. But I think that in 2026, it's hard to argue that any other -- other than genetic testing for lung cancer is appropriate, you -- this is the most treatable cancer on the planet, if you have a position on [ collagen ] mutation. I think that we just need to impress upon people of that fact. I think there's still -- especially maybe among older practitioners.

Only 15 years ago, lung cancer was considered a smoker's disease and incurable. And no matter what you did, it was a poor prognosis. That's changed in the last 15 years, but not everybody know that.

Yes. I would just add to that, Boris. We believe in our heart, [indiscernible] just have good intent. They have good intent. We talk about this effective testing rate, and that's where we're trying to educate and improve. So it's not only having that test performed, it's advocating for the RNA, which is more sensitive to the ROS1 fusion pickup. But then the effective testing rate goes all the way through the treatment decision. So making sure that test is received, it's understood by the care team within that office, and it's acted upon appropriately when these patients have an active mutation. That's really what we're trying to influence the effective testing rate of these patients.

There are no further questions at this time. I will now turn the call back to David Hung, CEO, for the closing remarks.

Well, thank you all for attending. We're super excited about the quarter, and we think things are going extremely well. We are really enthusiastic about what we're seeing in first line, which is the main driver of our model of revenue stacking, and we think that as the [ safu ] program is really flying now that we are in all these indications. So we're pretty excited about where we are. Our financing puts us in a very strong position. We're going to be talking about CDC shortly. So I think we're firing on all cylinders. I want to thank you all for your support, and we'll see you at the next call.

This concludes today's call. Thank you for attending. You may now disconnect.

Good morning, everyone. My name is Farzin Haque. I'm one of the biotech analysts at Jefferies. It's my pleasure to introduce David Hung, CEO; and Philippe Sauvage, CFO of Nuvation Bio. Thank you for joining us today. This is a fireside chat format. For those who may be new to the story, David, maybe you can start off with a 1-minute intro to Nuvation.

Sure. So we are a commercial stage company. Our 2 most advanced assets are IBTROZI, an inhibitor of ROS1 -- for ROS1-positive non-small cell lung cancer. We started our commercial launch 3 quarters ago. I think it is pretty clear now that IBTROZI is the leader in the ROS1 space with the highest response rate and longest duration of response yet seen in ROS1 lung cancer, 90% response rate, now 50-month median duration of response.

If you look at our first-line growth in our last 3 quarters, we've increased 35% of first-line patients from Q3 to Q4 and then again, from Q4 to Q1, we believe that's a very auspicious beginning to our launch. So we feel very confident of the trajectory for IBTROZI, I think that's going to be a very substantial commercial opportunity with the revenue stacking that we would anticipate from a 50-month duration of response.

Safusidenib is our mutant-IDH1 inhibitor for gliomas. We also believe that safusidenib will become a best-in-class agent with a response rate that we published in low-risk, low-grade glioma of 44% and a progression rate at 1 year of only 4% and progression rate at 2 years of only 12%, which we think compares extremely favorably with all other molecules that have been tried in the space. We are in the middle of 2 studies, the SIGMA study, which covers 3 of the 4 pieces of the glioma pie, all high risk as well as high risk, low grade. That's a PFS trial that I'll read out in '29.

But more importantly, we also initiated a grade 3 oligodendroglioma study in the low-risk, high-grade subset of glioma. This is a notable study because the endpoint is response rate. We will have that study fully accrued and read it out next year in 2027. We believe that because it's a response rate trial, looking at precedents for other glioma drugs, Chimerix was approved on 50 patients response rate with a response rate of 21% OJEMDA was approved on a 77% -- a 77-patient trial for pediatric glioma.

We think that's a very exciting program. And then we're looking at designing another study, a third study to look at post-vorasidenib failures, which we think will be also a very large unmet need. There are no drugs approved in any of these spaces that we're targeting with our 3 trials, and we should be kicking that off relatively soon.

Exciting progress. So considering the IBTROZI's profile and the ROS1 market, what is considered niche by many, how do you see the long-term opportunity unfolding that some investors may not be appreciating, especially the early days of the launch has been encouraging, like 50% mix in the first-line setting in the last quarterly update?

Yes. I think what many people fail to appreciate is that it's a very different market for many oncology markets. You start with a drug, which is like 50% higher price than ALK because of the rarity of the disease to your point, but it's still half of the epidemiology, so it's still very significant. But more importantly, you're talking about 90% response rate, 50 months median DOR, which is really exceptional in oncology.

So the dynamic of the buildup of the market and the size of the market is very different because you're almost talking about a chronic disease or chronic drug. So patients will stay on drug for a very, very long time, which is very unusual in oncology setting. So the dynamic of the launch of our growth is really that. It's like patients will come on drug and because of the tolerability profile, the extremely high response rate and the very high duration of response, they will stay on drug for a very long time and the market will build like that.

So I think what many people fail to appreciate is that, that you're moving into a space where the dynamic of your launch, the dynamic of your sales is almost what you will see with a chronic disease and a drug which is given for chronic disease. And that's very different from a typical oncology buildup of sales. And so I think that's what people are missing in general.

Makes sense. So how is the compounding effect of the 15-month median PFS in the frontline setting currently tracking versus your internal revenue stacking models for 2026 and beyond?

Yes, that's exactly the point, Farzin, is that what we are seeing right now is exactly what we are expecting in terms of buildup of the first-line patients. Like David was saying, growth of these first-line patients, 35% a quarter. So we started at 60, 80, 110, and we know there is lots of space to keep growing this first-line patient pool.

And as we grow, they will stay on drug for a long time, and all of this will appear in terms of this is a drug that will be given for a very, very long time. So we have seen so far in the launch exactly what we are expecting to see from a clinical trial, and that's very reassuring for the long-term dynamic for our sales.

Makes sense. And then recently at ASCO, you had HR, the quality of life data and the cognitive function data as well from the TRUST-II. So how does it influence prescriber behavior and differentiation in the frontline ROS1 setting?

Yes. I think our recent patient-reported outcomes were very important because not only does IBTROZI have the longest duration of response and highest response rate of any of the drugs of the TKIs in the ROS1 space, but we are now showing 88% of patients improved -- were improved or stable across multiple important outcomes. And importantly, if you look at cognition, which has been a significant issue for many of the ROS1 drugs, IBTROZI is now the only ROS1 drug to improve cognition in patients.

And I think that it's just yet another differentiator between not only the incredible efficacy of the drug, but also the tolerability of the drug. And I think the fact that if you look at the patient reported outcomes, the fact that many patients reported improvements in symptoms like cough or shortness of breath, even before their first scan showed benefit, this is an example of the kind of quick, very rapid benefit that patients are seeing with IBTROZI and another differentiator of us from other TKIs in the same space.

Cool. And then you had the -- last month or a couple of months ago, you had the inclusion in the NCCN CNS guidelines. So how is the dialogue with prescribers evolved regarding the use of IBTROZI to prevent brain mets?

Yes. Again, if you look at IBTROZI's intracranial response rate, even in the second-line setting, our response rate is 66%, which again is the highest of the ROS1 TKIs. And given the fact that ROS1 goes to the brain 85% of the time, it's really important to have good CNS coverage. And I think that the new NCCN guidelines for CNS drugs including IBTROZI is another important step and again, increasing the use of IBTROZI in patients who could benefit. And I think that given our CNS profile, I do believe that we have, by far, the most robust CNS coverage of any drug today in ROS1, and that will further differentiate us in the launch.

And then the NCCN also the contraindicates immunotherapy and chemotherapy for first-line agents -- first-line patients. So how does that streamline your commercial messaging to the community oncologists that see the majority of these patients?

Yes. So prior to 2025 and, in fact, until the end of 2024, oncologists could take 2 approaches to treating ROS1 patients. NCCN guidelines actually had 2 recommendations for the treatment of ROS1 lung cancer. One would be including IO chemo in that algorithm. The second would be using a ROS1 agent. In 2025, that changed with the guidelines now contraindicating IO and requiring the use of a ROS1 agent.

It always takes a little while to change physician practice, but we do think that, that was a very important change in the NCCN guidelines because now you do need to give a ROS1 agent and you cannot give IO for ROS1 disease. And looking at the other ROS1 agents available, as I mentioned earlier, there are really no agents that come close to the response rate of 90% and the durability of 50 months that we see with IBTROZI. So we feel very confident that the NCCN guideline changes will, again, lead to further sales of IBTROZI and dominance in the ROS1 market.

Makes sense. And then in the community settings, there's a much lower rate of testing generally, like constraining the addressable market. Like is there anything that you can do or initiatives you can take to essentially support to increase the testing?

Well, I think that testing in general has been increasing with the advent of precision oncology drugs ever since the development of EGFR and then ALK and then ROS and then RET drugs. I think that's all increasing. There was a really important new development at ASCO. The LIBRETTO study with selpercatinib now showed an extremely robust effect in the adjuvant setting, a hazard ratio of 0.17, which is just outstanding.

And because of that, that's going to mandate earlier testing because now that study shows you that physicians who intervene even earlier in the disease course can actually have a profound effect on their patients. So the fact that now with -- the patients with lung cancer, if they have RET, they really want to be testing that as early as possible because the LIBRETTO study suggests that they'll have substantially more benefit treating it earlier.

I think that's a rising tide that will float all boats. I think that's going to really increase testing earlier in lung cancer in general. That's just the beginning. We have an adjuvant study going on in ROS1, and we are now confident with the selpercatinib results that we should see the same thing as well. We're the only company running an adjuvant study for our ROS1 agent. So we think that testing will increase in the selpercatinib trial. It's just another example of why early intervention and more testing is so important for patients.

Great. And then on the competition side, like are there specific clinical or commercial levers that you can pull to maintain the IBTROZI's market share once the Nuvalent's zidesamtinib enters the space?

I think we just need to see what the Nuvalent label is. We'll see a second-line label in September probably. And I think that we feel very, very confident that 90% response rate is going to be very, very hard to beat. 50-month DOR, virtually impossible without another 4 years of follow-up. So I think we are the market leader. We think that there are no metrics close to ours for any agent so far, and we feel confident that we'll be market leader.

And then they -- Nuvalent recently showed 47% ORR post-taletrectinib. Does the availability of a highly active second-line salvage option actually lower the barrier for oncologists to prescribe IBTROZI in the frontline?

So that's a good -- important point. So Nuvalent did show some activity in the third-line setting. And just to refresh your memories, the FDA actually gave IBTROZI breakthrough designation in both the first and second-line setting and gave Nuvalent breakthrough designation in the third-line setting. And also, IBTROZI was granted priority review in our FDA cycle and Nuvalent was granted standard review.

So I think that the FDA has opined on the profiles of the drugs. And we think that we will be a first-line agent. Nuvalent will be launching in pretreated patients, and we think patients need other options when first-line therapies fail, and we feel extremely comfortable with where -- our launches and where it's going.

Given that Nuvalent plans to file for frontline expansion in second half, how much follow-ups -- like how much time advantage do you think you can have to basically entrench IBTROZI use as a standard of care versus when they come in?

So we will have -- even if they do get first-line approval in 2027, we will have launched -- we will have a 2-year head start in first line. But the more important number is our duration of response right now is 50 months. There are very few drugs in the history of oncology that have been able to match that. In fact, lorlatinib is the only agent that has a longer duration of response than we have and CROWN data were received extremely well at ASCO.

I think it's going to be very, very hard for anyone to catch up to our 50-month duration of response. And if you look and -- look at what patients seek in a drug, by far, the most important thing to patients is how long will I respond to the drug I'm getting. So we think that until someone has a duration of response better than IBTROZI's 50 months, it's going to be really hard to displace IBTROZI in the ROS1 space.

And then one of the nuanced point that a lot of people don't appreciate is that Nuvalent had excluded concomitant driver mutations. So how is your commercial team planning to communicate this specific nuance to prescribers?

I think we'll see what happens in the label. It's important to note that in the IBTROZI TRUST studies, both TRUST-I and TRUST-II, we did not exclude any concomitant driver mutations, which are common in lung cancer as you know. So our patient population and our data applied to a real-world population.

When you start to exclude patients, especially the more difficult-to-treat patients, I think that the question has to be raised, is that really reflective of a real-world population? No. We can say that our efficacy, our 90% response rate, our 50-month duration of response are in all patients, no exclusions, including the most difficult-to-treat patients. And that's why we feel so confident that this drug will be very, very difficult to displace.

And then you talked about the partial TRKb inhibition may prevent CNS mets and tumor migration. Has this mechanistic hypothesis been -- how has this mechanistic hypothesis been received by the medical community? Do physicians find this compelling? Or do they prefer the TRK-sparing narrative?

Well, I think the LORBRENA, the CROWN study at ASCO just showed you that if you look at the 3 now longest-acting drugs in oncology, lorlatinib, taletrectinib or IBTROZI and repotrectinib, all 3 have some measure of TRKb inhibition. Taletrectinib or IBTROZI has the least of the 3 drugs, but still some TRKb inhibition, and we do believe that the role of TRKb in CNS metastasis is extremely important. So we do believe that the recent CROWN data suggests that having some TRKb inhibition as long as the tolerability is acceptable is a very positive thing.

If you look at the discontinuation rate in the TRUST studies, of patients with any of the top 6 adverse events, ALT elevations, AST elevations, nausea, vomiting, diarrhea or dizziness, only 1 of 337 patients on IBTROZI discontinued therapy. So that's a really, really low discontinuation rate. So clearly, our amount of TRKb inhibition has not caused any issues with tolerability. And to the contrary, we believe that 15-month duration of response that we're seeing with IBTROZI could very well be in part due to the amount of TRKb inhibition that we have.

And if you look at now lorlatinib 7-year PFS and going, that's just an incredible result. And we do know they have a fair amount of TRKb inhibition, but clearly, I think that people always have to keep in mind that the greatest safety risk to patients isn't CNS side effects, it's progression of their disease. Once you get a brain met, you're in a -- you've a big problem. So I think that people need to keep in mind that lorlatinib for all its issues that the people talk about tolerability, the fact that they're on 7 years means it's actually pretty well tolerated.

And the fact that they now have a 7-year PFS and going means that they're incredibly effective. So I think we feel that our CNS profile is really attractive having TRKb, we believe is part of the reason that we have such a high intracranial response rate of 66%, which no one else has matched to date and a 50-month DOR, which no one else has matched to date. So we feel, again, very, very confident with the profile of our drug.

And the cognition on the patient-reported outcome at ASCO was also very important. You can see that patients report better cognition on our drug, which is pretty impressive in terms of -- when you compare to other drugs in that space.

Yes. And another example of not only no lack of CNS impairment, but actually a CNS benefit in addition to disease control. And now, we're actually seeing improvement in cognition in the brain. So that's, again, another feature of this drug that no one else has been able to match with any other drug.

And then I have one more question on the IBTROZI. So you have the adjuvant study ongoing, the TRUST-IV. So what is the current enrollment status? And how do you think the adjuvant opportunity related to the advanced disease market could shape up?

So our trials are right on track. So we feel very good about the enrollment of TRUST-IV. We think that the adjuvant market is really important. Diseases are always easier to treat the earlier you treat them. So finding the disease early, treating it early, we think it is really important for patients. I think the LIBRETTO study with selpercatinib just showed that in spades, 0.17 hazard ratio, incredible. So we think it's the right direction for the field. And again, it's a substantially larger market opportunity.

So we feel that we are very happy that we are in an adjuvant study. We are the only ROS1 agent doing an adjuvant study because to do an adjuvant study, you have to have a drug that's not only effective but also highly tolerable. And I think IBTROZI fits both bills. So that study is accruing, and we think that that's going to be a very important study for us to expand our ultimate commercial opportunity.

Cool. Switching gears to safusidenib. So can you discuss the IDH1-mutant glioma market? You're positioning it in 3 of the 4 subgroups, as you had mentioned, and versus vorasidenib, which is only approved for low-grade, low-risk glioma. So how large is the TAM?

So if you look at what vorasidenib sales have already been in just 1 of the 4 pieces of the pie, they generated $312 million in the fifth quarter. So they're already on a $1.5 billion a year run rate, and we think that's going to be a very big drug. The reason that the market is large is that even though the incidence of glioma is about the same as ROS1, the low-grade glioma patients can live for 20-plus, even grade 3 oligo patients can live for 12 to 14-plus years.

And even high-grade patients, including IDH1 GBMs, which are very different from non-IDH1 GBMs. These patients, even high grade can live for 6-plus years. So because of that, you do see revenue stacking in glioma that probably doesn't apply to any -- virtually any other oncology indication. There are really no oncology indications that have 20-plus year PFS in general.

So I think that because the survival is so long, that leads to an extremely large prevalence population. That prevalence population for IDH1 gliomas is probably in the tens of thousands of patients and the vorasidenib launch has already demonstrated that. So we think that -- we're going after all 4, not just 3 of the 4, but actually all 4 pieces of the pie. So the SIGMA study alone goes for 3 of the 4 pieces. The oligo -- the grade 3 oligo study goes for 1 of the 4 pieces, but then we're going to be targeting a post-vorasidenib failure study that goes after the rest of it for everything in the vorasidenib market. So we're actually going for all 4 pieces of the pie.

And then can you comment on the enrollment cadence so far like -- and the feedback from the site investigators. There's nothing approved, so you should potentially enroll faster than...

Yes. So we think that trial is enrolling very well. We've said that we're going to finish enrollment in the grade 3 oligo study next year, and we'll have data next year. And that's a response rate study. We think that, again, approval trial would probably be in the range of 50 to 80 patients. So we're looking forward to announcing that data. If you look at the Servier numbers, they've disclosed that they've treated over 5,500 patients so far in their launch with vorasidenib.

If you look at the progression rate of 23% at 1 year, given the fact that vorasidenib launch has now been out 16-plus months, you can expect about 1,000 patients on vorasidenib to be either failing or close to failing. So we need to enroll, we think, somewhere between 50 to 80 patients for a trial that we could bring to FDA to discuss the possibility of an accelerated approval if we hit a response rate north of 20%.

As I mentioned, Chimerix got approved, a 21% response rate in 50 patients. We think that that's the size and response level that we would need to start a serious discussion with FDA. So we're pretty excited about that. We think the [indiscernible] study will enroll very quickly, as I said, because there's about 1,000 patients already out there that are either failing or close to failing. So we look forward to finishing that study rapidly.

And beyond the IDH1 mutation itself that defines the population, are you looking at any other markers such as co-occurring mutations or metabolic indicators that might identify patients that most likely would benefit from safusidenib?

So first of all, if you just look at our response rate data right now at 44%, I mean that's almost half of all low-grade patients already responding to our drug. But more importantly, if you look at some data that we disclosed earlier -- just a few months ago, almost half of our patients from our Japanese study are still on drug 5 years out. Now the reason that's important is because not every one of those patients was a responder.

So certainly, the patients when you have a response, I mean those patients are all on drug. But what the other number tells you is that even if you're not a responder, but you are either not progressing or are progressing at a slower rate, physicians sometimes keep those patients on drug, too. So we think that a very large number of patients will be treated with safusidenib because there's nothing as an alternative. And brain tumors, if they start growing, don't have good outcomes.

So if you can shrink them or even make them grow slower or not progress as rapidly, I think that's a really important way to extend life and quality of life in these patients. So we think that, that's the reason -- another reason why this market opportunity will be so large. On top of that, we're going to be announcing new data later this year, where we're going to now present 3-year follow-up on our Daiichi data, and we think that's going to be very, very interesting to everyone.

Cool. And then do you have any plans to seek approval in the low-grade, low-risk market where vorasidenib is approved? You mentioned it previously, but just to double-click on it. Like what will be your approach there? Are there any additional data that you need to generate and then trials you're running?

So right now, vorasidenib is the only IDH1 approved in glioma at all, and it's approved in low grade. Once those patients fail, there is nothing for them. So we think that any patient who fails vorasidenib that responds to safusidenib, is a great alternative for them. And we think that, in fact, if the drug works after vorasidenib, most physicians and patients will also conclude that this drug is a better drug and probably use it earlier in treatment algorithm. So we think that showing activity after vorasidenib failure will be key to securing the low-grade market. And that's why we believe that ultimately, safusidenib will get approved in all 4 pieces of that glioma pie.

So that's the separate extension of the ongoing study?

That's a new study.

That's a new study, but non-registered?

We're designing it right now, but our plans are to look at a post-vorasidenib failure study.

And it will be non-registrational initially until you get that...

I think the FDA never always wants to see the data before they make any decisions. And so when we have data, we'll take it to them. We think that the response rate is north of 20% in at least 50 patients. We think that, as I said, there's precedent for FDA approval. With Chimerix, 21% response rate in 50 patients. So you can never say what FDA is going to do, but we think there's ample precedent to take the approach we're taking.

And just to refresh the memory, like why mechanistically patients should respond to safusidenib post vorasidenib, like mechanistically it is the same or...

No, they're not. They're not the same. So in fact, interestingly, if you looked at the adverse events of these 2 drugs, they're very different. We made the point that vorasidenib's main adverse event is liver function test abnormalities. If you look at 5 of the top 7 adverse events for safusidenib, even though almost all of them are grade 1, very mild, they're immune like. So we have skin hyperpigmentation. We see arthralgia like rheumatoid arthritis. We see some rash. We see some alopecia like alopecia areata. These are immune type effects.

And when you look at our responses, the fact that they take sometimes 6 to 12 months to kick in. But when they do kick in last 3 years, we have a GBM that's been in a complete remission for 3.5 years. We have a grade 3 oligo that has been gone for about 2 years. These are IO-like effects. We believe that safusidenib may have immune mechanism on top of its IDH1 inhibition, and we are actually in the process of characterizing that further. But we do not believe the drugs are identical.

Makes sense. In the last minute, I want to talk about the BD and the pipeline. So you have successfully integrated the AnHeart acquisition and then global rights acquired for safusidenib. So what's the current appetite and capacity for potentially in-licensing and M&A activities? And you also have the DDC platform, too.

So we'll make an announcement on the DDC platform later this year, which we're very excited about. In terms of BD, we will always have an appetite for programs that we think could give us a great ROI for our investors. But we're going to be very disciplined. We have $535 million in cash. We have another $30 million coming in from an Eisai payment next year.

So we have plenty of cash to get us to profitability. So if we do a BD deal, it's going to have to be really compelling for us to do it. But we are constantly looking at things, and we think that there's a lot of things out there, but we're going to be very careful and disciplined to make sure we bring in something that will be really value increasing for the company.

Thank you for your time. This is an excellent conversation.

Thanks a lot, Farzin.

Thanks.

All right. Well, good afternoon, everybody, and thank you once again for joining us for our seventh Annual Oncology Innovation Summit. I'm Yaron Werber from the TD Cowen Biotech team. And as the Extel survey is now launched, if you do feel that the TD Cowen Biotech team has earned your support, please do consider voting for us for both large cap and small and mid-cap.

It's a great pleasure to moderate the next session with Nuvation Bio. Really, we have 2 gentlemen that need no introduction. We have David Hung, Founder, President and CEO; and Philippe Sauvage, who is the Chief Financial Officer. So team, thanks for joining us. Good to see you.

Thanks for having us, Yaron.

So lots to talk about on IBTROZI, both commercially and then potentially to start even talking about other tumors that have ROS1 mutations. But let's maybe start on the commercial basis. As of Q1, now over 50% of patients are -- using IBTROZI are in the frontline setting. I think you've noted on your conference call that the early trends in April look -- continue to look encouraging. Can you give us maybe an update commercially on how usage is shaping up so far?

Sure. Philippe, do you want to answer that?

Yes. I mean what we've seen is very encouraging trends, right? And this is something we really want to talk about our commercial launch that's quarter-on-quarter, we had an increase of first-line patients. And, you know, Yaron, because of the incredible efficacy and duration of response of IBTROZI, first-line patients are really going to be the patients who are going to stay on drug for a very long time. So this is really, really what is important for us for the long-term potential of IBTROZI. And quarter on, we see an increase of this patient number of about 35% a quarter. And we think this is a trend we can maintain because the number of patients out there in need of IBTROZI is really high. It's still very much underpenetrated and still many potential for us to grow. So this growth that we've seen in the first quarter of this year of more than 50% of our patients means that it's growth of 35% again quarter-on-quarter of our number of first-line patients. So this is really what we see as the most encouraging recent data there.

And when you say, Philippe, when you say 35% -- what do you mean, 35% quarter-over-quarter growth?

Absolute number of first-line patients. Quarter-on-quarter, absolute number of first-line patients growing. So it's not only about the share of it, it's really the absolute number growing quarter-on-quarter.

Okay. And you think that's sustainable from this point onwards?

No. Because, again, if you think about the epidemiology, there are 750 patients a quarter that should be put on a targeted therapy. And we only have 110 or so for HRD in the first quarter. So still lots of room to grow there and see that incredible good trend of first-line patients.

And the 750 is the newly diagnosed patients per quarter?

That's the epidemiology, the number of patients out there that would need to be put on a TKI, ROS1, yes.

In the first-line setting?

In the first-line setting.

Got it. The -- are you able now -- do you have better line of sight into what's going on in the actual treatment setting, given that most patients are not going through your program, right? But it sounds like they're not going through you, right?

Most of our patients are coming through -- most of the patients we know perfectly about are the ones that are going through NuvationConnect. So this is a smaller share, which is why for a long time, we were careful about not sharing too much information on first-line patients because we didn't want to say anything wrong. But we've done a lot of work in the past few quarters, understanding what was going on in the marketplace, looking at the patients we had in the hub, but also looking at all the other trends we can see from the feedback from our reps, to doctors, to some systems in which we have good insights or what's going on in the systems to any data we can gather from IQVIA about, line et cetera. And when you compile data like that and you all end up with the same number, you feel pretty confident about where you are. So we really see this continuous growth of first-line trend, and we are very confident about it.

Okay. What about the use of crizotinib? Do you have any sense as to what the dynamics are in frontline there?

We do see a decrease in crizotinib use. And as you know, crizotinib has been one of the oldest TKIs out there, been around for the longest time, but doesn't get into the brain. And we've been looking at now a number of health care systems, some of the larger aggregators have shown some interesting trends. We've seen for the first time in one of our large aggregators, a significant reduction in crizotinib use in the first-line setting to IBTROZI. So I think that's a good trend, and we expect that to continue.

Okay. And you mentioned that this is going to be an ongoing sort of evolution quarter-over-quarter throughout the year. What drives that? Is it diagnosis? Or is it really more uptake in the community setting?

So I think there are a couple of things that drive it. If there was one criticism of AnHeart, I would say there was probably not as much U.S. experience and familiarity with the drug as it could have been. So we've now had 3 quarters to get the drug in front of physicians in the U.S., and that's been a great education for them. I think that they've gotten used to the tolerability profile, which is excellent. They've been impressed by the new changes in efficacy that we've just published and are updating in the sNDA of a DOR, duration of response of now 50 months, which is unprecedented. And I think that with that increase in familiarity, these physicians are now changing their practice from using a new drug that they don't know about in the late-line setting to now using a drug that they've had experience with now in the frontline setting. So we've seen scripts really change from primarily third line or later in the first -- in the very first quarter of launch is Q3 to now more than half in the first-line setting by the third quarter of launch, which is Q1.

Got it. Okay. And where do you think by the end of the year, sort of can you be at 75% more in frontline hopefully?

No. Philippe said that we feel pretty comfortable. If you look at the growth in first-line patients on an absolute number, we went from about 60 in the third quarter to about 80 in something in that range in the fourth quarter to about 110 in the third quarter. So that's about 35% quarter-over-quarter growth, and we feel pretty comfortable that we should continue to do that. Philippe has made a comment on other calls that if we continue that rate alone with no acceleration, we should hit our consensus pretty easily. If we accelerate beyond that, we might be able to even beat consensus. But I think that we're saying that this level of growth is something that we're -- we feel good about. We think it's sustainable. And that doesn't even take into account the gradual increase in testing, which we think is also happening in addition to changing practices due to familiarity of IBTROZI. So I think that as -- it has all genetic testing increases for all lung cancer, I think that, that's still a rising tide that will continue to float all boats. And I think that in addition to the increase in familiarity with IBTROZI, we should further benefit by increased testing as well.

Okay. And Philippe, what is consensus now for the year for IBTROZI?

It's around 130, between 130 and 140. And as David just said, we are -- if we keep increasing at that rate, our first-line patients will hit consensus. If we accelerate further, we will go beyond that. And we are feeling good about that number. And I think to your previous question, more -- it's not so much about proportion of patients. It's really about this first line of patients, the pool -- first-line pool growing and growing and growing because we know they are the patients that are going to benefit from the longer time on IBTROZI, this is incredible duration of response, 50 months. And this is really, really something that is important that they will put on as TKI first in first line so that they can stay on drug for as long as possible.

Yes. And in terms of the other TKI, the branded TKI, are you still seeing them sort of competing in the market or they've essentially ceded the share in the U.S. now?

I mean if you look at all the other TKIs, crizotinib use has probably started to decline. In fact, the use has already significantly declined. And I would say that the closest drug to us in metrics of performance is probably repotrectinib. But as you -- as we've just said, we are getting significant growth in first-line share in spite of repotrectinib. So we think that the tolerability profile of IBTROZI compares favorably with repotrectinib. And frankly, if you even look at just the performance metrics, and you mentioned CNS control in the second-line setting, IBTROZI's intracranial response rate is 66%, repotrectinib is 38%. So I would say that just overall, IBTROZI has a very compelling efficacy as well as tolerability profile.

Yes. Okay. Zidensamtinib, eventually, I'm going to learn how to say the name of the drug -- is expected to get approval in second-line setting in sort of early Q4. How do you think the competitive dynamic will work there?

I think that, again, as Philippe has already said, we start off our launch in Q3 with the majority third line or later patients. In Q4, we added second line and later patients. So we -- and in the 3 quarters since we've captured a significant amount of the pretreated market. But we've started to grow first-line share, which we will be at least 2 years ahead of zide for first-line launch. And by the time they launch in second line, I think we will have captured a significant amount of the market. And also, we look forward to seeing their label. We have not yet seen a publication of zidensamtinib. And we'd like to see what their metrics really are as they would appear in the label. As an example, even though zide has presented unconfirmed responses in their publications, that's not acceptable in the label, treatment-related adverse events, it's not acceptable label. So we like to see the real data, confirmed responses, treatment-emergent adverse events, things that would appear in the label. We are not aware of any drug today that has any metrics in efficacy or tolerability that are close to IBTROZI.

And you're expecting really approval in second line onwards, right?

Before zidensamtinib?

Yes.

So just to refresh your memory, FDA gave them breakthrough designation in the third-line setting, but they're applying for a second-line approval. We received breakthrough designation in the first and second-line setting. And on top of that, we got a priority review and they did not. So again, for an agency that's seen all the data sets, they've certainly prioritized IBTROZI over zide, and we expect them to have a late-line approval, and we expect their data to be inferior to ours.

And then I think they're planning on filing for frontline after the September 18 PDUFA. At that point, it's going to be a supplemental filing. What kind of a label do you think they can get in frontline? I think they have maybe 2 -- 18 months to 2 years of follow-up so far roughly.

I think it just comes down to how good the data are, and we just haven't seen it.

Yes. Okay. In terms of formulary...

Apologies, Yaron, we will not have the level of maturity of data that we currently have, which we think is something that, obviously, we will have for a very, very long time, more maturity than they do and also being 2 years ahead in the market is really, really important.

I mean our response rate in the first-line setting is 90%. I mean, how much better can you get than that? Our duration of response in the first-line setting is 50 months. That's virtually unprecedented in all of oncology. I don't know how much better you can get than that. So we feel really comfortable with our profile. I think it's going to be really, really hard to beat. And there's a reason that we got first-line BTD and no one else did. So I just think that the data should speak for itself, and we look forward to seeing it.

Yes. So at ASCO, zide is actually going to have data from other tumors, ROS1-positive other tumors. Is that something that you might be interested in doing studies as well?

So we actually had a small number of patients in our study who had ROS1-driven cancers that were not lung cancer. They are more rare. But in fact, we actually are currently treating a little girl with a ROS1 GBM, glioblastoma brain cancer, and she's had a great response to IBTROZI. So we -- where we do see them, we think that IBTROZI is a great drug for ROS1, no matter what it drives, but those other cancers are far rarer than lung cancer. So the main market for ROS1 is the lung cancer.

Okay. So that's not something that you're thinking about formally studying the drug in?

I mean I think everyone knows that our drug works great against the ROS1 fusion. So as an example, when this little girl had a ROS1 brain cancer, they put on IBTROZI, but that's not going to be the majority of our commercial opportunity.

Yes. Okay. Let's move -- and by the way, for the audience, if you have questions, you can go ahead and as you know, put them right into the channel. Otherwise, you can go ahead and e-mail them to me, and we're happy to take them on your behalf as well. The -- let's go to safu and talk about -- I guess there's definitely a lot going on, and that's a drug that's increasingly getting traction and attention from investors. In terms of the Daiichi Phase II in the non-enhancing low-grade glioma, now that you're controlling sort of the data, when do you think you might want to publish that data?

We're going to try to publish everything we have because I think the data are really compelling. We think that safu is really an interesting drug because where vorasidenib is the only IDH1 drug approved today in brain tumors, it's only approved in 1 of the 4 pieces of the glioma pie, only in low-risk, low grade. And we have data in both low and high-grade brain tumors with IDH1 showing really significantly more robust responses and progression-free survival. And so we feel it's important to publish that, and we're going to do that. But more importantly, we're now doing studies that are going to target all 3 pieces of that pie. So our SIGMA study will now target everything where vora isn't, which is high grade -- sorry, high-grade, both low and high-risk high grade as well as high-risk low-grade tumor. That's 3 of the 4 pieces. We're doing a second study in the Grade 3 oligos, which are the lower risk subset of the high-grade patients, again, where vora has shown a 0% response rate in high grade. And now we're even looking at some, designing another study in post vora failures. And that's particularly interesting because as you know, from vora's response rate and PFS, at 1 year, about 23% of vora patients progress in that low-risk, low-grade population, which means that they've been out for about 15, 16 months already. And Servier has already said they've treated 5,500 patients. So if 1/4 of them are going to progress within a year, we think there could be 1,000 patients approaching failure right now. And we think that the number of patients we would have to show responses in to potentially get an accelerated approval could number as low as 50 to 80 patients. As you know, Chimerix got approved on response rate in 50 patients with a 21% response rate. Day 1 got OJEMDA approved based on 77 patients in pediatric glioma. So we think that we were to show responses in the post vora setting of greater than 20% in 50 to 80 patients. We think that's potentially a registerable study. So we are now designing that study and think that out of the 1,000 or so post vora failure patients that should be happening within a year, we think that we could pretty easily get 50 to 80 patients to assemble a package that would be pretty compelling to FDA.

And this is going to be essentially adults at that point, anything outside of pediatrics or...

We're going to start within adults first.

Yes. And at that point, you'll use the same dose, the 250 BID?

Correct.

The -- okay. The -- So you mentioned the SIGMA study, which is essentially enrolling all 3 subtypes that Voranigo is not approved in. And then also a study that's going to be targeting that fourth indication where Voranigo is approved, right? Can you discuss that study, that second study?

Well, so the SIGMA study is 3 of the 4 patients that vorasidenib is not approved. The second study is actually the Grade 3 oligo study, which -- where vorasidenib is also not approved. It's not approved in anything that has a high grade in it. And so that study is a response rate trial. And those patients can stay on drug for 12 to 14-plus years. So it's a very significant commercial opportunity because of the revenue stacking that could occur. And because there's nothing approved in it, we think that, again, a trial that could be approved on as little as somewhere between 50 to 80 patients. We cite OJEMDA with 77 patients approved on a response rate only as a precedent for that. And then the third study is the study I mentioned that we're designing, which is a post-vorasidenib failure study. Their population is low risk, low grade. So we're talking about patients who fail vorasidenib for which there's absolutely nothing, a large market, a lot of patients out there right now because they've treated 5,500 patients, about 1/4 of them will fail within a year. And so we think that we need 50 to 80 patients to get a pretty compelling package assembled.

Right. So This is okay -- that's okay. Thanks for the clarification. So that's actually that indication we talked about the Grade 3 oligo. That's actually the 40 patients as part of SIGMA.

So, not [ exactly ], it's actually part of SIGMA, but it's really a separate study in itself because it's specifically a pure population of Grade 3 oligos. And while that trial is targeting 40 patients which we should complete by next year, if we see responses in our first few patients, we would probably expand that to 80 patients instead of waiting for it to finish and then expanding because, as I said, we just want to be ready to go with a package that we think FDA would find substantially enough to consider approval in, which we think at 80 patients would be larger than both the Chimerix and Day 1 packages.

Okay. Got it. And the bar -- okay, right. So it's sort of a part of SIGMA, but it's obviously the same protocol, the same study...

And unlike SIGMA, which is a PFS readout, this grade 3 is a response rate readout, which is much, much faster.

And what's the bar there? Is the bar still the 20%? Or is it really 30%?

Chimerix got approved on 21%. So we think north of 20%. If you look at the bar to beat, which is chemotherapy, chemotherapy response rate is in the single digits. So we're talking 5% to 8%. We think 20% easily beats that. We think anything north of 20% like Chimerix did is enough.

Yes. Okay. And at that point, what's the durability? Is that also -- does FDA want to see 6 months or once you get a response that's fairly durable?

I think we need to wait and see what FDA actually says. But I would -- I'm going to guess that there's nothing for these patients, it wouldn't be a really long time.

Okay. And you have 30 sites that you're opening or opened already, right?

And we're opening more. So yes, I think we are all about trying to move this fast now. And we would expect to have data from the Grade 3 oligo study next year and as well as we should have some data from the post-vorasidenib study in at least some patients by next year as well.

Got it. Okay. The -- and then in terms of that you've signed up, I'm going to switch back to IBTROZI. You've signed the deal with Eisai. What's the next step in Europe now for IBTROZI?

The next step in...

In Europe, David.

Okay. Yes. So we submitted for full approval in Europe. We expect to be reviewed in about 9 months. That would be a normal time line, Yaron. So that would be early next year, somewhere Q1 or Q2 next year for an approval. And then it will be the typical European launch country after country, starting with probably Nordics and Germany is usually the case, but we've not discussed that yet with Eisai. We're still on the approval path.

Got it. And remind us what's the remaining milestones under -- for approval for Eisai?

So we have a milestone for approval, yes, coming at time of approval of EUR 25 million, and that would be either for early next year. And that will reinforce even further our very solid balance sheet. We already have $530 million, as you know, so that will add to that.

Okay. And then you potentially could draw down another $50 million from Sagard, from your tranche, that...

Yes, we could. We've not made the decision yet, but we'll wait to the last possible time to make sure that we have the right strategy there that we can.

Okay. And then in terms of SG&A, you've been kind of flattish between $38 million and $40 million a quarter. Is that sort of a good place where you'll remain for the time being?

Well, obviously, we have a big acceleration of our commercial spend last year with the launch, but now we're getting more to a kind of stable situation from a launch perspective. So we don't expect that to go up and down too much. There are always variabilities quarter-on-quarter, as you know, but we don't expect that to be huge.

Okay. And then finally, any thoughts on business development and what kind of assets you're potentially looking at? And does it make sense to bring in other commercial assets even if they're not huge, let's say, and they're fairly undervalued right now?

I think it really just depends on the price we have to pay for them and where they are, how close they are to commercial. Clearly, later-stage assets are more attractive to us, but they're more costly. So we have to balance what we think is a great deal and where the product fits into our pipeline to make a decision. We know we are really happy with the AnHeart acquisition. That was a great acquisition. We do that all over again. So for us going forward to move the needle for us, we know we would have to look at something that would be additive or at least sits additive or synergistic with our IBTROZI commercial opportunity and had to be something within a reasonable price.

Okay. There are so many assets in China. Does it make sense to go and bring something that was developed in China?

No, we're looking at China. We have a big footprint there. So we definitely are looking there, but we're looking everywhere because they're good assets everywhere. And this is still a difficult financing environment. Many of these companies don't have a lot of options. And so there are a lot of assets we think that could be good opportunities for us. So we're going to be patient and very disciplined about it.

All right. Well, David and Philippe, good to see you as always. Looking forward to seeing you at ASCO. Thanks for the interest.

Thanks, Yaron.

And the next session starts in about 4 minutes.

All right. Take care.

Sure. Bye-bye.

[ Thank you ] for joining us for our next session at the RBC Healthcare Conference. Here, we've got Nuvation, represented by David, their CEO; and Philippe, their CFO. Thanks for being here.

Thanks for having us.

So, there's a lot going on at the company, but I figured maybe we'd start on the commercial side of the business first. So, first you achieved $18.5 million in first quarter revenues, about 200 new patient starts, and you talked about revenue stacking as a goal. So I guess, what are your expectations for how you're going to be driving growth for the balance of the year?

So if you look at, we've been out for 3 quarters and if you look at new patient starts in each quarter, it's been about 200 new patient starts per quarter, which is more than the combined new patient starts of Augtyro and entrectinib combined. So it's a good start. But the number that we find most important is the percentage of first-line patients because the duration of response of first-line patients is over 4 years, which -- so every patient who starts in the first-line setting would be expected to generate revenue for 4 years plus, about 4.2 years.

If you look at third-line patients or fourth-line patients, they're on drug for a few months. And so when you look at new patient starts, while they appear to be roughly the same, about 200 is because the late-line patients, which all oncology launches start with, are dropping off very quickly. Sometimes if you're a fourth-line patient, you might last a month or two. So they're going to drop. So it's really only the first-line patients that really matter. So if you look at our new patients -- our first-line patients on percentage among the new patient starts, in the first quarter, it was 30%; in the second quarter, it was 40%; in the third quarter, it was over 50%. So we're generating about 35% quarter-over-quarter growth in first-line patients, which I think is really, really exciting.

So we can continue to do that. If we have no acceleration, we should still hit consensus for the year which is about $125 million to $130 million. If we accelerate beyond that, which we would expect to do at some point, we should beat consensus. So I think we're comfortable with the number right now. But we do think that there are a couple of other ways that we will further increase revenue. Number one is testing. So, as you know, as recently as the beginning of 2025, the NCCN guidelines said there were 2 options to treat ROS1 lung cancer. One was IO chemo, the other was a ROS1 agent.

On January 7, 2025, so just a little over a year ago, that changed to say that not only can you not use IO chemo, but it's actually contraindicated. And now you have to use a ROS1 agent. So that just changed a little over a year ago. Physician practice never changes overnight, but we think that is going to change, and that's going to drive more ROS1 use because now the other main therapy that's prescribed for decades is now contraindicated. So that's number one. Number two, I think that familiarity with IBTROZI is increasing. So if there's one shortcoming of our AnHeart acquisition was that AnHeart had a very little U.S. presence. So even though they did a global study, which included the U.S., Canada, Europe, it didn't -- they didn't have a ton of KOL exposure, and we now have 3/4 of that.

So I think that we're getting familiar -- physicians are getting familiar with IBTROZI that should further drive revenue. So I think there are really three things that will drive revenue. One is continued increase in first-line patients because if you look at our tolerability and our efficacy, there isn't anything close to us right now. We are over 4 months -- 4 years of duration of response. We're 90% response rate, which is the highest. Our tolerability is excellent. If you look at our top 6 adverse events, out of 337 patients, 1 patient discontinued for any of the top 6 AEs. So a really good profile. So I think we're going to increase first-line share from familiarity, from increasing testing, and I think that's going to drive our revenue further.

Yes. Really helpful. There's a couple of things you touched on that I want to dive a little deeper on. The first is testing, as you just mentioned. Testing rates vary between academic centers, between community centers. At the same time, there's also new tests being developed with mRNA. I guess how much do you expect testing rates to improve? How do you think that's going to change the epidemiology of the disease? And is there anything that you as a company can actually do to drive the testing rates?

So I do think that's going to change. So a couple of things. Number one, if you look at academic centers, they test about 100%. So it's very, very high. If you look at community centers and some of the large community centers, we see testing rates 80% to 90%. For some of the middle or smaller sized centers, we see testing rates as low as 40% to 50%. So now there's a couple of reasons for that. One is just lack of awareness and that we have to improve that. But one of them is the fact that until a year -- a little over a year ago, the NCCN said that you have 2 options for ROS1 lung cancer. You can give IO chemo, which you don't have to get an NGS test for or you can give a ROS1 agent, which you need an NGS test for.

But if for those who opted for option 1, which was sanctioned, not only sanctioned but recommended by NCCN, you wouldn't necessarily have to get an NGS test. Well, now that's changed because on January 7 of last year, that's now contraindicated. So we think that testing will increase for just by awareness, but also number two, by the fact that the NCCN guidelines have changed to contraindicate IO chemo. And then the third development is now we just got included in the new NCCN guidelines for CNS disease because of the brain activity of IBTROZI and that's going to further push for this drug to be used, which will mandate a genetic testing.

Now in terms of new tests, the RNA test is about 30% more sensitive for ROS1 fusions than the DNA test, and that was just introduced and approved about a year ago. So that's made it into NCCN guidelines. And it's going to be, again, a little while to get that to be mainstream, but we do think that DNA will ultimately shift to either DNA plus RNA or RNA, and that will increase the epidemiology from 3,000 U.S. patients a year to about 4,000.

I think to your point, I need to add just a little bit, what's important to note is that, of course, we're doing AnHeart, but we are not alone. Lots of initiatives, NCCN guidelines, some state sponsored initiative where it becomes mandatory to test, lots of companies out there, either the testing companies or other companies with targeted oncologist is pushing for tests. So the whole field is changing. Everybody is pushing the same direction, which is the right direction for patients.

If you think about it, it's really important because one of the reasons why we're stable as we were talking about is not because of our first-line growth because those late-line patients, they are not that many. Why have they not that many because they were not tested appropriately. Many patients out there never benefited from a TKI. So that's really what needs to change, and that's what everybody is pushing in the same direction. Technology is easier, Liquid biopsy is getting good. All kind of things are pushing in that direction, and we really believe it's going to change.

And to Philippe's point about the national guidelines, so Louisiana became the first state in the U.S. to now require NGS testing if you have lung cancer because the outcome of patients with a genetic mutation is so much different than one who doesn't have one. So it's actually required by law in Louisiana. Now dozens of states have legislation before them doing -- mandating the same thing. So it's a national movement that is going to change genetic testing.

You also mentioned CNS activity. I guess, is that a differentiating feature of IBTROZI? I guess how important is that going forward? Is that something you sort of leverage in any of your commercial conversations, especially just given the rate of metastasis?

Yes. That's a really, really good question. So I think it's a huge differentiator. And the reason is ROS1 lung cancer either starts with the brain or goes to the brain. It's only -- it's going to happen. So 36% of the time when a patient is diagnosed, they already have a brain met. And then another 50% of patients when they progress, they're going to progress in the brain at the first sign of the disease progression. So that's already 86% of patients. So that's the vast majority.

If you look at the first -- crizotinib, the first-generation TKI, it doesn't even get in the brain. If you look at entrectinib, one of the other first-generation TKIs, it's progression-free survival 16 months, 1/3 of what we're talking about. Repotrectinib is the most effective second-generation agent, but it's intracranial response rate is 38%. Ours is 66%. So again, not even close. If you look at Nuvalent, which is trying to get a second-line approval this September, their intracranial response rate is 45%, excluding any oncogenic driver. Again, our response rate in the brain is 66%, including all drivers. So much more reflective of a real-world situation. So there isn't any agent that has CNS activity that's close to ours.

And you mentioned one of the competitors, and I guess I have to follow up on that. How are you thinking about how the market might evolve as new agents enter? I mean you talked a little bit about the KOL feedback. I guess what is it that they're looking for in a drug? Is it the efficacy? Is it the safety? And I guess, how do you play to your strengths as that market gets more competitive?

So the first point I'll make is that efficacy and safety are indistinguishable in the sense that the single greatest safety risk for a patient is progression. But by far, whether you talk about dizziness or anything, GI side effects, the worst thing that can happen to a patient is progression. If you look at our duration of response, how long do patients on IBTROZI stay on drug, how long do they respond to our drug, it's over 4 years. The second closest drug is about 1.5 years shorter than that.

So just to wrap the top, I'm going to say efficacy and safety are indistinguishable. Whoever lasts the longest on a drug is the drug that's the safest because once you have a brain met, once you have progression, you're not going to do well. On top of that, if you look at our safety profile, out of the top 6 adverse events, which are AST elevation, ALT elevation, nausea, vomiting, diarrhea and dizziness in that order, out of 337 patients in our safety database, 1 patient discontinued for any of those 6 events, that's 0.3% discontinuation. So from a tolerability standpoint, there isn't a drug that's close to that.

If you look at our adjuvant study, we are the only company that's doing an adjuvant study in ROS1 because you have to have a drug that can be taken for years. And our drug is tolerable enough that we are actually doing that study. And the best testament to tolerability is your duration of response. Our median duration of response is over 4 years, which means patients are taking that drug for over 4 years. If it were intolerable, they wouldn't get close to that. So they're taking it for 4-plus years. This drug is highly tolerable, but it also has a 90% response rate and a 50-month duration of response. There are no drugs in that space that has anything close to those metrics.

Got it. So lot more we can talk about IBTROZI, but I want to make sure we also have some time to talk about safusidenib program that I'm really excited about. So maybe we'll pivot there. I guess maybe to set the groundwork, I mean, you've recently shared additional data on that program, including data that was at one point owned by one of your partners. I guess just to level set, I mean, how do you compare what you're seeing there with the approved agent?

Yes. So IDH1 gliomas right now are a pie composed of 4 parts. Half the pie is low grade, half the pie is high grade. But within each of those sides, half of them are -- roughly half of them are high risk and the other are low risk. Vorasidenib is approved in 1 of the 4 pieces. It's approved in low-risk, low-grade glioma. If you look at their response rate to get them their approval in low-risk, low-grade glioma, it was 11%. At 1 year, they had 23% progression. At 2 years, they had 41% progression.

If you look at our data in the identical subset of patients, low risk, low grade, instead of 11% response rate, we had 44%. Instead of 23% progression at 1 year, we had 4%. Instead of 41% progression at 2 years, we had 12%. So when we look at low-risk, low-grade glioma, we think that our safusidenib data are hands down better data. And so if you look at the high-grade part of the pie, vorasidenib's response rate is 0. If you look at our response rate with safusidenib, in high-grade glioma, it was 17%, but 1/3 of those were complete responses. Complete response is the tumor has disappeared. One of the tumors that disappeared in one of our patients was a GBM glioblastoma, the most difficult of all tumors. That tumor has been gone for 3.5 years. We have a second high-grade response, Grade 3 oligo, which has been gone for about 2 years. Again, responses that we just don't see with vorasidenib. So we're doing two studies and contemplating a third.

The SIGMA study will take 3 of the 4 pieces of the pie where vora isn't. So vora is in that low-risk, low-grade piece of the pie, but SIGMA will target everything else. That's a PFS study, so it's longer, it reads out in 2029. But we're doing a second study, which is a Grade 3 oligo study, which is part of the high-grade pie where vora has no response. And because Grade 3 oligo patients all have measurable disease, unlike the SIGMA study, the endpoint of this study is response rate. And there is nothing approved there. We think that if we see anything north of 20% response, that is a potentially approvable pathway. If we look at Chimerix, they were approved on 50 patients who response with a 21% response rate. And if you look at OJEMDA, they were approved on 77 (sic) [ 76 ] patients with response rate. So we think that somewhere between 50 to 80 patients with a response rate over 20% potentially gets us approved in Grade 3 oligo, that's high risk.

We're doing -- contemplating and designing a third study. When you look at the vora low-risk, low-grade market, I just mentioned that if you look at vora's data, 23% of their patients get treated with vora, progress within 1 year. Well, Servier has announced that they've treated more than 5,000 patients since launch with vora. So if 23% of them progress within a year, around 1,250 patients will progress around 12 months out. Servier launched that drug 15 months ago.

We need somewhere between 50 to 80 patients showing a response rate post-vora, we think, to get approval. So we're designing that study now. We think that, that's a quick response rate readout. We think anything north of 20% and somewhere between 50 to 80 patients get us a conversation with FDA to discuss accelerated approval. So those are the three studies. So two of the three studies we're talking about are response rate trials. We should have the Grade 3 oligo study reads out next year. And potentially, the vora study should be quite fast because there should be 1,000 patients or so who are failing vora out of the 5,000, 23% fail within a year, there should be 1,000 to pick from and we need 50 to 80. So I think that's going to be a quick enrollment and a relatively quick readout. So two of the three studies will have response rate readout probably within a year or so. And the SIGMA study will be a confirmatory study with PFS that will read out in '29.

When people think about brain cancer, they don't necessarily think it's a large opportunity. You just mentioned that in about a year, Servier treated 5,000 patients, right? So can you help us maybe better understand what the size of this opportunity actually is?

Yes. The reason for that is because the incidence of brain cancer, IDH1 brain cancer is about the same as ROS1, about 2,500 patients a year. But unlike ROS1, they live even longer. High-grade IDH gliomas live 6-plus years on the high end. but Grade 3 oligos can live 12 to 14 years. Low-grade gliomas can live 20-plus years. So we're talking about a prevalence pool that's in the tens of thousands of patients. And vora is showing that because in their last quarter, they generated $312 million in 1 quarter. They're already well over $1 billion run rate because there's such a large prevalence pool, and they're going to be on drug for years.

Now if you look at the vora data in low grade at 2 years, 41% of their patients progress. If you look at our data, 12% have progressed at 2 years. If you just make it linear, which probably isn't even linear, you can see that that's already -- we're talking about a long -- many, many years on therapy. But here's another fact. If you look at our recent Daiichi data out of 27 patients that Daiichi treated in the study, 12 of them are still on drug at 5 years, but not all of those 12 were even progressors -- responders. So they're not -- so what that means is that you don't even have to have a response for patients to be kept on drug because non-progression for a disease that invariably progresses and kills you is a good thing.

So you don't even -- even though we have a 44% response rate, so you would think that 44% of people would be on drug. The point of the Daiichi study that we just disclosed at 5 years means that beyond 44%, those who don't progress, even if they didn't respond, could be kept on drug. So now you're talking about a really large number of that prevalence pool of tens of thousands of patients. So the commercial opportunity of safusidenib is probably a multiple of IBTROZI. IBTROZI is big. We think at the peak, it should be $4 billion to $5 billion. But if you look at vora, it's already well over $1 billion in its fifth quarter. We think that's going to be a multibillion-dollar drug, and we think safu should do better than that.

I guess you talked about the excitement and the potential to enroll quickly. And I guess the SIGMA trial is in progress. So can you talk about what you're hearing from investigators and how sort of the clin ops execution there is going?

Yes. So the SIGMA trial is exactly on track. So our predictions on enrollment rate were spot on. So we've said that the latest will read that out in '29, will stand by that. Interestingly, we're actually getting a lot of calls from KOLs and patients to see whether or not they can put their low-risk, low-grade patients on safu instead of vora even though we're not approved because they've seen the data and they think that given our response rate in both low and high grade, they've inquired whether or not they can get their patients on safu instead. And I think that's a pretty good marker of interest in safu.

The unmet need is immense, so the patients are out there, they are all identified. We don't have the same problems we have in ROS1, and we have a very, very good drug. So I mean, so far, the recruitment seen in the trials have been very positive, and we think it's going to continue.

And you've laid out that the data looks pretty impressive. I guess what do we know about why safu might be more potent than some of the other inhibitors? I mean, is there some secret sauce kind of a thing that is the mechanism here?

So when we look at the adverse events, what we've pointed out is that of the top 7 adverse events of safusidenib, even though they're almost all Grade 1, 5 of the 7 are immune-type AEs, things like skin hyperpigmentation. You just don't see that very often. And arthritis and rash and these are things that are associated with many known autoimmune disorders. And if you look at the response rate of safu, often it takes a few months to kick in. And when you get a response, it lasts for a really long time. And it's very reminiscent of IO.

So we've been doing some preclinical experiments, and we have reason to believe that safu does have an immune component to its activity that's perhaps even independent of just IDH1. And so we are further dissecting that. But we think that our clinical profile speaks for itself. The efficacy is very different. The safety is very different. So we think that this drug is just an unusually effective drug for this disorder. And we are pretty confident that we're going to see pretty robust effects in our trials.

I wanted to just touch on sort of the market one more time. You segmented the market into 4 pieces, right? And there's sort of the high-risk, high-grade patients that don't have any options right now, but presumably, they won't necessarily stay on drug for a while. So I guess, how do you think about the component in like each piece of the pie, not just in terms of the patient number, but how they might ultimately contribute to the revenue opportunity and sort of the timing as those come online?

So high-risk high grade, unlike non-IDH1 mutated tumors, these patients live much longer. So even the high-risk high grade can live 6-plus years, unlike GBM that's non-IDH1 mutated. Those patients can live 6 months. So every piece of the glioma pie could live 6-plus years in the highest risk subset of high grade, up to 20-plus years in the low-risk subset of low grade. So it's a large -- it's really a long survival in a large prevalence population. So we think that the patients will be on drug for potentially a decade or longer on average.

Got it. We've got just a minute left. So maybe I'll end with a bigger picture strategy question. You guys are commercializing IBTROZI, working on safu, you've also historically been active on the BD front. I guess how do you think about all these potential capital commitments?

So, we have $535 million right now. We have enough to get to profitability. The launch is going well. So we're going to focus on IBTROZI and really make sure we stick to launch and make sure that we continue to grow first line. We're going to get safu to clinical trials as quickly as possible. We think those -- especially those two response rate trials will give us a relatively soon readout. I mean we're talking about 2027 next year.

And then the PFS study could be a confirmatory study. We're going to announce a new DDC program later this year. We think that's pretty exciting. And we're capitalized to do all of it. But of course, we also always look at BD. I think that there are a lot of really interesting opportunities out there. Of course, we have to pay the right price for it. So, we're going to be very selective and disciplined about that. But if we see an opportunity that is clearly as value-generating as [indiscernible] AnHeart acquisition was, which worked out well for us, I think we'd do that in a heartbeat. So we're going to just be very disciplined and careful about our BD, but it is certainly in our future.

We have the resources to do all of the above and beyond.

Great. Excellent. That's all the time we have, but really appreciate it, speaking with you guys today.

Thanks so much.

Good afternoon, and welcome to the HCW BioConnect Conference. I'm Robert Burns, the Managing Director and Senior Biotech Analyst at H.C. Wainwright. And I'm joined today by David Hung and Philippe Sauvage, the CEO and CFO of Nuvation Bio, respectively. Gentlemen, thank you for joining us today.

Thanks for having us.

Thanks, Robert.

So for those who may be unfamiliar with Nuvation, give us a brief overview of the company and its pipeline.

So we have 3 programs right now. IBTROZI is a best-in-class ROS1 inhibitor for a type of non-small cell lung cancer. That drug was approved in July last year. We've had 3 quarters of launch, which has been very successful. We have a second asset called safusidenib. It's an IDH1 inhibitor for brain tumors. And we believe that data also will make it a best-in-class drug. That drug is in pivotal studies. And then we have a third platform, our Drug-Drug Conjugate platform which we're going to be providing an update on later this year.

Awesome. Yes, I can't wait to speak about the DDC platform. I'm a big fan of it. But it's coming up in almost a year since the approval of taletrectinib. And I know that you presented some updated pooled data from TRUST-I and TRUST-II. So talk to me a little bit about those updated results and how you see taletrectinib in the landscape and how it's differentiated relative to all its predecessors or any other compound that's in development for ROS1.

So ROS1 lung cancer is a particularly aggressive form of lung cancer. And the problem with that disease is that the standard of care used to be IO-chemo and the progression-free survival is about a year. First-generation ROS1 TKIs had a PFS of about 16 to 18 months, but a response rate in the 70% range. Repotrectinib was the first second-generation agent, and it improved the response rate from 70% to about 79%. But more importantly, the PFS doubled from about 1.5 years to 3 years.

Our recent updated AACR showed a response rate now of 90%, so by far the highest response rate among the ROS1 TKIs. But most importantly, a duration of response now of 50 months. If you look at the number of times in the history of oncology that a drug has had a 90% response rate and a DOR of over 4 years, it actually not happened. The only drug with a PFS in our range is lorlatinib, but with a lower response rate. So there are no drugs today in oncology that have a combined 90% response rate and over 4-year DOR.

Yes. No, it's quite impressive. One of the things that I'm still trying to wrap my -- I've always been trying to wrap my head around this one. A lot of people will cite one of the other competitor ROS1 drugs that's in development from Nuvalent. First, I want to get your thoughts on NVL-520. Obviously, we got the second-line data. And how that sort of stacks up against taletrectinib?

Sure. Well, I think, first of all, I think the FDA's opinion is a lot more important than mine. So the FDA granted IBTROZI, taletrectinib breakthrough designation in the first and second-line setting, and the FDA granted Nuvalent's 520 breakthrough designation in the third-line setting. So that's the first important fact. The second thing is that IBTROZI was granted priority review. And we had a very, very fast approval. Nuvalent's drug was -- they applied for an RTOR that was denied and they did not get priority review.

They actually were downgraded to a standard review. So I think that probably says a bit about what FDA's perspectives on the drug are. When you look at the Nuvalent data, they only have really second-line data. There are no published data with Nuvalent drug. But the second-line response rate is 51%, excluding any concomitant oncogenic drivers. Our second-line response rate is 56%, including all oncogenic drivers.

So it makes a much more real world, more difficult to treat. But more importantly, for a disease that will get to the brain 85% of the time, Nuvalent's intracranial response rate in the second line is 45%, excluding oncogenic drivers. Our intracranial response rate is 21 percentage points higher than that, 66%, including all drivers. So right now, we don't see a single metric where Nuvalent drug can compare with the data we've generated even in the second line plus.

Yes. From my perspective, taletrectinib is the end all be all as of right now within ROS1 positive. So why the hell are we seeing such a market cap discrepancy between Nuvation and Nuvalent from your perspective? Because obviously, I think -- I think the market cap should be inverted.

They do have an ALK program. I think that people have high hopes for that program, but we think that we can't really explain the ROS1 discrepancy. And even the ALK program, I think it's going to be very difficult to beat lorlatinib. Lorlatinib has a 6-month PFS from the CROWN study, and they're going to have 7-year CROWN readout at ASCO. So I think that's going to be a really, really hard drug to beat. So I can't answer your question, but we are very pleased with the results we've generated. We think IBTROZI is clearly best-in-class. And our launch has gone extremely well. We think that's reflective of the profile of the drug.

Yes. I want to get your thoughts on this, too, because I know you're evaluating taletrectinib in the adjuvant setting, so I want to get your thoughts as to how you view that market opportunity in that particular setting because that's a pretty large market.

Yes. So moving it upstream to the adjuvant setting will increase the market size another 30% on top of what we already have. And what's really important is that we are actually the only ROS1 drug that's doing an adjuvant trial. The reason it's hard to do an adjuvant trial is that you have to have a drug that's incredibly well tolerated.

And if you look at our top 6 adverse events, which are AST, ALT elevations, nausea, vomiting, diarrhea and dizziness. Out of 337 patients in our safety database, the number of patients who have discontinued our drug for any of those top 6 adverse events was 1 out of 337. So 0.3% discontinuation rate, which is why it's being used in the adjuvant setting because you have to have an incredibly well-tolerated drug.

There are no other drugs that have attempted to go to the adjuvant setting. I think for -- in many cases, because their tolerability is more difficult. So I think that the adjuvant trial is another differentiator for IBTROZI because we'll be the only drug upstream, and that does increase the market opportunity another 30% beyond what we've already...

Yes. I know the NCCN recently updated its guidelines to include IBTROZI for ROS1-positive NSCLC patients that also have brain mets. So talk to me a little bit about how this provides a tailwind for IBTROZI sales and revenue projections.

Yes. So the NCCN Guidelines are important because prior to IBTROZI's really unique data, I think that there was still a lot of IO-chemo use in ROS1 lung cancer, even though IOs PFS, as I mentioned, is about a year. So up until 2024, though, the NCCN Guidelines said if you had ROS1 disease, you had 2 options for treatment. One would be IO-chemo, one would be a ROS1 agent. That all changed in the beginning of 2025.

So about a year ago, the NCCN changed their guidelines and said that now we have ROS1 lung cancer, IO is not only not an option, it's actually contraindicated. And now you have to give a ROS an agent for ROS1 disease. And that just happened a year ago, which is why that market is still evolving as physicians change their practice. But that's a significant tailwind. But it just takes a while to change practice.

So we're seeing that already. But the NCCN recently changed their guidance again recently, just about 1.5 months ago to now include IBTROZI in the CNS guidelines because of IBTROZI's really robust intracranial response rate, 66% is the highest intracranial response we've seen in ROS1 TKI so far. So we are now in the NCCN guidelines for CNS disease, and that's going to be another...

So with regard to modeling revenues for taletrectinib, can you discuss how investors should be thinking about their forecast for this year in terms of revenue stacking? And what do you forecast internally for peak taletrectinib sales? Give us a little thought about what that range, that window looks like for you guys.

So if you look at the theoretical market maximum, there's about 3,000 new cases of ROS1 lung cancer every year in the United States alone. So if you were to multiply 3,000 patients -- new patients a year, this is the first-line setting by the drug price, it's about $1 billion a year. But because the duration of response is now over 4 years, that means that $1 billion in the first year goes to the second year and the third and fourth year. And everyone who starts in the second year goes in the third, fourth, fifth and sixth year and goes on and on.

So by the fourth year, you have about revenue stacking of about $4 billion. By DNA testing, that will increase to another 30% beyond that to about $5 billion with RNA testing because RNA is about 30% more sensitive than DNA. So because of that revenue stacking and because you really see that in the first-line setting, the percentage of first-line patients is critical. So if you look at our launch so far in 3 quarters, in our first quarter, we had 30% first-line patients. But in the second quarter, we had 40% first-line patients.

And now in the third quarter, we've had over 50% first-line patients, yes. So that's the trend that's going to be important because as you see that first-line patient number grow, that's what contributes to the revenue stack. And we think that if that continues, the peak sales of the drug should be in the range of $4 billion to $5 billion if you capture that market. That market will need to be addressed by testing. In the academic centers, that's about 100%. But in community settings, it's not quite as high. So there is room for improvement in testing in the community setting, but we think the market opportunity is probably going to be about $5 billion a year with RNA testing.

To go back to your point about short-term modeling, Robert, I think what's really important to note is that quarter on to David's point, we've been increasing our first-line patient number by 35%. Q3, roughly 60%, Q4, roughly a bit more than 80, Q1, 110, so 35% quarter-on-quarter. And if we keep increasing by 35% because of the extreme long durability of treatment in the first line, we get to consensus sales for the year like roughly $130 million. If we manage to accelerate further, we beat that. So this is really the trend we are on.

More and more first-line patients, and we know these patients will stay on drug for a very long time. The reason why the overall patient number quarter on can seem a little bit flattish is that because you have 2 phenomenons. You have first-line patients growing and you have those later-line patients going down. And they are going down because there are just not that many of them. We launched in a space which was incredibly dormant when nobody was promoting, not enough people were talking about this disease.

So the number of patients that were eligible for second line was not that high, and we are completing that pool. But what's really important and encouraging for us and for the modeling is really first-line patient building up because that's where more and more patients are coming all the time, pretty further again.

Yes. No, that makes complete sense. Why don't we shift gears now to safusidenib. I really like this program a lot. But let's help frame what this program is and how it stacks up against some of the competitors such as vorasidenib.

Sure. So brain tumors that have IDH1 is a 4-piece pie. And the only drug approved today in IDH1 gliomas is vorasidenib. It's only approved in 1 of the 4 pieces of the pie. So the pie is 4 parts. Half of them are low grade, half of them are high grade. And of those, half of them are high risk, half of them are low risk. So vorasidenib is only approved in low-risk, low-grade gliomas. Their response rate to get them that approval was 11%. And at 2 years, the progression rate was 41%. In the same piece of the pie, safusidenib has a 44% response rate.

So 4x vorasidenib is 11%. At 2 years, instead of 41% progression, we had 12%. So in the low-risk, low-grade part of the pie, we have data that we believe are hands down better than vorasidenib. In the other 3 parts of the pie, vorasidenib in the high-grade setting has a 0% response rate. Our response rate was 17%, but 1/3 of those responses were complete responses, which means the tumor disappears. We've had a glioblastoma multiforme that's been gone for 3.5 years, unheard of.

We've had a high-grade oligodendroglioma gone for 2 years, unheard of. So we're doing 2 studies right now and planning a third. In a study called SIGMA, we're taking -- targeting 3 pieces of that 4-piece pie, everything that's not the vorasidenib piece. And that's a progression-free survival readout because it's a PFS, it takes a long time. It will read out in 2029. We're doing a second study targeting half of the high-grade pie, which is the grade 3 oligodendrogliomas.

And because those patients all have measurable disease, the endpoint for that study is response rate. It's a very fast readout. That study will read out next year. And then for the last part of the pie, we're contemplating a trial to target patients who have failed -- if you look at Servier's numbers, they have treated over 5,000 people on vorasidenib. But I just mentioned a little bit ago that if you look at the Kaplan-Meier curve for vorasidenib, they have 23% progression at 1 year. So if they've treated 5,000 people, they started the launch 15 months ago, a significant number of those 5,000 patients will already start to fail now.

I mean you already got -- that's 1,000 patients, right?

So if we were to show responses in the post-vora setting, there are no approved agents post-vora. We think that's a potential accelerated approval. When we look at Chimerix, which got a brain drug approved based on 50 patients with an overall response rate and OJEMDA from Day One getting approved on 77 patients, with response rate. We think that a post Vora response rate anywhere north of 20% in 50 to 80 patients could be enough for potential approval.

Okay. So when are you thinking about initiating that sort of evaluation for that bucket of patients?

So we're actually working on that right now. So we are already started on the first 2, and we're finalizing the design on the piece.

So for the grade 3 oligodendroglioma obviously, that data is coming in 2027. That's an objective response rate readout. How are you thinking about -- is that something that you could then approach the FDA with? And what do you think the benchmark needs to be? What do you think you need to hit in that patient population?

So the response rate for chemotherapy, which is standard of care is single digits. So we think anything over 20% is approvable. If you look at Chimerix, they were approved on 50 patients with a response rate of 21%. So we think anything over 20% is approvable in somewhere between 50 to 80 patients. So both the Grade 3 Oligodendroglioma study as well as the post-vora study are both response rate trials that we think could be approved on somewhere between 50 to 80 patients.

Okay. What's the sort of time frame for that last bucket that mentioned. Obviously, you're starting to get the planning ready for that post-vora subpopulation. What that time line looks like then?

Well, because there are so many patients who've already gotten vora and are already failing it, we think that the enrollment of that study will be quite rapid. And then it's just looking for responses. So I think that if we were to see any responses in that population since there's nothing there at all as an alternative, we would go straight to FDA and ask them, what do you want to see in terms of size to make an approval study.

I don't currently include revenue projections for safusidenib. I'm not sure a lot of any other analysts do. But I'm curious to get your sense as to the market opportunity here in each of those 3 buckets out of those 4, can you talk to me a little bit about the market opportunity there?

So the reason the market opportunity for IDH1 gliomas may very well be unprecedented because there's almost no indications in oncology that have survival that long. Even high-grade patients with IDH1 live up to 6-plus years. So it's unlike high-grade GBM that's not IDH1, they don't live very long. But IDH1 tumors live much longer. So even high-grade astrocytomas can live 6-plus years. If you look at oligodendroglioma, they can live 13, 14, 15 years. If you look about -- talk about low-grade glioma, they can live 20-plus years. So you're talking about revenue stacking that could be literally 4 to 5x the IBTROZI duration of response, which would be literally unprecedented.

Yes. I think when you put it in that context, it goes back to my point earlier, I don't know how Nuvalent's point [ gap ] because what it is and yours is less, especially with the revenue stacking potentials here.

We feel very comfortable where we are. We have a ton of cash. We have $535 million. That's all more than we need to get to profitability. We've got a commercial asset that ramp is going well. We've got a great pipeline. So we feel very comfortable.

Yes. Why don't we shift gears to your DDC? I've always been fascinated by this platform. I know the story of how you came up with it, David. I love that story. But I know that you discontinued one of the earlier versions of -- one of the earlier assets out of this platform. Talk to me about the learnings that you got from that asset. And what sort of uptake can we expect later this year with regards to the DDC platform?

So ADCs are antibody drug conjugates. They work. They're -- some of the best drugs in the world are ADCs, but they're really big. So we started Nuvation Bio based on a concept of Drug-Drug Conjugates, which are much, much smaller than ADCs, but have bispecific -- we had taken a molecule called 1511 in the clinic.

And while we did see responses with it, before we invest $100 million to $150 million in Phase III study, we want to take for a drug that we think is the best shot we have before making that kind of investment. So we thought there was -- we learned a lot in that program and thought there are ways to improve it. So we actually have now made those changes, and we will be announcing a new program later this year.

Okay. When you announced this program, is this going to be -- you're going to start the Phase I relatively soon? Or is this -- it's still preclinical?

We haven't said yet.

Well, I'm excited to learn what it's going to be. I guess with the limited time that we have left, talk to me a little bit about the catalysts for this year. And then last question to you, Philippe, talk to me about the war chest, what the operational runway provides.

I can start with the war chest it's easy. So as David said, we have a little bit more than $530 million. As we've said multiple times, that will be enough to drive us to profitability. So we are not looking for anything else right now from that perspective. And then we're feeling very, very confident about the level of cash. In terms of catalysts, I mean, obviously, continuous performance of IBTROZI, we're incredibly encouraged by the ramp-up, especially this move towards first-line patients, plus our recruitment on safu trials, which we think is going to be rapid in many of them. I think that's the main point and DDC at the end of the year.

Awesome. Well, gentlemen, thank you so much for joining us today. I really appreciate it.

Thanks so much.

Thanks, Robert.

Welcome to day 2 of the 2026 Bank of America Healthcare Conference. My name is Alec Stranahan. I cover biotech at Bank of America, and welcome to this session with Nuvation Bio.

Very pleased to introduce, to my left, David Hung, Chief Executive Officer; and Philippe Sauvage, the Chief Financial Officer of Nuvation. Thanks for being here, guys.

Thanks for having us.

Yes. Looking forward to our conversation here.

I guess maybe just jumping right in. You've reported 3 consecutive quarters of accelerating and growing new patient starts. Net product revenues beginning to catch up with that. I guess how has the launch been tracking with sort of your expectations? And what are sort of the near-term catalysts to look out for, for continuing the growth?

I think the launch has gone very well. We've said that if you look at our new patient starts, so far in our launch, we've had more new patient starts than both previous TKIs combined. So we're pretty excited about that.

The real name of the game is to move to the first-line setting. And I think this is something that's maybe an unusual concept in oncology because very few oncology drugs have durations of response in the range of what we've seen with IBTROZI. So we mentioned previously, having a DOR of over 4 years is highly unusual. In fact, in all of oncology -- if you look at any drug in the history of oncology in any indication, there's actually only one drug that actually has a response rate even approaching ours with a PFS that's longer than ours, that's lorlatinib.

So we think that having a 90% response rate in the first-line setting and over 4-year duration of response sets up a very interesting dynamic for this drug commercially because as you start to get first-line patients and you expect them to stay on therapy for years, you start to see revenue stacking, which is not very commonly seen with most oncology drugs because their durations of response are so short.

So we're just starting to see that now. We've gone from about 30% first-line patients in our first quarter of launch to over 40% in our second quarter and now over 50% in our third quarter. And as we start to see that dynamic increase, we think that the duration of response should be significantly longer with additional follow-up, and we're really looking forward to seeing how that grows our revenue, and we're pretty excited about that.

Great. Well, maybe on that point, I think for the first time this quarter, like you said, more than half of new starts were TKI naive. I guess what's sort of driving the acceleration? Is it physician confidence with the clinical data? Is it maybe increased testing in the community setting? What are sort of the tailwinds for that?

So I think if there was a shortcoming of AnHeart when we -- before we acquired the company, it was that they had a relatively limited U.S. So they did two pivotal studies. TRUST-I was an all-Chinese study. TRUST-II was a global study, but that included the U.S., Europe, Canada and other western sites. And so if you look at the actual U.S. experience, it was relatively limited.

Most physicians, when they're unfamiliar with the drug will start off in late-line settings where there are really no alternatives to get familiar with the drug, and that's what we saw. So if you look at our first quarter, we had primarily third-line or later patients. And when you see very late patients, they stay on drug very short -- for a very short period. So some of these third-, fourth-line patients will last a month or 2, and they drop off very quickly, which is why you don't really see revenue stacking for late-line patients. As you move now from late-line patients to early-line patients, not only do you not get the same level of dropouts that you see in late-line patients, but you now start to see very durable treatment durations and that starts to really change your revenue.

So I think what's happened in this launch is as expected, we were primarily used in the very late-line setting, third-, fourth-line plus. When we started in the first quarter, that already came down in the second quarter and the third quarter, we're now seeing now more than half of our starts in the first-line setting and correspondingly, that late-line use has dropped considerably, and we expect that to continue.

I also think that there is just more familiarity with ROS1. I think that although there were three previous TKIs in the ROS1 space, durability and response rates like IBTROZI have not previously been seen. And when physicians see that profile, I think it's impressive. And I think that for those who are not as familiar with ROS1, it's hard to ignore any new product with a profile like that. When you have a profile and you're -- of a drug, even though the first-gens might have a duration of response of 1.5 years, it's not 4-plus years. And I think that seeing a new drug that has a 90% response rate and a 4-plus year duration of response is hard to ignore.

So I think what's happening in the market is that physicians are getting comfortable with the drug, having started in the later-line patients, even seeing it work there, but now are moving it to the first line. And secondly, I think just the appreciation that this efficacy profile is pretty unique, I think, is causing physicians to adopt it more rapidly than we might have thought.

Okay. So it's kind of a build it and they will come.

I think so.

Yes. And I guess there was some foundation laid by the prior ROS1s. Is that -- what have been the benefits of that? Is it adoption of ROS1 testing at academic centers...

So I think that the whole lung cancer space has shown the utility of finding precision oncology mutations because lung cancer in 20 years has moved from one of the worst, most untreatable cancers to now maybe the most treatable cancer on the planet. If you look at EGFR, ALK, ROS, RET, these are mutations where the survival with precision oncology drugs is dramatically different from what used to be standard of care IO chemo.

So I think that that's a rising tide that's floating all boats. But I think the stage has been well set for IBTROZI because if you look at the predecessor to IBTROZI, repotrectinib, even though the ORR and the DOR of repotrectinib was significantly better than first-generation agents like crizotinib or entrectinib, the tolerability profile left much to be desired. And if you look at the discontinuation rate of repotrectinib, it was pretty high due to CNS toxicity.

So I think that set a stage for what to look for, for physicians and seeing now an efficacy profile that now shows a 90% response rate and more than 4-year PFS, but coupled with really, really tolerable profile, I think, has led to the adoption of IBTROZI the way it has been adopted in the last 3 quarters.

Yes. Yes. Especially, I imagine on the durability piece, like an extra year on the PFS is very meaningful...

Yes. If you look at all marketing studies, the single most important attribute for a drug in terms of what physicians and patients look for when they select a drug is actually durability of response because no -- because once you fail a drug, you're not going to do nearly as well. You're going to have a lot of other issues. So having a drug that works a long time is the single most important thing that patients and doctors look for when they pick a drug. And we think it's appropriate that they're picking IBTROZI, and that's what we're seeing.

Okay. Maybe you can just speak to the intracranial response rate. I think it was 66% versus 45% for competitors. I guess, how does this sort of feed into the CNS NCCN guideline addition you mentioned?

So yes, that's a great point. So we just got listed on NCCN guidelines for CNS control. And I think that's because the response rate of IBTROZI in the brain is outstanding. It's -- as you mentioned, 66% intracranial response rate in the second-line setting.

So ROS1 lung cancer is a particularly aggressive disease because, number one, it starts in the brain 36% of the time. But in another 50%, patients progress in the brain as the first sign of disease progression. Once you have CNS disease, you don't do nearly as well as brain tumors are just really, really hard to treat. So the fact that we have such a durability in the first-line setting suggests that we protect the brain for a really, really long time. That DOR of over 4 years suggests that we control CNS development of metastases, which we think is a really, really important attribute. But even when they do get it in the second-line setting, 2/3 of the time, they still have responses to IBTROZI, which is really heartening.

There isn't any other ROS1 TKI that has a published CNS response rate close to our response rate, as you mentioned. So we think that it's appropriate that NCCN lists us as an agent for CNS control because no one has been able to match our CNS response rates. And we think that our durability in both the first- and second-line setting speaks to that.

Does that allow for any unique aspects in terms of reimbursement on the guidelines?

Yes. So we do -- so we've had really good experience with reimbursement with IBTROZI so far. And Philippe can talk a little bit more about how we decide to price it and all that. But I think that overall, I would say that the data are so compelling, it's really hard to [indiscernible] this drug because there is no other agent that has shown a response rate or durability anywhere near the ballpark of IBTROZI.

And maybe, Philippe, if you want to talk about gross to net and...

Yes. I mean to David's point, it was really important for us to make sure that patients could access IBTROZI in the first line because there is no comparison between the experience of a patient that goes on [ other ] drug and then on IBTROZI or goes straight on IBTROZI, exactly the point that David was making. And so in terms of discussion with payers, that was really something important to us to make sure that there was access.

Our gross to net is pretty -- has been increasing a little bit in the first quarter, and that's mostly driven by phenomenon that have nothing to do with general reimbursement debate. It's driven by 340B use, which is typically something that goes up when a drug is launched. It basically takes some time from hospital to get the drug on their 340B listing. And so your 340B use just drives at the beginning. And then it will stabilize. That's what we think we're going to see.

And the other thing is that we did a price increase like many company does. And when you do that in a period that until the end of last year with low inflation, you get some additional rebates in 340B and Medicaid that again drives your gross to net up. But nothing there, which is really different from what we were expecting at launch.

And the success, to David's point, was really to get this broad access to patients because that's what we wanted in a market that was very dormant, we felt before us. And really being there, being accessible, giving to doctors and patients the possibility to use IBTROZI in first line where it is the most impactful was what we wanted to achieve.

It does sound like that pricing dynamic that you observed in 1Q should stabilize sort of on the course of the year.

Yes.

Yes. Okay. I want to ask on safusidenib. You recently regained -- you gained the rights from Daiichi Sankyo. Maybe just talk about what gets you excited about this asset? I think its -- first stop is IDH1-mutant glioma. What's sort of the unmet need here? And how do you plan to push this forward?

So we are really excited about this program because we think our data are unprecedented. And if you look at the only drug approved in glioma, and I divide glioma to a 4-piece pie, the only drug on the market for glioma, vorasidenib, is approved in 1 of the 4 pieces of that pie. It's only low-risk, low-grade glioma.

And in spite of the response rate of only 11% in that population, and a progression rate of 41% at 2 years in low-risk, low-grade glioma, in their first year of sales, they have generated almost $1 billion of revenue. Their revenue for the last quarter was $312 million, which is just incredible for a first year launch. So that just speaks to how large the opportunity is.

If you look at safusidenib's data in the same population as vorasidenib's, low-risk, low-grade, our response rate was 44%. So 4x higher than that. At 2 years instead of a 41% progression rate, our progression rate was 12%. But even beyond that, if you look at the high-risk population, which is half of glioma patients, the high-grade patients, and that's divided into high-risk and low-risk, vorasidenib's response rate there is 0%. Ours is still 17%, but 1/3 of those responses were complete responses, including a GBM that's been gone for 3.5 years and another high-grade glioma that's been gone for about 2 years.

So we're seeing significant responses in the high-grade population, which vorasidenib doesn't have, as well as responses in the low-grade population that we think are superior to vora. So we think that safusidenib is good for the entire pie, all 4 pieces of that pie, and we're doing now a number of pivotal studies to address that. But we think this is an extremely large unmet need. As good as vorasidenib data are compared to what was prior -- previously available, we think that there's still a lot of room for improvement and are really excited about this asset. So we acquired worldwide rights -- the last rights from Japan because we just think this is such an incredible opportunity, and we want to maximize the potential of that.

Okay. And just in terms of upcoming data timing and path to approval, is it accelerated approval in some of these...

We're doing a number of studies. We have a pivotal study called SIGMA. It's a progression-free survival study. As a result, it doesn't read out until 2029. But we are also starting pivotal studies that are hopefully going to be much shorter than that. We're starting a Grade 3 oligodendroglioma study, which is a response rate study. We're going to have a significant number of patients enrolled this year, and we're going to complete it by next year. If we see a significant response rate there, anything north of 20%, we think that's that warrants a discussion with FDA on potential accelerated approval.

We're also looking at other ways to get safusidenib developed in the vora space, the low-risk, low-grade glioma space. And so we're going to be announcing plans on that later this year. And we think that those are much shorter-term opportunities to create value with safusidenib.

Great. And maybe just last question on the cash runway. I think you ended 1Q with just over $500 million in cash. How does this help you support the SIGMA study and also leave room for sort of development out of the pipeline?

Well, from our perspective, it really helps us to support everything. Like we've said multiple times that we have enough cash to get us to profitability, to cash flow positivity with the launch of IBTROZI. So we're very confident about that and very confident about the future and our ability to invest behind our great assets being safu or drug-drug conjugate program.

Okay. Very good. Well, with that, I think we're out of time. So David, Philippe, thank you so much for the conversation. Thanks for...

Thank you.

Hello, and welcome to Nuvation Bio's First Quarter 2026 Financial Results and Corporate Update Call. Today's call is being recorded, and a replay will be available on the company's website. [Operator Instructions]

Now I'd like to turn the call over to JR DeVita, Vice President of Corporate Development and Investor Relations at Nuvation Bio. Please go ahead.

Thank you, and good afternoon, everyone. Earlier today, we issued a press release summarizing our financial results for the quarter ending March 31, 2026, and provided a business update. The press release is available on the Investors section of our website at nuvation.com.

Today's call includes forward-looking statements, including statements about the therapeutic and commercial potential of IBTROZI and safusidenib, our plans for safusidenib development and future data presentations, the components of our anticipated product revenue, expected milestone payments and our cash runway. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our quarterly report on Form 10-Q, which we filed with the U.S. Securities and Exchange Commission today.

Joining me on today's call are our Founder, President and Chief Executive Officer, Dr. David Hung; our Chief Commercial Officer, Colleen Sjogren; and our Chief Financial Officer, Philippe Sauvage.

Now, I'll turn the call over to Dr. David Hung. David, please go ahead.

Thanks, JR. Good afternoon, everyone, and thank you all for joining us. Today, I'm excited to discuss the progress we have made across our business in the first quarter. Following the line-agnostic FDA approval of IBTROZI in June 2025, we entered 2026 focused on continuing to build a successful commercial launch in ROS1-positive non-small cell lung cancer, with specific focus on educating physicians, supporting patients and generating new clinical evidence that reinforces IBTROZI's differentiated profile.

Overall, we are very pleased with our continued execution, highlighted by strong demand for IBTROZI and our ability to significantly increase the percentage of new patients treated in the first-line setting. We successfully treated approximately 200 new patients with IBTROZI in the first quarter, which makes 3 consecutive quarters of about 200 new patient starts, bringing our total to over 600 since launch.

We see a growing trend of more new patients coming from the first-line setting and in turn, a lower percentage of patients coming from the third-line setting or later. In fact, for the first time since launch, more than half of the new patients who started IBTROZI in the quarter were TKI naive.

Given the changing dynamics of patient mix and moving from later line to the first-line setting and considering the significantly increased durability of IBTROZI in earlier versus later line settings, we are just beginning to see revenue stocking this quarter, as Philippe will shortly discuss. This revenue dynamic is the most important metric for the launch going forward. Therefore, at some point in the future, we will focus on revenue and no longer report new patient starts.

This has meaningful implications for the long-term opportunity for our medicine, especially now given that based on a recent new analysis presented at AACR, IBTROZI has now extended its median duration of response to 50 months in TKI-naive patients in the pooled results from the pivotal TRUST studies. When patients are treated earlier in their disease course, they are often in a better position to realize increased benefit from a therapy with durable efficacy and generally favorable tolerability.

Over time, we believe this can build a larger, longer duration base of active patients on IBTROZI and support more substantial revenue growth. Since launch, our discontinuations have been driven primarily by disease progression in later-line patients. This is expected in any oncology launch as these patients have already progressed through other approved therapies.

From the data that we see, discontinuations in earlier line patients or for adverse events are consistent with clinical trial results that remain relatively low. As a reminder, and as detailed in IBTROZI's prescribing information, 6.5% of the 337 patients with advanced ROS1-positive NSCLC in our pivotal Trust studies discontinued therapy due to any adverse reaction. And as we have previously presented, only one of these patients or 0.3% discontinued treatment due to any of the 6 most common adverse events, including liver enzyme elevations, diarrhea, nausea, vomiting or dizziness.

The feedback we continue to receive from both key opinion leaders and our sales organization has been highly consistent. Physicians are impressed with IBTROZI's clinical profile, citing the durability and tolerability and our real-world experience is giving physicians increased confidence to both keep patients on therapy longer and to choose IBTROZI when considering a preferred first-line treatment option. This response further supports our belief in both consensus net revenue estimates for IBTROZI in 2026 and its long-term potential.

We are also encouraged by the addition of IBTROZI to the latest CNS NCCN guidelines as a systemic therapy option for ROS1-positive NSCLC patients with brain metastases. We believe this is an important recognition of IBTROZI's demonstrated intracranial activity and further supports its differentiated position in the ROS1 treatment landscape.

Turning to our recent abstracts and publications. We were thrilled to present updated pooled results from the August 2025 data cutoff of the TRUST-I and TRUST-II studies at the American Association of Clinical Research Congress, or AACR. These updated data continue to reinforce the strength of IBTROZI's profile.

In TKI-naive patients in TRUST-I, as recently published in the Journal of Clinical Oncology, median duration of response and median progression-free survival have both now increased to approximately 50 months or more than 4 years. As presented at AACR in TKI pretreated patients, the median duration of response was nearly 20 months in TRUST-II and the overall survival in the pool TKI pretreated population showed a median of nearly 30 months, which is unprecedented in this space.

And with this longer follow-up, IBTROZI continues to demonstrate a manageable and consistent safety profile, including lower rates of neurologic adverse events and no new safety signals. We believe these durability data matter not only clinically but commercially. Drugs that combine deep and durable efficacy with a favorable tolerability profile are well positioned to become the therapy of choice for TKI-naive patients, and that is exactly the trend we are seeing in our launch.

With approximately 3 years of follow-up in the pooled analysis and more than 4 years of follow-up in TRUST-I, we believe these data further supports IBTROZI as an effective, durable and tolerable treatment option for patients living with advanced ROS1-positive NSCLC.

At AACR, we also presented preclinical data, which continues to build on our broader scientific understanding of IBTROZI's differentiated profile. As I discussed on our last earnings call, IBTROZI is designed to achieve deep and durable inhibition of ROS1, while maintaining measured activity against TRKb.

Our presentation showed 2 important points. First, taletrectinib has nearly complete coverage of ROS1 fusions at clinically relevant concentrations and is effective against ROS1 resistance mutations. Second, taletrectinib has partial yet biologically meaningful inhibition of TRKb, while being sufficiently balanced to avoid significant CNS-related adverse events as seen in our clinical trials and real-world experience.

Of note, in the same experiment, a TRKb sparing agent failed to control tumor migration and markers of invasion and metastases, which were well controlled by taletrectinib. These data support the concept that some degree of TRKb inhibition may be required to inhibit systemic progression, prevent the migration of lung cancer cells and protect against metastases to the brain. This analysis showed that our medicine may have a mechanistic profile, which we believe leads to a potential impact on tumor invasiveness and metastatic behavior in patients while limiting neurologic adverse events.

This balanced approach and ability to prevent resistance could ultimately play an important role in the long-term durable control of ROS1-positive lung cancer as demonstrated in IBTROZI's median progression-free survival of over 4 years.

At ASCO in June, we will be presenting additional data from our TRUST program on patient-reported outcomes and our ongoing TRUST-IV study in the adjuvant setting.

Turning to safusidenib. We remain very excited about the potential of this program and the opportunity it represents for patients with IDH1 mutant glioma. Beyond its potential clinical importance, we believe safusidenib could address a broad segment of the glioma market and therefore, represent a meaningful long-term value opportunity for the company. Safusidenib is currently being evaluated in the ongoing Phase III SIGMA study for the maintenance treatment of patients with IDH1 mutant atrocytoma who have high-risk features following standard of care and in a nonpivotal cohort with Grade 3 oligodendroglioma following surgery.

In Phase I and Phase II single-arm studies, safusidenib has shown very encouraging efficacy signals, including durable responses and prolonged progression-free survival across both low and high-grade IDH1 mutant gliomas. We think about the glioma market as a pie with 4 parts: low-grade, low risk, low-grade high risk, high-grade low risk and high-grade high-risk tumors.

Today, the only approved glioma drug, vorasidenib, is approved in the low-grade, low-risk glioma setting and prior data have shown limited activity in enhancing our high-risk, high-grade tumors. In contrast, safusidenib has shown significant activity in clinical studies across all 4 subgroups of IDH1 mutant glioma.

The safusidenib SIGMA pivotal trial will target 3 of the 4 pieces of the glioma pie, enrolling high-grade high-risk, high-grade low-risk and low-grade high-risk IDH1 mutant glioma patients. We're also exploring potential studies to further develop safusidenib in the final piece of the pie, low-grade low-risk glioma, and we'll provide an update on our plans later this year.

I'd also like to highlight that a November 2025 publication in neuro-oncology summarized the Phase II study of safusidenib patients with chemotherapy and radiotherapy naive Grade 2 IDH1 mutant gliomas as of a March 10, 2023 data cutoff.

Strikingly, as of February 2026, 12 of the 27 patients evaluated in this study remained on treatment with a median follow-up of more than 5 years. We believe these data continue to support the potential of safusidenib in patient populations with significant unmet need and limited or no FDA-approved targeted treatment options.

Importantly, in April, we acquired exclusive rights to safusidenib in Japan from our partner, Daiichi Sankyo. With that agreement now complete, we plan to expand the pivotal Phase III SIGMA study into Japan, continue to advance the global development program and pursue presentation and publication of longer-term Phase II data, so the scientific community remains current on these findings.

Finally, we remain on track to provide an update on our drug-drug conjugate platform by the end of the year. Overall, the first quarter confirmed important points for our 2026 outlook. We are seeing solid new patient demand, improving mix towards first-line use and continued confirmation of IBTROZI's encouraging efficacy and tolerability profile in the real world.

We believe these trends position IBTROZI well for long-term success while we continue to advance a broader pipeline designed to address significant patient needs and create additional future value.

With that, I'll turn the call over to Colleen.

Thank you, David, and hello, everyone. We continue to see strong momentum in the launch of IBTROZI, and we are particularly encouraged by what we have accomplished in just 3 quarters, especially when viewed against relevant targeted therapy launch analogs. Based on our internal data, we have generated more new patient starts than the prior ROS1 launches combined over the same time period.

We believe this early success reflects the compelling clinical profile of IBTROZI and the focused execution of our commercial team. In addition, it represents a strong foundation for long-term value creation.

As David mentioned, new patient starts remained robust at approximately 200 for the third quarter in a row, and this included a greater proportion of patients initiating treatment in the first-line setting. Importantly, our internal data sources indicate that for the first time, over half of new patient starts in the quarter were TKI naive compared to approximately 30% in the first full quarter following launch.

This continued shift from later line to frontline use is one of the clearest indicators of the strength of the launch and is in line with what we would expect based on typical uptake trends with new oncology agents. This gives us confidence in IBTROZI's long-term trajectory because these patients respond at a higher rate, have the potential to remain on therapy for years and contribute to a more durable active patient base over time. This dynamic is also important in understanding the discontinuation patterns we have observed as we are encouraged by how IBTROZI's clinical profile has translated to the commercial setting.

Discontinuations continue to be concentrated among later-line patients, which is expected given the more advanced disease in this population and exposure to multiple prior therapies. As we discussed last quarter, most discontinuations are driven by disease progression in later-line patients rather than tolerability. And this dynamic can introduce some variability in near-term revenue even when new patient demand is steady. Importantly, adverse event-related discontinuations remain low and in line with what we observed in clinical trials, reinforcing the strong overall clinical profile of IBTROZI, including its favorable tolerability.

Taken together, these observations, along with feedback from both patients and physicians, reinforce our view that IBTROZI is well positioned to serve patients across the ROS1 lung cancer treatment landscape and has not changed our view of the potential for IBTROZI in this setting. This increasing strength in patient mix and positive real-world feedback on IBTROZI's treatment profile is matched by expanding adoption across both academic and community settings. We are especially encouraged by the pace of uptake we are seeing, particularly given that ROS1 is a rare disease and the prescriber base is relatively broad.

Our commercial efforts continue to translate into strong physician awareness, which we believe is a meaningful indicator of successful launch execution. Based on our most recent market research, aided awareness of IBTROZI among target physicians has reached 97%, underscoring the breadth of our commercial reach and the growing visibility of IBTROZI in the market.

We understand that academic and community customers have different needs, and we have been deliberate in aligning our commercial strategy with the distinct value drivers for each setting. As a result, 100% of the top 50 historical TKI accounts in the country have prescribed IBTROZI.

Our broad account adoption is another important indicator of launch strength. And when paired with favorable placement on pathways and formularies, it reinforces our belief that institutions recognize the differentiated clinical profile of IBTROZI.

We believe the launch progress we have seen to date also reflects the strength of a team that knows how to win in targeted oncology. We are seeing our efforts translate into meaningful account and physician traction. The result and appreciation for the durability that IBTROZI has to offer and the openness to partnering with Nuvation Bio.

Taken together, we believe this positions us well to continue building momentum and capture the full ROS1 market over time. Lastly, we believe there is meaningful opportunity to increase the number of ROS1-positive patients who are diagnosed and treated with a ROS1 TKI today.

Publications and data from the field suggest there should be approximately 3,000 patients with advanced ROS1-positive non-small cell lung cancer diagnosed annually in the U.S. based on DNA testing.

As the field shifts to using RNA and DNA-based testing together, which may detect an additional 30% of fusions, the annual addressable population could expand to approximately 4,000 patients. Unfortunately, although effective testing is better in most academic centers, it is currently significantly lower in parts of the community, including below 50% in some centers.

To combat this, we have implemented several initiatives to partner with and educate the community on the importance of testing for oncogenic drivers. We strongly believe all patients should have the opportunity to benefit from the prolonged durability and high response rates IBTROZI has shown in the first-line setting, consistent with the NCCN guidelines issued last year. Improving patient identification is the right thing to do for patients and will be a key driver of long-term value for Nuvation Bio.

Overall, we are encouraged by the level of demand we are seeing, the shift towards earlier line use and the strength of the launch execution to date. The medical community recognizes that IBTROZI's long durability gives physicians an important tool and offers patients the potential for long-lasting benefit with a generally favorable safety profile so they can stay on therapy for years.

With an experienced commercial team, a clear strategy and disciplined execution across the launch, we believe we are well positioned to continue building momentum and support the long-term success of IBTROZI.

Now I'll turn it over to Philippe.

Thanks, Colleen, and good afternoon, everyone. For detailed first quarter 2026 financials, please refer to our earnings press release, which is available on our website.

Now, I will highlight a few key points from the quarter. In the first quarter, we generated $83.2 million in total revenue, including $18.5 million in IBTROZI net U.S. product revenue. This represents 18% growth in net product revenue from the prior quarter, which was not only driven by yet another quarter of about 200 new patient starts, but importantly, from a growing population of active patients remaining on IBTROZI due to increasing frontline use.

As you can see on this slide, the number of patients starting IBTROZI in the last 3 quarters has been consistent. However, due to the percentage of first-line patients increasing from approximately 30% in the first quarter last year to approximately 40% in the fourth quarter last year to now more than 50%, net product revenue has grown from $7.7 million to $15.7 million to now $18.5 million, in spite of an expected uptick in gross to net.

We expect this trend to continue and also expect the number of new patient starts to increase as more U.S. physicians become aware of IBTROZI and testing rates in the community continue to improve. As previously mentioned, our long-term success will be driven by the exceptional duration of response of IBTROZI in the first-line setting, and we are pleased that a growing number of TKI-naive patients have started on medicines since the early months of our launch. This trend, combined with our ability to grow revenue despite later line patients dropping off IBTROZI, demonstrate the potential impact of revenue stacking going forward.

Lastly, as I noted, while we did see an expected uptick in gross to net discount at the start of the year, we still expect our gross to net expansion to gradually stabilize from here. In addition to product revenue, we recognized $64.7 million in collaboration and license revenue in the quarter, including an upfront payment of nearly $60 million from Eisai pursuant to our partnership, which was announced in January.

We also received approximately $1.7 million in royalty payments from our partnerships in Japan and China, both of which are exceeding initial expectations on a new patient starts and net revenue basis. As a reminder, taletrectinib was listed in China's National Reimbursement Drug List, or NRDL, in January. And since then, sales from Innovent's launch have increased rapidly.

We believe this significant commercial uptake is due to a greater appreciation for effective setting in China and also believe this rate of adoption will translate to the U.S. market as patient identification improves over time.

We continue to invest in our business and our programs, resulting in total operating expenses of $73.5 million for the quarter. R&D expenses were $35 million, driven by increased investment in the SIGMA and TRUST clinical studies and SG&A expenses were $38.3 million, primarily driven by commercialization activities.

Turning to the balance sheet. We ended the quarter with $533.7 million in cash, cash equivalents and marketable securities. In addition, $50 million remains available under our existing term loan agreement with Sagard Healthcare Partners through June 30. We also expect to receive a milestone payment of approximately $30 million for Eisai upon the approval of IBTROZI in Europe in the first half of 2027.

Lastly, on the business development front, we announced our partnership with Eisai in January to commercialize IBTROZI in Europe and other territories outside of China and Japan, which we discussed on our previous earnings call.

In April, we also announced an agreement with Daiichi Sankyo to acquire rights to safusidenib in Japan. This transaction made sense to us from a strategic and financial perspective as it allowed us to fully secure global rights to safusidenib, including ownership of all clinical data and rights to future publications and data generation without changing our expected cash run rate.

Acquiring full global rights will reinforce our speed of execution and now allow us to expand our commercial reach to Japan. I'd like to thank Daiichi Sankyo for their efforts in developing tofacitinib and for their confidence in us to take the program forward toward potential global regulatory approvals.

Overall, our capital position continues to provide us with the flexibility to support IBTROZI launch, advance our pipeline and evaluate additional strategic opportunities, all while maintaining a disciplined approach to spending. We continue to believe we are well positioned to execute on our priorities without the need for additional external financing given our current revenue trajectory and operating plan.

I'll now turn it back to David for closing remarks.

Thanks, Philippe. As we move through 2026, we remain focused on disciplined execution, continuing to build on the momentum of the launch, advancing our clinical and scientific understanding of IBTROZI and progressing our broader pipeline.

I want to thank our team for their continued commitment and our investigators, partners, shareholders and most importantly, patients and their families for their ongoing support.

I'll now ask the operator to open the line for questions.

[Operator Instructions] Your first question comes from the line of Farzin Haque with Jefferies.

Congrats on the progress. Can you comment on whether the growing first-line patients are coming from the academic or the community settings? And then what specific educational field force initiatives are being implemented to accelerate adoption in the high-volume community?

Farzin, it's Colleen. I'll take that one. So you may have heard me mention that, first of all, we're very encouraged. We have about 97% awareness right now across -- and this is uniform adoption IBTROZI across both academic and community. And most importantly, when we look at historically, the top ROS1 accounts, which we have a historical list of about 50 of those accounts, 100% of them, in fact, have prescribed. So we're seeing broad adoption across all channels, academic, IDN and community. And really, we believe that, that just speaks to -- directly to the oncologists that are driven by the clinical evidence IBTROZI's trust data.

It's so compelling that in each channel, we're seeing really, really good uptake and adoption. And on your second question, you asked about specific initiatives. Are you talking about adoption there? Do you want me to go in more of that? Which kind of initiatives are you looking for me to answer?

Right. Adoption and basically use over the chemo IO agents.

Yes. I would say that one of the things, Farzin, that we really are focused on is testing rates. And this is a real challenge, and I'll say that we're not dismissive of it, but we're also not passive about this. And the gap between really academic and community testing is very well documented. And frankly, in some of the community centers, we're seeing testing rates that still remain below 50%.

So in our opinion, that's unacceptable from a patient care standpoint and it represents just a really meaningful community opportunity. So what really gives us confidence is that we do have a targeted strategy in place. So we're partnering directly with community oncology practices -- we're investing in a lot of educational initiatives, and we're also directly working with testing platforms to make sure that, in fact, comprehensive molecular testing is the standard of care and not the exception. So we believe in this market. We believe in the size of the market. We do believe and have acknowledged that we have an issue with testing that we're addressing directly.

Farzin, this is David. Just to add a little more precision to the question you asked. The -- getting first-line patients really depends on them being diagnosed. And as Colleen mentioned, while we have great awareness in both community and academic centers, the testing rates are higher currently in academic centers and community centers. And therefore, the diagnosis of new patients are right now higher in academic centers because that's where more testing is being done. But we've already seen significant improvement in multiple community centers, and we are very heartened by that improvement in testing rates and the awareness that there's a drug that's highly efficacious, durable and well tolerated to use when those diagnoses are made.

So we're pretty excited about this change that we've seen in first-line percentage, as we mentioned, 20% or 30% in the first quarter after launch to about 40% now to over 50% that's a pretty exciting growth trajectory for us because we think that's going to allow us to meet our consensus guidelines for the year if that were to continue.

Your next question comes from the line of Leonid Timashev with RBC Capital Markets.

I wanted to follow up on that a little bit. Just maybe trying to better understand the dynamic of the new patient starts. I mean it seems like it's been 200 for the past 3 quarters. And you've laid out a lot of reasons why there should be growing awareness, better testing. But I guess I'm just trying to better understand why that hasn't pulled through into more new patient starts yet, for example, why you aren't seeing why the proportion is changing towards first line, but you're not necessarily also seeing more of the later line patients coming on as well? I mean, whether there's a bottleneck somewhere, if this is something that could be helped by expanding the sales force and hitting more prescribers? And just if you can talk about the dynamic, that would be great.

Yes. It's a great question, but the main reason is because remember, in the early quarters of our launch, we're getting mainly late-line patients, third line, fourth line, fifth line patients. Those patients can discontinue therapy in literally a month or 2. And when you see very late-line patients, they drop out very quickly, unfortunately, to pursue other therapies or they unfortunately pass away.

So the reason that you see right now what appears to be a plateau, it's not. It's just that the late-line patients are dropping out very quickly. We're getting new line patients, but those are incidents. Remember, that the presence pool has already been diagnosed. So when they enter the study, they're much easier to find because they've already had a ROS1 diagnosed, they've already been on therapy, but they don't stay on very long and they drop off very quickly.

The new patients are newly diagnosed. I mean, the first-line patients have to be newly diagnosed, and that's an incidence pool, which obviously takes longer time. So when you see what's happening now, the fact that we're getting from 30% to 40% to now over 50% first line, we are finding those first-line patients. But the third, fourth, fifth line patients are dropping off rapidly. That should stabilize because eventually, we're going to deplete that whole pool.

In fact, we think we've already captured a significant amount of the late-line patients. So now that's why we're really focused on first line. That's all that really matters given the fact that we now have a PFS or DOR of more than 4 years, 15 months, which is there's no drug even within a year of that. We think that, that's going to lead to revenue stacking that will really start to kick in, and we're just seeing that this year.

So even in spite of a quarter with roughly the same number of new patient starts and in spite of an increase in GTN, revenue still went up 18%. So we're just starting to see the beginnings of that. But we think that if we were just to keep the same growth rate in first-line patients that we've seen in the last -- from Q3 to Q4, Q4 to Q1, we think that we should make our consensus for the year comfortably.

Your next question comes from the line of Kaveri Pohlman with Clear Street.

So maybe a question on the repeat prescription. I believe any details you can provide on -- the previous call mentioned the academic was 70% versus 30% distribution for academic versus community. But today's call also mentioned that 100% of top 50 accounts have prescribed IBTROZI, which I assume are mostly community-based. So any insight you can provide there?

And if you can also tell us how this NCCN and CNS guideline inclusion helps you get more of the first-line adoption? And then my follow-up question is a quick on the previous comments you made regarding lower testing rates in the community setting. So are these rates simply lower because of lack of awareness regarding the importance of testing or there could be some other hurdles that could take longer period for changes to happen?

Kaveri, it's Colleen. So what I can tell you, a couple of things that I think we need to keep in mind. So when we look at across these top historical accounts, and we're looking at 100% of those 50 accounts have now written, we see a much greater, I would say, usage by community, IDN and now academic. And you're right, in the first -- when we first launched, we saw real fast uptake in the academics. Now we're seeing just as much strength in the uptake across other channels and especially in the community.

And one of the things that we've seen when we first launched, obviously, the academic oncologists right? They're driven by the clinical evidence and IBTROZI's trust data speaks to that directly. And we look now at the community oncologists and what they need, right? They need the practical support, the reimbursement pathways, patient support programs and the confidence of their patients can tolerate the therapy over time. They're now seeing all of that. They're seeing the surround sound of Nuvation Connect.

They're seeing reimbursement pathways that have now taken effect. They're seeing our patient support program. So we believe that, that's directly linked now to the channel of community really increasing their uptake and identifying patients.

The other thing you asked about was the testing. And one thing I want to say is that we know that our accounts are increasingly prioritizing the flagging of these mutation statuses. And as RNA-based testing continues to gain ground alongside with using DNA, we know that more ROS1-positive patients are starting to be identified each month and every year. So we're laying that groundwork in terms of education, and we know that's now positioning IBTROZI to benefit as these identification rates improve.

So we're seeing the educational part of our efforts really taking traction in the community. I will also say we're educating on effective testing rates, making sure that our oncologists are waiting until they get all the oncogenic driver testing back to make a treatment decision. That's what we talk about influencing effective testing rates.

And Kaveri, let me add one more thing to add to your question about the NCCN CNS guidelines. The reason that's so important is actually it turns out that one of the most widely used previous TKIs ROS1 is crizotinib. Crizotinib doesn't even get to the brain.

Now we have guidelines from the NCCN that specifically call out the CNS profile of IBTROZI and that contrasts even more starkly against crizotinib's complete absence of brain penetration. So as you know, 36% of ROS1 begins in the brain at first diagnosis and then another 50% will progress in the brain upon first progression. So it literally would be medical malpractice to get the drug that is not CNS penetrant. And not only is IBTROZI highly CNS penetrant.

If you look at our intracranial response rate, even in the second-line setting, even in the most difficult to treat patients, our intracranial response rate is 66%, which is so far the highest recorded intracranial response rate of any TKI in the pretreated space. And that's independent of our unmatched durability and response in the first-line setting. So we think that the new NCCN CNS guidelines make it even more imperative that doctors need to give patients the right therapy, which is IBTROZI.

And Kaveri, just to add on that, to put an explanation point on that point by David, we've already received early feedback from HCPs that this will only enhance IBTROZI's profile and really impact their treatment decision.

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

Congrats on the progress and results today. David, maybe I'll just stay with IBTROZI and add another question on this topic. A competitor recently presented some data suggesting activity in patients previously treated with taletrectinib is there. I'm just curious, how would you expect treating physicians to interpret such results? Would you see this influencing sequencing decisions or the positioning with IBTROZI as compared to competing or potential agents in the market?

Yes, I think it actually does have some implications. So first of all, we are delighted that new treatment options becoming available for patients as they fail therapy. But if you look at IBTROZI's efficacy with a response rate of 90% and now a PFS of more than 5 -- more than 4 years, almost 50 months, there is nothing close to it in the first-line space.

Repotrectinib's PFS is 36 months. So you're still talking about almost 1.5 years difference. If you look at the second-line setting, now with a DOR approaching at 20 months and again, a response rate in second line of 56% without excluding any oncogenic drivers and an intracranial response rate of 66%, again, without excluding any oncogenic drivers, there are no age today that can claim any numbers that match those.

So when a competitor has data in the third-line setting showing responses after IBTROZI fails in the second-line setting, we're delighted that patients have another option in the third-line setting. And I will refresh your memory I think the competitor you're referring to actually got breakthrough designation in the third-line setting while IBTROZI got breakthrough designation in the first and second-line setting.

We think things are playing out the way FDA initially thought them, which is that IBTROZI will be used in the first and second-line setting. And we think other agents are needed in the third-line setting, and we welcome that because that's what patients need.

Your next question comes from the line of Mayank Mamtani with B. Riley.

And maybe just to build on the prior point of IBTROZI is being now considered relative to crizotinib and maybe the entrenched position could be protected with additional market entrant. How much is the development of new CNS mets relevant to the clinicians you talk to? And then if you are able to comment also on the dose interruption reductions that are tracking in the frontline patients versus what you may have seen in the later lines? And then I have a follow-up.

Yes. So that's a great question. So ROS1 non-small cell lung cancer is a really aggressive disease, not only because the tumors grow aggressively, but because where they go. So more than 1/3 of the time, they already are in the brain when you even make your first diagnosis. And in 50% of the cases on progression, the brain is the first site of tumor metastasis. That makes it imperative that you get CNS coverage as quickly as possible with an agent that has proven and long-term efficacy.

As I said, the intracranial response rate of IBTROZI in the second-line setting is 66%. And our duration of response in the second-line setting is 20 months with the now overall survival of almost 3 years. So in the second-line setting, there are no agents today that have published any data that can close to that.

In the first-line setting, it's completely universal difference. There's no agent remotely within IBTROZI 90% response rate and 50-month PFS. So I think CNS is important. And because CNS is so important, that's the reason that IBTROZI is being adopted so quickly, especially in the first-line setting as clinicians know they need an agent that covers the brain. They need to see proven data that this drug has durability and our 15-month durability is unprecedented. So that's the reason that we're getting such adoption in the first-line setting.

And also still significant use in the second-line setting. We -- as I said, we probably captured the majority of patients already in the second-line plus setting. So I think that's I think that would be expected, and that's what we're seeing.

Now to get on to your question about discontinuations and interruptions, the great thing about this drug is it's pretty well tolerated. And as we said on the call script, we are not seeing anything new that we haven't seen in the clinical trial. And that's really important because the thing you always worry about with any drug is that real-world experience parallel your clinical trial experience. Oftentimes, in the clinical trial experience, when you're under the careful supervision of the principal investigators and they may control those patients better. So sometimes in the real-world study, you don't see metrics that exactly parallel what you would hope for based on a clinical trial.

In our case, we have seen no new developments. While we are really encouraged by tolerability IBTROZI's pretty much exactly what we saw in the clinical trials. Our dose reduction interruption rates are pretty much what we saw in clinical trials. Our efficacy is too early to see now how long these patients will last. We expect them to last 50 months in the first-line setting, 20 months in the second-line setting, just like reflecting clinical trials.

So overall, the great news for us is no surprises. We feel very confident in what we're seeing or what we're hearing from physicians echoes that. I think that the uptake that we've seen and the growth in the first-line setting we're seeing are all consistent with the fact that our data in the real-world setting are as good as they were in the clinical trial setting.

Very helpful, David. And then just on a go-forward basis, I understand new patient adds not a very relevant metric. What should we focus on? Should we get more updates on the proportion of first-line patients? Would you have some information on durability? I understand gross to net, you have some thoughts. Just help us think about the modeling beyond 2026. And I understand everyone's focused on 2026, but I just wanted to get some color on how you're thinking about metrics on a go-forward basis.

Yes. We are very excited by the dynamics there. And I think what we've said again and again is that we see a profile which is very similar to our clinical trial, which means that patients, especially first-line patients will stay on drug for a very long time. That's why we shared some more information on this because we think this is really the driver of our long-term potential.

And if you look at our story, there in the past 2 quarters, I mean, we grew this first-line patient number by 35% from Q3 to Q4. We grew again by 35%, roughly Q1 to Q4. And if we keep increasing at that rate, we will hit consensus. And if we do better than that, if we accelerate further, we will beat consensus. So everything there is really happening as we thought it would, which is really, really encouraging.

And to the question that I heard earlier about the stability you can see, well, it's because you have like 2 different mechanisms going on, right? You have those first-line patients increasing again and again, as I said, 35% from Q3 to Q4, 35% again Q4 to Q1, and we expect it to keep increasing over time. And at the same time, we have this pool of late-line patients where, unfortunately, many of them will not stay on drug. But this pool is limited. And that's why this is as a total, relatively stable.

But looking ahead and looking forward, really what is important for us is really this buildup of first line patients, and we'll keep talking about that because we know that's where is the promise of IBTROZI, incredible tolerability, incredible durability and all of that together to help patients stay on for a long time and to help ourselves progress quarter after quarter.

So that's really what we see. We think that's going to drive ourselves forward further. And to your point about GTN, I think, again, we hinted about that in our past quarter. Q1, typically, because of our price increase, you will have a rise of GTN driven by the fact that Medicaid and 340B price are stable, as you know, so higher than inflation, and we were that drives the GTN a little bit higher.

You also see the launch of the 340B use gradually progress a little bit until it stabilized -- that's typically in the oncology launch. So for all of these reasons, our GTN has raised a little bit by a few percent this quarter. We still believe it's going to stabilize, and this is nothing abnormal there. Again, as I said, no surprise, no surprise on our GTN, no surprise in our patients, no surprise in our OpEx. Everything is happening exactly like we said.

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

Just a couple of questions. When -- if we're looking at number of patients, let's say, that you started each quarter, like the 30 and then 40 and let's say, greater than 50% who are new, it looks like really an increasing number of patients now are going to be sort of in the naive setting, right, or treatment naive patients. And so can you give us maybe a sense kind of what percentage of those now are treatment naive as a percentage of the total? Just some thoughts. And then gross to net, should we sort of assume that you're going to be in the high 20s, and that's kind of where you're going to stabilize this year, Philippe? Or I think it was kind of in the 25% last quarter.

Yes. So on your first question, yes, that's exactly what you're saying, increase of first-line patients quarter after quarter, and we expect this first-line patients to come on drug to keep increasing over the year. As I said, if we stay on the same rhythm of plus 35%, roughly every quarter, that takes us to consensus. If we go beyond that, that will help us to beat consensus. So that's the dynamic here.

To your point about patients on drug today, you know we have limitations in our data. So it's kind of hard to answer to that question. But you can run your own estimate based on our first-line patients, a very good tolerability profile plus what we said about late line versus first line.

To the point about -- I think your second question was about GTN, yes. It's pretty mechanical, if you think about it. So you have an increase of 340B. And we -- and if you look at the CPI-U, the index rate for inflation between June, the time we launched in December, you can see it's pretty much aligned.

So for all our 340B and Medicaid patients, this basically drive our gross to net higher by the amount of our price increase, that makes sense to you. So if you think about that, yes, we will be around 30%, and we expect to stabilize around that level as gradually inflation start to ease on our inflation penalty, if that makes sense. And I can elaborate if it's not clear to you. So that's where we are. And we think, again, it's very much aligned with what we said in the previous quarter, really no surprise there.

Your next question comes from the line of Boris Peaker with Jones Trading.

Just want to understand how is the duration of therapy in some of these first-line patients compare to your expectation based on the clinical trial results?

So I mean, it's still early now. We -- they're clearly staying on way longer because that's why our revenues are going up, and that's why our -- as we would expect, but we expect them to be on for an average of over four years. So we won't know until we get to the fourth year, but I think we feel very confident that if you look at the discontinuations, as Colleen said earlier, almost all of our discontinuations are from late line patients, not early line patients, just as we would expect.

And as we mentioned earlier, the side effect profile is exactly aligned. So there is no reason for first-line patients to stop drug.

Got it. And with the recently addition to NCCN guidelines, is there can you see an inflection with that? Like can you see how much that really benefited? Or is that kind of just in the background and it's not something that could be noticed?

I think that it's just -- there's always a lag in this stuff. So the first NCCN change was a year ago, and it took a while for practices to actually realize that IO is actually contraindicated in this disease. We're just starting to see some practice shifts there. That's a year after that guideline came out. So the CNS guidelines are great. The awareness is already pretty high that RAS1 is a brain trophic disease. So I think the guidelines -- the impact of these guidelines might be appreciated a little bit earlier than the original ones IO -- with IO is a pretty ingrained practice in many centers, but everyone knows that when you get a brain met, you're not going to do well.

So I think I'm guessing that the NCCN guidelines will be appreciated maybe a little sooner. But it's all good direction for us because everything the NCCN is saying is basically taken frozen.

Great. And lastly, do you expect to issue annual sales guidance sometime this year?

I think we're getting to the point where we now have hundreds of patients under our belt. And when we see the growth the way we're seeing it, I think we would probably be willing to issue guidance at some point in the future.

Your final question comes from the line of Silvan Tuerkcan with Citizens Bank.

This is Josh on for Silvan. Congrats on the results here. It seems like we have gotten a lot of color on the CNS efficacy. But maybe could we get the team's perspective on the comparison of taletrectinib and CNS maybe to emerging clinical candidates rather than what's already been approved. What do we know here and maybe not to be too repetitive, but how does the CNS NCCN guideline reinforce the benefit here?

Well, I mean, the nearest competitor that's not yet approved has so far an intracranial response rate of 45%, all excluding oncogenic drivers. Ours is 21 percentage points higher than that at 66% without excluding oncogenic drivers. That's all I can say about the CNS data that are available today for competitors. So if you look at our intracranial response rate compared to the approved TKIs, Itri is far higher than that. But even compared to up-and-coming competitors, as I said, there's no one close so far on intracranial response rate in the second-line setting.

Your next question comes from the line of Michael Yee with UBS.ss

This is Matt on for Mike. I just wanted to ask a quick one on the IDH1 program. Could you just remind us what the standard of care is there in that high-grade glioma setting? And then speak to what PFS would be clinically meaningful, both in the broader population and then also on that ORR readout that could come maybe next year in a subset of patients, what would a good result look like? And what could the next steps be in that smaller subset? And just trying to think through any kind of nearer-term milestones for the IDH1 program.

So the SIGMA trial is a placebo-controlled study. So given the fact that, there's absolutely nothing approved for the management of high-grade glioma, the management of high-grade glioma today is third for tumor debulking radiation and chemo. And as you know, the patients don't do well when they have multiple surgeries. You can't just keep the tumors in the brain, chemo and radiation are just not effective with very, very low response rate.

So our -- for a response rate, we would be looking at anything north of 20%. We think that anything north of 20% for an indication that has absolutely no other therapies would be certainly a response where we go to FDA and have a discussion about approval pathway. So we feel pretty good about that, especially given our -- the data that we've presented so far. For Grade 3 oligodendroglioma, those are less aggressive than the grade 4 astrocytoma, which are GBM. So we would expect response rates to be even higher. because it's a little bit of an easier indication to treat.

And again, I would say anything north of 20%, we would think the FDA would be pretty interested given the fact there's nothing even in Grade 3 oligodendroglioma. So we think anything in that range would be potentially an approvable pathway.

There are no further questions at this time. I will now turn the call back to David for closing remarks.

Well, I just wanted to thank you all for your support. We're really excited about what we are seeing with the IBTROZI launch, and it's gone pretty much what we had hoped, and we will continue to -- we can't wait for our next quarter because we'd love to report our next quarter earnings, and we hope that you'll follow up with great enthusiasm. And thank you very much.

This concludes today's call. Thank you for attending. You may now disconnect.

Welcome to Day 2 of the Citizens Life Science Conferences. My name is Silvan Tuerkcan, and I cover Precision Medicines at Citizens, and it's a pleasure to have everybody here. And now I'll be hosting Nuvation. David Hung, Co-Founder and President, thank you so much for joining us; and Philippe Sauvage, CFO.

Thank you.

Thank you.

Maybe to kick it off, recently the earnings, if you could just talk to us about the IBTROZI launch, how that's going and some of the dynamics that you've discussed.

Yes. I think the IBTROZI launch has gone very well. We have 2 full quarters so far. In the first 2 quarters, we had 432 patients, a little over 200 a quarter, which is about 6x what we saw in the first 2 quarters of the AUGTYRO launch. And by the way, our 2 quarters with all other ROS1 TKIs combined, we have exceeded that by a significant margin. So we're pretty pleased with that.

We have seen lines, all lines of therapy prescribed, even though the majority of our prescriptions still are in later lines because this is typical of oncology launches, but we have seen first-line use and we've seen that growing. So we are excited about that. And I think that we've had sales in every sales territory. Our 47 sales reps in the field have all had success in all the geographies. So we think the launch is going pretty much as we had hoped.

Maybe talk about these lines of therapy. And I think it's -- obviously, there was some volatility around the earnings call, and I think there's a lot of eyes on it. But in my mind, it is because of the duration of therapy is so long in the front line and obviously, then decays. And so that kind of maybe threw people a curveball. So if you could just discuss like what the dynamics there are and how you penetrate into early lines? And maybe if you can point to some examples from other launches where is this very typical to start in.

Right. So if you look at the duration of therapy by different lines of therapy, it exponentially decreases with later lines. So if you look at our progression-free survival in the first-line setting, we're talking about 46 months or longer. If you look at second-line setting, that drops by 1/4 -- by down to 1/4 of that. And if you look at probably third-line plus, you're talking about probably 1/4 of that.

So I think that what you generally see in oncology launches is later line patients because, number one, they are already identified because they've all been on previous TKIs and already have a ROS1 diagnosis, whereas incidence patients have to be diagnosed new. And so it's a slower process. So the prevalence pool is the easiest pool to address, but they tend to be experienced and have shorter durations of therapy.

If you look at the kind of patients we're getting, we don't have complete visibility into that yet because unless the patients seek reimbursement assistance and unless they come through our portal called NuvationConnect for that, we don't really know anything about their profile. And because we've had actually relatively few reimbursement challenges, so not that many patients have come through our portal for reimbursement assistance, out of the 432 patients that we have treated so far, the number of patients who have come through our portal looking for assistance is only into the double digits.

So the only glimpse into the lines of therapy that we see are from those double-digit numbers of patients. That's such a small fraction of our 430-plus patients that it's hard for us to make a guess at this point that we're confident in as to what the lines of therapy will be. We've said that the majority of them are still third-line -- second, third-line plus, but we do have first-line patients, and we do expect that to change virtually monthly. And we are already seeing some decrease in third-line plus. We're seeing some increase in first-line. But we have said that 75-plus percent of our discontinuations are third-line plus patients, as you would expect. As I said, the duration of therapy drops off exponentially with later lines.

So to your point, Silvan, when you're asking about benchmark, this is really typical, right? You start with patients in late line in oncology and you gradually get to first-line. And what's really encouraging is every data, like David said, points to the same direction. We're getting more of these first-line patients. We don't see any emerging adverse events, which is outside of what we saw in clinical trial. We see the kind of duration on therapy of all those lines that were to be expected. So exactly as expected.

Yes. And I guess with your long duration of therapy, it makes a real big difference like KRAS inhibitors. If you go from 4 months to 6 months, it's not that big of an effect. And then just to clarify, and we got this question from a few investors is about the discontinuation. So the discontinuation is due to progression, right, in the late-line patients?

Pretty much.

And the discontinuation rate due to side effects, is that in line with what you've seen in the study?

So we haven't seen any discontinuations due to something that was unexpected. We think that our -- and again, we're looking at a relatively small portal of patients. But from what we've seen, everything seems to be in line with our clinical trials. And we actually view the fact that 75% of our discontinuations being third-line plus to be a very positive thing because it confirms that our earlier line patients are actually lasting a long time on drug.

So I think that, as Philippe said, no surprises, which is always a good thing because you always want to make sure that your real-world data are similar to your clinical trial data, and we have every reason to believe that it is.

And then as of when I put these questions together, I think the consensus was just shy of $150 million. How do you view that estimate for this year for your first full year of sales?

Yes, I think we're comfortable with that. We have said that the -- it won't be a linear road to that $150 million, but I think that we are seeing the kind of growth that we expect, and we do see an increase in first-line. So revenue stacking will become more important in the second half of the year, and we think that we feel pretty comfortable with that consensus number.

Yes. A way to think about it, Silvan, for your model is that those first-line patients, these numbers is growing quarter-on-quarter. Of course, at the beginning, we had those late-line patients, which are going down. So the total seems flat, but actually, the dynamic of the first-line patients is really going up. And of course, the accumulation of a line is a curve, right? And so it's going to be more at the later part of the year that we'll have those sales as we have more and more first-line patients stay on the drug.

And often, as it happens with launches, can you just talk a little bit about the gross to net dynamics? Are they -- were you giving away a lot of free drug in the beginning or not? And how can we think about that?

So of course, like all pharma companies, we are trying to be responsible citizens. So there are multiple ways to get access to IBTROZI. The STAR program, which you referred to free drug has been very, very limited, which is, I think, a testament to how good we have been in terms of reimbursement. Typically at most a couple of weeks, I don't think we have any patients that has been on the samples for more than a month. So really, really good there.

We do have a PAP program for patients that are functionally uninsured or don't have any reimbursement. It's also very typical. But beyond that, it's just typical negotiation. It's a space with multiple drugs. So we had to negotiate with some payers, very important for us to have access. And that's why our gross to net has been increasing a little bit. We said that in the fourth quarter, we were a little bit above 25%, and we still expect it to increase a little bit and then stabilize.

Great. And maybe about the one number that stuck out is that you mentioned on the earnings report that your growth was 6x or your on-ramp 6x the patient numbers than the other, I don't know if it was all ROS1 combined or one of them. But can you just talk about that on-ramp in terms of patient -- like does that point to an expansion of the ROS1 opportunity? Or is it just very fast penetration into the existing share?

I mean I think that -- so we were talking about the actual number of new patient starts. If you look at AUGTYRO's first 2 quarters, they are doing 30-something patients per quarter. We did about 200. So we do think that we have a pretty rapid adoption of our drug. But we do think that good drugs expand markets. And if you look at what happened with osimertinib, you look at what happened with alectinib in lung cancer, we know that drugs that actually work do expand markets. We would anticipate the same thing in ROS1.

But also there's a lot of upside in terms of ROS1 testing. It's still not where it needs to be. Academic testing is probably close to 100%, but community testing is definitely south of that. But because of the precedent set by EGFR in ALK, RET and now ROS1, I think that testing will increase. So I think the market will increase.

The other change in the dynamics of the market is that current DNA testing would predict 3,000 patients a year. But RNA testing is now becoming standard of care and certainly many academic centers are hopefully in the community soon. And RNA testing is about 30% more sensitive than DNA testing. So the market will grow about 30% if we just move from DNA to RNA testing.

And then the NCCN guidelines, obviously, they changed early in the year with respect to ROS1 what you do once you find out and you are supposed to switch a patient of the IO and replace treatment with ROS1. Do you experience that already or this early in the launch? Any more tangible data that you're collecting on this?

Yes. So the NCCN guidelines changed on January 7 of last year, so it's about a year ago. So now IO is contraindicated and because of that contraindication and now the recommendation to use a ROS1 agent, that alone should grow the ROS1 market as well because a lot of those other patients used to just take IO. And by the time they got -- if they ever got to a ROS1 agent, they were much farther advanced and probably did not do as well.

So I think that, that's going to increase ROS1 TKI use. And physician behaviors never immediately change, but I do think that we're already seeing some changes in practice based on those NCCN guidelines. And we would expect that to accelerate, especially when a drug like IBTROZI has the kind of efficacy profile and tolerability profile that we have. We think that there's a really good reason now to use a drug, not only because NCCN contraindicates IO and recommends ROS1 TKIs, but because now we have a ROS1 TKI with literally unprecedented duration of response and a tolerability profile that makes it really easy to use.

Right. And can you talk a little bit about your maybe commercial capabilities at this point? Is it the sales force? Is it rightsized at this point? And what are kind of the next focus point for the sales force in terms of getting in new hospitals or convincing some doctors that are not prescribing yet or just staying on top of the ones that are already prescribing?

Sure. So we look at where the ROS1 patients are. We believe that about 25% to 30% will be in academic centers and about 65% to 70% will be in the community. Right now, where we're finding our patients is the reverse of that. So we're finding most of our patients right now in academic centers because they tend to be early adopters and community takes a little longer. But what our sales force has been focused on is now trying to reverse that. And we're already seeing movement now towards increasing community use where the majority of patients are. It just takes a little bit longer in the community.

We think the sales force is rightsized. We have 47 reps. But because of the way that community oncology is structured out, the vast majority of community practice, you don't really see mom-and-pop practices anymore like decades ago, but they're now aggregated into large community systems like OneOncology or Florida Cancer or U.S. Oncology. And because of that, it's a lot more efficient to reach those patients because now we go to these centers and we familiarize them with IBTROZI, and we can reach a lot more physicians with more efficiency than previously. So I think we aim to see the patients come from academic and community sources in accordance with their epidemiological split.

Great. And maybe for those not as familiar with your asset, could you just like review let's say, the label and the benefits it brings to the ROS1 indication with respect to the other TKIs that are out there?

Yes. So if you look at first-generation TKIs and ROS1, the PFS for entrectinib is16 months. For crizotinib, it's 19 months. The response rate for both those drugs is between 68% and 72%, so average of 70%. If you look at repotrectinib or AUGTYRO, the response rate is up to 79% and the PFS in the first-line is 36 months. But if you now look at IBTROZI, our overall response rate is now 89% with a PFS in the JCO publication of a year ago, which is still maturing at 46 months.

So pretty clear that the benefits that we're seeing are substantial. In fact, there are actually no oncology drugs in any cancer that have shown a combined response rate and PFS as long as IBTROZI. So we think that's a pretty unique profile. And we're going to keep updating that label. We recently updated it last year, at the end of the year, showing now that duration of response has now moved up to 50 months, which now puts it among the very, very elite. Only LORBRENA or lorlatinib with a PFS of 60 months exceeds that. But we -- our data is still maturing. So we expect that to even -- that could even change further. But we are already in a very rarefied atmosphere in terms of our responses and durability of response.

So we think that's pretty competitive. Also very importantly, if you look at our intracranial response rates, they're also very high, and that's important because ROS1 lung cancer is a disease that's going to get to your brain at least 86% of the time, 36% of the time, it starts in your brain at diagnosis, and then another 50% progressed in the brain as the first site of disease progression. So you need to have good central nervous system coverage. And if you look at our -- even in the second-line setting, if you look at our intracranial response rate of 66%, that's so far the highest seen of any ROS1 TKI. So we feel that the profile is pretty robust.

Yes. What's the kind of the impact or what could be the dynamics with generic crizotinib and entrectinib, like how would that...

Crizotinib doesn't get to the brain at all. So it's -- even though it used to be used in ROS1, it's actually not medically appropriate today. I guess if 86% of the time, you're going to get a brain met, to use a drug that doesn't even get in the brain, it's just not good medical practice. So we think crizotinib is a drug that should no longer be used in ROS1 disease because if you give it, you're just taking a gamble with whether or not you're going to get CNS coverage. And 86% of the time, you're going to lose because it's going to get to the brain.

So I think that if you look at ROS1 treatments for ROS1 lung cancer, I think you need to pick drugs that have really durable responses because that means, by definition, you are working well against resistance mutations, and you need to use drugs that get to the brain that have high brain activity because that means that you're actually addressing the single biggest determinant of long-term survival, which is the development of brain mets.

And then I know you had some liver monitoring in the very beginning. Does that come up as any issue stopping uptake or?

Not at all. So LFT elevation is a paper issue and most patients don't even know they have it because they're not symptomatic. If you look at our 6 most common adverse events, LFT elevation were #1 and #2. And in spite of that, despite of being the 2 most common of our 6 most common adverse events out of 337 patients in our database, a number of patients who discontinued IBTROZI due to either elevation of AST or ALT was 1 patient. So 1 out of 337 is 0.3%. So that was our discontinuation rate for liver function test elevation, which we think is really the best among the TKIs that you've seen.

And then obviously, there are some eyeballs on Nuvalent who may launch a competitor later in the year in a later line and then maybe next year in earlier line. Can you just talk about how you view the competitiveness here versus potential profile?

Sure. So Nuvalent is applying for a second-line plus label. And their launch will be in second-line plus. If you look at the data they presented so far in the second-line setting, their response rate is 51%. But that 51% response rate is caveated by the fact that the ARROS-1 study excluded any secondary oncogenic driver mutation that wasn't ROS1.

Our response rate in the second-line is 56%, so about 10% higher than Nuvalent's, but that 56% includes every oncogenic driver. So we made no exclusion. So we would argue that 56% with no exclusions beats 51% with exclusions. If you look at Nuvalent's confirmed response rate in the intracranial response rate in second-line setting, it's 45%. Again, excluding any secondary oncogenic drivers. Our intracranial response rate in second-line, including all drivers was 21 percentage points higher than that at 66%. We think that's pretty significant.

If you look at the post entrectinib response rate of Nuvalent's drug, after you fail entrectinib, the response rate is 33%, ours is 80%. So we do think that there is a significant difference between the 2 drugs. We don't see -- we have not seen any metric so far where Nuvalent's drug has been able to match, much less exceed any metric of performance that we've seen.

So we think that IBTROZI is a really efficacious drug. As I said, there are no cancer drugs in any indication that have matched our efficacy in the first-line setting. And by the way, we think the prevalence pool of second-line plus patients is probably in the range of 1,000. Well, we're getting 200-plus patients per quarter. By the time Nuvalent launches in the third quarter, we will have probably treated a majority of those patients and then moved upstream to first-line. So we think that we're really well positioned with the way this drug is working.

And to your point, Silvan. Just reminding everyone one more time. So we'll be launching first-line 2 years after this. That's a lot of time in our industry.

Yes. And you need to bring something better to the table, otherwise hard to penetrate.

Exactly.

Maybe, can you talk to us about your adjuvant plans? It's a very big population also.

Yes. So we are the only ROS1 TKI that's doing adjuvant. So that says several things. Number one, to go to the adjuvant setting where patients are generally asymptomatic, you have to have a drug that's really tolerable. And the fact that we've been encouraged by KOLs to do that, and we have now done it, again, speaks to the tolerability profile of our drug. As I said, if you look at our top 6 adverse events, our discontinuation rate for any of those is 0.3%. So pretty tolerable.

So the reason the adjuvant space is important is because now you're talking about the farthest upstream you can go. When osimertinib did their adjuvant study, that led to them getting 100% market share. And we think that we're the only ROS1 TKI that's doing an adjuvant study. So we're -- even if anyone decides to try to get to the adjuvant space, they'll be significantly behind us. So we think that we're going to own that space and subsequently, we'll be the first drug used in the ROS1 lung cancer period.

Right. And maybe switching gears. I have many more questions on this, but it's a very interesting asset, and that's why we picked up coverage in the first place. But you also have safusidenib. If you could just talk about your progress here and with your IDH1 inhibitor.

Sure. So safu is a mutant IDH1 inhibitor. There's only one mutant IDH1 inhibitor approved in glioma. It's called vorasidenib or VORANIGO made by Servier. What's been striking about that compound is that in just their last quarter, they generated $258 million in sales in their fourth full quarter, which is remarkable. So that means that they're already on a $1 billion run rate for a drug that's only approved in 1 of the 4 parts of the glioma pie. So I mean divide the glioma pie into high risk -- high grade and low grade, it's about 50-50. But each of those segments can be divided further into high risk, low risk. So there's 4 pieces of that pie. Vorasidenib is only improved in one of those pieces, low risk, low grade.

So if you look at vorasidenib's response rate in low risk, low grade, the response rate is 11%. And at 1 year, 23% of their patients had progressed. At 2 years, 41% of their patients had progressed. If you look at safusidenib's response rate and PFS in the same population, the low risk, low grade, instead of 11% response, we had a 44% response rate. Instead of 23% progression at 1 year, we had 4% progression at 1 year. Instead of 41% progression at 2 years, we had 12% progression in 2 years.

So when we look at the low risk, low grade part of that pie, we think that safu's data is more robust. But importantly, vorasidenib is not approved in the other 3 pieces of the pie. So high risk, low grade; low risk, high grade; high risk, high grade. And we're doing a study called SIGMA that addresses all the other 3 pieces of that pie. So if that gets approved, we'll be the only drug approved in 3 of the 4 pieces of the pie.

We're also doing a second study targeting grade 3 oligodendrogliomas because in that population, they all have measurable disease, but they can't -- because they live so long, in 12 to 14 years on average, they can't take radiation and chemo for those 12 to 14 years, so they need an oral therapy like safu. Because they have measurable disease, that trial was a response rate trial, and we think that potentially, if the response rate is very robust, a drug could be improved based on response rate alone in that population.

We cite as precedent OJEMDA's approval in pediatric glioma for Day One in -- based on the response rate trial in 77 patients. So we are kicking off -- we have kicked off a 40-patient trial in the grade 3 oligodendroglioma patients. We will have a readout on that data set next year, but we'll start to see some data this year. If we start to see any response rates that are significantly higher than chemo, which is about 5% response rate, we think that warrants a discussion with the FDA to ask them what number of patients they would want to see to make this an approvable trial. As I said, OJEMDA was approved on 77 patients. So we had to make a wild guess, we think maybe 80 or so. We'll see what the FDA says. It depends on how robust the responses are. But we think there probably is a pathway to approval with response rate if the response rate is robust enough. So we're going to start to think about that toward the end of the year and we start to get our first patient data back.

Great. Well, thank you, David. Thank you, Philippe. Thanks for joining us today.

Well, thank you so much. Good to see you.

Thanks.

Good morning, once again, and welcome to the 46th Annual TD Cowen Healthcare Conference. I'm Yaron Werber from the biotech team. And it's a great pleasure to moderate the next fireside chat with Nuvation Bio. With us today really needs an introduction, David Hung, Co-Founder, President and CEO; and Philippe Sauvage as well, Chief Financial Officer. Gentlemen, thanks for joining us.

Thanks, Yaron.

So maybe, David and Philippe for both of you, give us a little bit of a sense, first of all, the market reaction, I mean, this week has been kind of bananas with everything that's going on. We've seen a lot of volatility in stocks. You printed a decent Q4. It was preannounced at JPMorgan. Any sense sort of what happened with the stock? What's your best sense? And what was your main takeaway from your conference call?

Yes. So there -- we think the stock reaction after the call was a little bit unusual. There's really no new news. As you said, we preannounced our results at JPMorgan, and we're just trying to give some more color on the preannounced news from JPMorgan. One of the questions that we received at JPMorgan was if you look at our new patient starts, which have been very robust, 6x the BMS launch going from 204 in Q3 to 216 in Q4, why did there appear to be some gap between the new patient starts and the revenue. And the reason for that is that if you were modeling 12 months of revenue for every patient that started, that's not reflective of generally how oncology launches start.

So as you know, almost always in oncology launches, you take the sickest patients first, especially when physicians don't have familiarity with a new drug, they'll take the sickest patients, so the farthest along, maybe third, fourth, fifth line patients and then you get experience and move them upstream. Secondly, as you know, if you look at TKI experienced patients, we calculate there's about a pool of about 1,000 of those patients. But because that's a pre-existing pool, they've all been identified. They already are known to have ROS1, having filled other ROS1 agents. That's a pool that's very easy to access, whereas incidence patients, which are new diagnoses, these are patients who have to develop their disease, get diagnosed with their disease and then figure out a treatment.

So clearly, it's a lot easier to access the TKI experienced patients than the new patients. So what we've said is that most of our -- the majority of our patients in the Q3 and Q4 were TKI-experienced patients with some first-line patients, which are increasing literally as we speak. But what we -- the comment we made that I believe may have been misinterpreted was that if you look at our discontinuation rate, we have very little visibility into the profiles of our patients unless they come through the NuvationConnect hub.

So the NuvationConnect hub is a hub that we have for patients who need reimbursement assistance. But because reimbursement has been pretty easy to secure for IBTROZI, very few patients go through that hub. So of the 432 patients we've treated to date, the number of patients who have gone through our hub is in the double digits. So because we only have a double-digit number of patients and that's coming through that hub, that's all we see in their profile, it's virtually impossible for us to be very confident what number of patients are in first line versus second line versus third line.

We will get more visibility of that over time as the number of patients we see increases certainly to the triple digits, but not in the double digits. And how long they stay on drug, we have no visibility into. So what we did say is that from the limited number of patients we've seen in the NuvationConnect hub, 75-plus percent of our discontinuations are in the third, fourth line or longer setting.

So I believe that comment might have been misinterpreted. We heard some feedback this morning that people were concerned that, oh my goodness, you have a 75% discontinuation rate. That's not what we meant. We meant that of the patients that we've seen discontinuations in, 75% of them are in the third line or greater setting. Now to the contrary, I would expect that to be reassuring because the first thing you never want to see in a drug launch is that the drug performs differently than you saw in your clinical trial.

If you look at the durations of response in the first versus second versus third-line setting, durations of response decreased exponentially with later lines of therapy. So our duration of response in the first-line setting is 15 months. Our duration of response in the second-line setting is probably closer to 12 months, so not even a quarter. Duration of response in the third-line setting is probably a matter of a couple of months or in that ballpark, and the fourth line would be even shorter.

So if 75% of our discontinuations are in the third line or later setting, that means that 25% of our discontinuations have to be in the first- or second-line setting, given the limited visibility we have to these hub patients. If we just apply the 4:1 ratio of DOR from our first line to our second-line setting, that would suggest that of the 25% that may be in first and second line, 3/4 of that or 4/5 of that would be in second line and 1/5 of that in the first-line setting, which would be actually very consistent with our total trial discontinuation rate of about 6.5%. So to the contrary, I think that, that 75% discontinuation rate in the third line gave us confidence that our drug is behaving exactly as we would have expected from our clinical trial results in the second and first-line setting.

Now I still have the caveat that we only have visibility into a double-digit number of patients out of our 432 patients treated so far. But we think that, that is suggestive of a duration or discontinuation rate that we think is really good. And the reason that discontinuation rate is so important is because with a 50-month DOR, as long as you stay on drug, you can expect significant revenue stacking over 4 years into the fifth year.

So we think that perhaps that comment was perhaps misunderstood. We think the 75% discontinuation rate in the third-line setting is actually a positive reflection of the durability of the drug and the tolerability of the drug in earlier line settings, and we expect that to play out throughout the year. That also said, we made the point that because third-line patients drop off quickly, of course, those revenues will stop earlier than in second line and then in first-line patients.

So you would expect the gap between new patient starts and revenue to narrow as we move from a mix of a lot of third-line patients to mainly second and first-line patients and ultimately to just first-line patients. So we've always said that the name of the game is first-line treatment. And we do expect over time to have primarily first-line patients. And we're already seeing with every month an increase in our first-line patients and a decrease in third-line patients.

Now again, this is based on just that double-digit number of patients we've seen so far through our NuvationConnect hub. But at least even in that limited number of patients, we're seeing first-line grow and third line come down just as you would expect. So what I said on the call that things were going directionally the way we would have hoped they are. We're seeing first lines increase. We're seeing third lines come down, and we would expect that to narrow the revenue gap over time.

Now that's not going to happen immediately because for -- in the beginning of the launch, those third-line patients have very, very short duration of response and they come off drug. But in the second half of the year, we believe that the second half revenue will be certainly bigger than the first half and so this is not a linear ramp. It's going to be a little bit more of an inflection upwards in the second half. We've said on the call that our consensus for the year is, I think, $147 million, and we're comfortable with that for the year.

So we're going to get there, but we're not going to get there in a linear fashion. We're going to have increasing revenues in the second half of the year. But -- all that to say, we think that the launch has gone incredibly well, 6x the BMS launch. We see no reason that's going to change. We said we're going to keep growing. But even if we have no further growth, we made the point previously on another call that even if we just do 200-something patients per quarter, if we assume 12 months of treatment, that would already equilibrate out around $220 million a year with no other growth.

Of course, we anticipate further growth. But we're already at a number of patients per quarter that if we had no growth and they just stayed on for 12 months, which they all will once they get to second line and first line, they'll be longer than that, we'll equilibrate at around $220 million. And then any growth on top of that is just upside to that number.

So we feel comfortable with the consensus of $147 million for the year. We think that the back half will have more revenue than the first half. It's not going to be a linear ramp, but it is going to get to that number. And we think that the launch is going really well, and the drug is performing exactly as we would have predicted from the clinical trial results, which is something that we find to be a very positive.

Yes, that's very useful, David. When you're looking at dynamics into Q1, there's a little bit of seasonality. I mean, look, this quarter, there's going to be snow effect for everybody, and we're going to kind of hear that everywhere. So it's one thing we'll all just have to keep in mind a little bit, at least in the U.S., which is obviously where majority of your market, but obviously, I imagine a lot of your sales are not sitting in the Northeast on the East Coast. But should we expect growth in Q1? And what about gross to net dynamics right now? I think you said kind of low 20s.

I think what's important is that we are extremely bullish long term for IBTROZI. It's an extraordinary drug. 90% response rate in first line, 90% response rate in first line. I want everybody to understand that. In the cancer space, it's kind of unheard of. And because of this 90% response rate in first line, of course, these patients will respond, overwhelming majority of them.

They will stay on drug to David's point, median DOR 50 months, so they will stay on drug for a long time. That's the first-line patient. And that's what ultimately will drive this market, extraordinary response rate, patients staying on therapy for a very long time. What you're worried about in the launch is, do we see anything which is abnormal? We don't. Contribution driven by first line, as David said. So late-line patients.

Response rates in late line is lower because that's what it is for everyone in oncology. And the reality is that there is no meaningful potential for very late line in ROS1. So the steady state, where we're going, where we are on track to go is extraordinary because of those first-line patients. But the launch is not a steady state, and I think it's exactly your point. So at the beginning, you gradually grow your first-line patients, but you have second-line patients, you have third-line patients, you have beyond, and those could come off.

On top of that, you have snowstorm in the East, maybe you have patients not visiting their doctors for something they do not expect. I would like everybody to remember, ROS1 patients never smoker, 50 years old, female. So you don't necessarily expect to have lung cancer. So this is not something like, oh, I really need to see my physician now. So there could be evolution there.

But the steady state, the growth, the first-line patients, the promise of IBTROZI is extraordinary. So yes, first -- Q1, we'll see exactly where we land, but we have -- the dynamic is great. We are accruing patients at a rhythm, which is 6x the others. And those patients will be first-line patients over time. And that will drive the growth, and that's exactly where we go.

Are you ...

And gross to net, I'm sorry, I didn't answer your part about gross to net. So yes, there is always a little bit of gross to net variability. You have some reset of co-pays, et cetera. This is our first year of launch. So it's hard for us to see exactly where it's going to be. We have had so far extraordinary access. We had very limited free drug programs and everything. So we are confident it should not impact us too much, but it's hard to say before we get the deals to some extent because we've never seen that.

And last year, you said I'm sorry, was low 20s, 25% last year.

We said last quarter in Q4, we were at 25%, a little bit beyond 25%, and we still expect it to grow a little bit further. Net sales to decline, you prefer the growth to go away.

Yes. Is it really driven by 340B? Is that what it is?

340B, some Medicaid, obviously, in terms of share of Medicare, more limited because, again, 50 years old, never smoker, so less Medicare and some contracting as well. It's very important in a space like that when you have kind of limited number of patients to make sure that at least there is not too much -- so access is critical. So we are doing what we need to do to make sure that access is there. It's still a relatively expensive drug, and we are doing great, and we're doing good.

Yes. So ROZLYTREK sales have been going down. I mean, there were $17 million in Q1 '25, and they've been down $2 million in the quarter. Is that sort of what you're seeing? I mean, frankly, BMS reported AUGTYRO and then they stopped reporting AUGTYRO altogether. So it's de minimis, it sounds like. But are you taking over ROZLYTREK? And then any signs yet what's going on with crizotinib?

Again, so we have -- again, we see what we see through our limited portal window. But what we have seen there is that we believe that we are already the standard of care among existing ROS1 TKI. So if you look at ROZLYTREK's progression-free survival of 16 months in the first-line setting, it's just really, really hard to justify use of that when you have drugs again, that have 4-year plus DOR. So I think that's just going to be increasingly hard to justify.

We don't know what repotrectinib sales are, but we do know that, again, the discontinuation rate of that drug for CNS side effects is significant. And as you look at our adverse events in our 6 most common adverse events, out of 337 patients, there was one discontinuation for any of those 6 events. So we just think that, that it's going to be difficult to compete with our efficacy profile, especially response rate, like Philippe said, 90% plus of durability of 4 years plus in the first-line setting.

It's also going to be hard to compete with our tolerability. I mean 1 out of 37 patient discontinuation. That's a 0.3% discontinuation rate for the top 6 adverse events. So we do think that over time, we will be the preferred agent, and we're already starting to see glimpse of that. But I want to just go back to the first one because I was so shocked to hear this morning the misunderstanding. 75% discontinuation -- of the discontinuations we have, 75% were in the third-line setting. We do not have a 75% discontinuation.

To the contrary, it is a -- that's a very, very low number, very similar to our clinical trial results. But of the ones that we do have, it was 75% in the third-line setting or later.

And they were not for any emerging adverse events or just for progression, which is a sad reality of very late-line patients in oncology. We would love to get great response in late line like everybody else, but this is not the case anywhere, honestly. And we had a couple of miracle stories of very late-line patients that responded super well.

One of them went back skiing and went back to work. I mean this is -- why we are in this business. As you know, this is the kind of miracle story you want to hear. But the sad reality of oncology is that when you're very, very late-line patients, in most cases, you just want response -- respond, sorry.

The -- do you have a sense -- it sounds like the academic community was the initial bigger one to adopt and looks the community is picking up. Any sense on trends and what you can do because a lot of all the first liners are probably sitting there?

Yes. So I think that if you look at where the patients are, we believe that about 70% of the patients are going to be in the community versus about 30% in the academic centers. If you look at the beginning of our launch, 70% of our scripts came from the academics and 30% from the community. So it was actually backwards because academic centers tend to be the early adopters, and they are the ones who tend to know the literature better and they are more familiar with the cutting-edge drugs.

But we are already seeing a shift in that. We're already seeing now an increase in community. And as a result, the academic percentage will come down, the community will go up. The challenge that we'll face is that testing in academic centers is near 100%. In community centers, it isn't there. But that is a rising tide because of the treatability of lung cancer in particular. If you look at now all the mutations in lung cancer, EGFR, ALK, RET, ROS1, lung cancer has suddenly become one of the most treatable cancers on the planet.

And in fact, what's very interesting, there is now a nationwide shift in approach to genetic testing. Louisiana became the first state in the union to now mandate NGS for lung cancer, and that's starting -- we're starting to see that in other states. So this is a tide that is rising, and we think that it will certainly help to increase testing rates in the community.

But right now, we still have a lot more to go in the community because we start off mainly academic centers. That's already shifting. And ultimately, we think that scripts will follow the distribution of patients between academic and community settings.

Maybe just to present in a different angle, Yaron, as well. And we spend a lot of time talking to doctors in KOL, of course. And for those that are very much plugged in the science and aware of the data, there's just no doubt that IBTROZI is the best thing out there. So what we need and what we're working on very hard is to make sure that everybody is getting tested. More and more patients can benefit from a TKI because once their doctors know that's what they need, they will put them on IBTROZI.

Yes. You announced a deal with Eisai in January. I think Eisai is going to file in Europe in the first half of the year. In parallel, in China, you're doing a head-to-head study against or Innovent is doing a head-to-head against crizotinib. But you don't think you need that for Europe?

No, we're going to get a full approval in Europe. That head-to-head study is really not for Europe, but we do need it for the Chinese authorities. So we're doing that study. It's also, in some sense, is defensive because BMS is doing a similar study with AUGTYRO. And it's always good, especially if you look at NCCN guidelines right now, all the ROS1 agents are considered recommended therapies for ROS1, but to show that you actually are better than one of the earlier first-generation agents is probably somewhat helpful. So I think we know our plans are to continue that study, but we do not need it for European approval.

Okay. Any questions from the audience? If anybody has a question by all means, just let us know at any point. Okay. So in Europe, and in terms of pricing, the current data can be sufficient for pricing?

Yes. Yes. I mean we have lots of discussions with our partner, Eisai there. They are very well used to those discussions. And of course, we know the pricing in Europe will probably be lower than in the U.S. That's to be expected, just like it was a bit lower in Japan and China. But this is also a slightly larger population, and it's a good opportunity. And I think in terms of time line, getting there in Q2 for an approval early next year is really positive and I think better than their expectations. So that's great.

Can you just remind us the financial terms to you? And did you ever disclose what the milestone would be on approval?

So yes, we did disclose -- we got EUR 50 million already. We will get EUR 25 million more on approval, so early next year. That has further reinforced our balance sheet, which is always useful, especially in times of movements like these days in the market. And we have great ways to use it to drive our portfolio of product forward. IBTROZI and safusidenib, we can talk about in development. And then we have high double-digit milestone getting to the high double-digit royalties, I mean...

Yes. Okay. So let's move to safu, which is an area that's getting a lot more attention just given the progress for IDH1 mutant glioma, it's about 2,400 patients per year. Survival for low grade is 12 to 20 years plus. And then for high grade, that's grade 3 or 4, it's about 12 to 24 years. Population is split half and half between low and high risk. diagnosis usually late 30s, sort of mid-40s.

So you recently announced the SIGMA Phase III. That's going to enroll 300 patients 1:1, 250 mg BID safu against placebo. And this is where it's fairly innovative. You're doing grade 2, 3 astrocytoma with high risk. sort of a little bit lower with high-risk features and then the grade 4 astrocytoma, obviously, higher risk. These are experienced patients post surgery, radiation and chemo. Primary endpoint is PFS. How fast do you think you can enroll this?

So first of all, if you look at the glioma pie, we've always said it's about 50-50 low grade versus high grade. But within low grade and high grade, they can be further subdivided into low risk and high risk. So vorasidenib, the only glioma drug approved today is approved in low risk, low grade. So there's 3 other parts of that pie where they're not approved. The SIGMA study goes after 3 of the 4 pieces of that pie, just to be clear about that. Because there's nothing approved in those areas and remember that in the half of the pie that's high-grade disease, vorasidenib's response rate was 0.

So we believe that study can enroll pretty quickly because there are -- there's nothing else for those patients. That said, it's still a PFS study. So the length of that readout to 2029 is not because of necessarily enrollment. It's because it has -- patients have to be followed for a certain amount of time to allow for a PFS readout. But we are well aware though that it would be nice to have data sooner and to have ways of entering the market sooner.

So we started a second study called the -- it's a -- it's a Grade 3 oligodendroglioma study. The difference between this population of patients and the others is that these patients have measurable disease. So they would be considered the low-risk, high-grade patients. Now there's a lot of overlap between low-risk, high grade and high-risk, low grade. okay? So -- but neither are approved for -- vorasidenib is approved. So in this subset of patients with Grade 3 oligodendroglioma, because they have measurable disease, we can look at response rate.

So that study has started, and we're going to enroll at least 40 patients and a readout will be sometime next year. But we will start to see glimpses of our own data sometime hopefully later in the year. And we start to see responses that we consider interesting. We will consider the possible of increasing size of that trial because just as a reminder, Day One's glioma drug OJEMDA was approved based on response rate in 77 patients.

So there is nothing approved in Grade 3 oligodendroglioma. In fact, there's nothing approved in anything of the 3 of the 4 pieces of that pie I was talking about. So we're going to have some data on response rate in a population where these patients can live 12 to 14-plus years. So really long survival, significant revenue stacking opportunity, huge unmet clinical need, just nothing is approved. These patients can't take radiation and chemo for 15 years.

So we think that's going to be a very interesting study. So we will have a readout -- a full readout on that study from the 40 patients in '27. But if we start to see glimpses of any activity, we're going to probably increase that, go to FDA and have a discussion about what they would want to see to convert that to a registration study.

Would that -- the registration would be based on ORR or PFS?

So OJEMDA was approved based on ORR.

And that was for pediatric.

Pediatric glioma and the only difference between that population and ours is their age. It's still the glioma, high unmet need, invariably fatal disease. So we think that is just as important.

And it's still a disease of relatively young patients, right?

And these patients are actually -- they're not pediatric, but many of them are in their 20s and 30s.

And how many patients are in that -- in the low-risk, high-grade oligos?

There's probably about 400 patients a year in the United States alone. But then given the fact that they live for 12 to 14-plus years, you're talking about, again, a really significant commercial opportunity. And because they live that long, that 400 patients I mentioned is an incidence number. If you multiply that times just 15, now you're talking about thousands of patients out there in the prevalence pool.

Yes. The SIGMA, just to go back to the previous study, the -- is that -- do they have measurable disease at baseline as well?

No, they've been resected and have had chemo and radiation. And so that's why -- PFS is the endpoint in the SIGMA study. But in the Grade 3 oligos, they all have measurable disease, and they just cannot take radiation for 15 years. So their brains won't do well. So they need an alternative therapy that can be given for 15 years.

If they don't have measurable disease, what the risk is it's not measurable now, but it's an aggressive tumor. So it comes...

The Sigma patients?

The Sigma.

Yes. So they will relapse at some point. But once they relapse, they're not going to do well.

Super tough disorder. So Voranigo is approved, as you mentioned, 11% response rate. This is the low-grade population. They were approved for low grade, low grade.

Low risk, low grade.

Low risk.

Yes. So there -- so in the same population, low risk, low grade, our response rate was 44% and with all the caveats of cross-trial comparisons, of course. But still, we think that, that's still noticeably different. If you look at the vorasidenib progression rate at 2 years, it was 41% in our study, again, with the same caveats of cross-trial comparisons, it was 12% progression at 2 years.

We just think that's -- no matter how you look at it, even without comparison, 12% progression at 2 years in any glioma study would be considered remarkable. If you just were to extrapolate that out, you're talking about 10-year plus survival for patients, and that's going to be something that I think every patient and physician will find attractive.

Yes. The -- when we look at Voranigo, Royalty Pharma disclosed $118 million in royalty and they get 15% up to the first $1 billion, so you can actually back into it to $788 million, right, in sales of the first.

So in the last quarter, if you back out the sales from Servier's -- from the royalty based on Servier sales, vorasidenib generated $258 million in the fourth quarter. So they're already at a $1 billion run rate in their fourth full quarter of launch, which I think is remarkable.

Yes. It's already the biggest product, and it shows the level of unmet need. It's incredible. And then safu, do you think you'll commercialize it yourself globally? Or is that something you'll partner eventually?

No, I think that we'll probably reach that position when we get further along. But certainly, in the United States, we think that we have a great commercial team, and we would love to do that. In Europe and Asia, it's just harder, and we'll have to see what the math works out to be.

Maybe final question. I know I think we're just a little over now. Any more room to do BD?

Sure. I mean, as Philippe said, after we get our next milestone payment from Eisai, we'll have about $620 million in the bank. That's far more than we need to get to profitability. So we'll certainly look at BD, but again, it has to be really a good deal for us.

Yes. Well, terrific, David and Philippe. Thank you.

Thank you.

Appreciate it.

Thank you. Thank you.

Hello, and welcome to Nuvation Bio's Fourth Quarter and Full Year 2020 Financial Results and Corporate Update Call. Today's call is being recorded, and a replay will be available. [Operator Instructions]

Now I'd like to turn the call over to JR DeVita, Executive Director of Corporate Development and Investor Relations at Nuvation Bio. Please go ahead.

Thank you, and good afternoon, everyone. Welcome to the Nuvation Bio Fourth Quarter and Full Year 2025 Earnings Conference Call. Earlier today, we released financial results for the quarter and year ending December 31, 2025, and provided a business update. The press release is available on the Investors section of our website, nuvationbio.com and a recording of this conference call will also be available on our website following its completion.

I'd like to remind you that today's call includes forward-looking statements, including statements about the therapeutic and commercial potential of IBTROZI and safusidenib, the components of our anticipated product revenue expected milestone payments and our cash runway. Because such statements deal with future events and are subject to many risks and uncertainties, actual results may differ materially from those in the forward-looking statements. For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K, which we filed with the U.S. Securities and Exchange Commission today.

Joining me on today's call are our Founder, President and Chief Executive Officer; Dr. David Hung; our Chief Commercial Officer, Colleen Sjogren, and our Chief Financial Officer, Philippe Sauvage. David will provide an overview of our key achievements in 2025 and other business updates, Colleen will provide details on the commercial launch of IBTROZI and Philippe will discuss our financial, partnering and operating updates. David will then conclude with closing remarks.

Now I'll turn the call over to Dr. David Hung. David?

Thanks, JR. Good afternoon, everyone. Thank you for joining us. 2025 was a pivotal year for Nuvation Bio, and I'm pleased to discuss our full year and fourth quarter results with you today. Our most significant achievement occurred on June 11 with the full U.S. FDA approval of our first therapy IBTROZI indicated to treat people living with advanced ROS1-positive non-small cell lung cancer, or NSCLC.

Since then, we've been working tirelessly to bring IBTROZI to patients with this aggressive disease. And based on the number of patients who have started our therapy, and the confidence we have in this differentiated profile, we believe that IBTROZI is becoming the new standard of care for ROS1-positive NSCLC.

By the end of 2025, new patients started on Nesincluding 216 in the fourth quarter. For IQVIA data, patients are being prescribed intros at a rate that is approximately 6x faster than the 2 prior ROS1 TKI [indiscernible] launches over their first 2 full quarters following approval. Our fourth quarter patient starts also reflect an increase the 204 new patient starts in the third quarter during the time of year that may be impacted by seasonal factors. We continue to see a steady cadence of new patient starts in the first 2 months of 2026 from those who have filled a TKI, those currently on a TKI, who have switched to Emtrol and those naive to therapy. This broad patient mix further highlights the strength of our launch and collective belief in our medicine. Feedback from key opinion leaders, daily interactions with health care providers and results from our market research have consistently been overwhelmingly positive.

Since launch, we've learned that Atos's efficacy profile resonates strongly with physicians and equally important, its safety profile, especially limited CNS toxicity may allow earlier line patients to remain on therapy for years. the special factor in a space for a long-term duration of therapies, paramount. As I mentioned, -- and consistent with this, we continue to see switches to EMTs from all 3 of the other therapies approved for Robin positive lung cancer.

The reasons for these switches include disease progression tolerability challenges, brain penetrants and physician confidence in the strength of IBTROZI's clinical data, particularly in the durability of response. I'm thrilled with how our team has executed despite the fact that rare disease launches always provide a variety of challenges. Their efforts have resulted in significant impact and most importantly, patients but also on how providers choose to treat this disease. Colleen and Philippe will provide more detail on launch dynamics and net product revenue later in the call.

Looking ahead, we are focusing on increasing our prescriber base and identifying more newly diagnosed first-line patients to be treated with intros. We believe that treating these patients will significantly increase the collective time our active patient population stays on therapy while we continue to simultaneously treat patients in the later line setting who are in urgent need of our medicines.

We also plan to present additional long-term intros data at multiple medical conferences in 2026. As a reminder, on our prior earnings call, we reported that as of August 2025, it chose this median duration of response has now reached 5 months in a pooled analysis of TTI naive patients in the TRUST-I and TRUST-II pivotal studies. -- population of which Troy has previously shown an 89% confirmed overall response rate or ORR. We believe these long-term intros data represent the greatest patient benefit seen to date in ROS positive NSCLC.

And unlike ongoing studies of other ROS1 TKIs, our pivotal study did not exclude patients with other concomitant epigenic mutations making the results with ITRs, we believe, representative and applicable to real-world patients. We look forward to providing more clinical analysis from the August 2025 data cutoff in the first half of this year.

Our scientific updates in 2026 may also further characterize IBTROZI's unique balance of activity against 2 important targets: ROS1 and TrkB. IBTROZI TRUST-1 to 20 fold more selective for ROS and over TrkB and remains strikingly potent against ROS1 with picomolar level inhibitory activity.

But importantly, IBTROZI also has measured inhibitory activity against TrkB. While just starting to emerge with improved scientific understanding is that the degree to which a lung cancer therapy inhibits TrkB -- in addition to its primary optogetic driver, may play a significant role in not only controlling the growth of the primary tumor, but may also inhibit the ability of that primary tumor to metastasize and grow in distant sites, particularly in the brain. Remember that ROS1-positive lung cancer has a particularly high propensity to spread the brain. -- as 36% of newly diagnosed patients present with brain metastases.

And in an additional 50% of cases, the first site of disease progression will be in the brain. We believe the ability to control and even prevent brain metastases in Roman positive lung cancer may be 1 of the most important determinants of long-term survival and will be reflected in a therapy's durability of benefit. TrkB is an oncogene, meaning that it drives cancer growth and metastasis and the natural ligand for the TrkB receptor is BDNF or brain-derived neurotrophic factor, -- as the name implies, this factor is expressed at high levels in the brain and can fuel the growth of cancer cells via the TRB pathway if that pathway is not inhibited sufficiently.

However, too much inhibition has been shown to lead to neurological side effects. If Truvis far more potent against ROS1 and TrkB, about 20 gold which may explain why it has such a high response rate and durability in ROS-driven lung cancer. And yet, while Aptos does have adequate activity against Treat B, -- this inhibition is measured enough that its business rate is similar to that of crizotinib, a drug that doesn't cross the blood-brain barrier. In a recent commentary in publishing the Journal of Soriastic Oncology, renowned thoracic oncologists, Dr. Ross Camidge, Dr. William Phillips, Dr. Rafael Navina and Dr. Diana Satelli, hypothesize that this selectivity could make IBTROZI the best tolerated next-generation ROS1 inhibitor. And we believe IBTROZI's intentional, but well-tolerated TrkB inhibition may contribute meaningfully to intracranial disease control and ultimately survival without introducing the significant CNS toxicity that has limited other agents, a point Dr. Kamageen team emphasized in their analysis.

Separately, published data have linked uninhibited TrkB signaling to larger tumor burden, higher stage disease, increased risk of CNS metastases and poor outcomes across multiple solid tumors, including lung cancer. In our view, IBTROZI strikes a particularly effective balance, deep durable inhibition of ROS1, paired with measured TrkB activity that potentially supports CNS disease control while preserving tolerability.

Interestingly, the only other approved TKI to demonstrate longer durability in TKI-naive patients than IBTROZI is lorlatinib in ALK-positive NSCLC which showed a median progression-free survival, or PFS, of over 5 years in the CROWN study. Lorlatinib has even greater TRK inhibition than IBROZI which we believe is likely related to lalatinib's high rate of sales events like mood disorders.

However, given the high propensity for CNS involvement in ALK-positive disease, Dr. Kamal speculates that it is lorlatinib significant TRP inhibition that may account for its high intracranial response rate in 5-year duration of response. We do not view the shared prolonged durability of lorlatinib and IBTROZI as points of demo.

Taken together, we believe that IBROZI's ability to strongly suppress ROS1 while moduling TrkB in a tolerable way could help explain durability into crane activity and safety profile we continue to observe as real-world use increases.

We also continue to envision and develop IBTROZI for a broader ROS1 positive lung cancer population. Based on our label, IBTROZI has been prescribed to a significant number of patients in the advanced setting across lines of therapy. And the next step for us is to move to earlier stage of lung cancer.

As previously shared, we have dosed the first patient in Trust 4, a randomized, placebo-controlled Phase III study evaluating taletrectab as an adjuvant therapy for patients with respected ROS1-positive early-stage non-small cell lung cancer.

Adjuvant therapy is fundamentally different from treatment in advanced disease and is an area we targeted for study only after garnering support for multiple lung cancer CLL. These patients have undergone surgery, official healthy and are understandably unwilling to remain on our therapy is difficult to tolerate [indiscernible] daily life.

As a result, only a drug with a manageable and highly tolerable safety profile can realistically be developed in this study. We believe it is particularly meaningful that IBTROZI is the only ROS1 inhibitor currently being studied in the adjuvant setting, and we view this as a further testament to its safety and tolerability profile.

Across our clinical database of 337 patients with advanced ROS1-positive non-small cell lung cancer, only 1 patient discontinued treatment due to any of the 6 most common adverse events, including diarrhea, nausea, vomiting, business or liver enzyme elevations.

While this does not summarize all adverse events detailed in our prescribing information, this level of tolerability for our most prevalent adverse events is critical when considering use immediately following surgery and while we believe IBTROZI may provide benefit in the adjuvant setting.

Lastly, we not only aim to bring in IBTROZI to patients across the ROS1 positive disease spectrum, but also the patients and providers around the world. Last year, we received approval for IBTROZI in China and our partners at Innovent Biologics and in Japan with our partners at Nippon Kayaku.

In January, we were thrilled to announce a strategic partnership with Esai to develop IBTROZI in Europe and other ex U.S. territories outside China and Japan. We are working diligently with Eisai to submit ICOS for approval in Europe in the first half of this year. In short, we believe our continued launch performance, the latest updates reconfirming IBTROZI efficacy and tolerability profile and additional development, regulatory and commercial achievements all show why we believe it chose us to becoming the standard of care for a positive lung cancer.

We also made exciting progress developing our second program, safusidenib is an inhibitor of IDH1 being developed for IDH1 mutant glioma, a devasiting type of brain cancer. Importantly, not only are there very few treatment options available for this disease, but these younger patients are typically diagnosed between the ages of 38 to 45. Clearly, there is an opportunity to make an impact for these patients family.

IDH1 glioma described using 2 types of terminology, grade and tumor classification. A grade of a glioma indicates the level of risk while the classification describes certain biological features of the tumor. Malignant IDH1 mutant tumors can be defined using range 2, 3 and 4, and these tumors can be classified as an oligodendrogliomaor an astrocytoma. Both the script our together indicate the level of risk, aggressiveness of disease and estimated time pages may live with their disease.

To simplify this, we describe both grade 2 oligodendroglioma and astrocytoma as low-grade IDH1 mutant glioma, while high-grade IDH1 mutant gliomas consists of grade 3 oligodendrolioma, grade 3 astrocytoma and grade IV atrocytoma. Each year, there are approximately 2,400 new cases of IDH1 glioma in the U.S. split almost evenly between the low-grade and high-grade population.

The key difference is that based on published median overall survival data, patients with low-grade IDH1-mutant glioma live approximately 12 to 20 years, while high-grade patients live on average approximately 2 to 12 years. The only targeted treatment option available for patients with IDH mutant glioma is vorasitinib, which was approved by the U.S. FDA in August 2024 were only patients with grade 2 oligodendrogliomas and grade 2 astrocytoma or the low-grade population.

In this pivotal INDIGO study, which included 168 Grade 2 patients with non-enhancing or low-risk disease in the active study arm, vorucitinib demonstrated a median PFS of 27.7 months a 41% progression rate at 24 months and an ORR of 11%. In a separate Phase I study of 30 patients or acitinib showed a confirmed ORR of 0% and in a high-grade enhancing population, which is not included in its approved label.

In November, results from our Phase II study of safusidenib for low-grade IDH1 mutant glioma were published in neuro-oncology. This patient population was treated with safusidenib following surgery and prior to radiation or chemotherapy. The same types of prior treatment patients received in the INDIGO study.

In this study of 27 patients, safusidenib demonstrated a median PFS have not reached a 12% progression rate at 24 months and a confirmed ORR of 44%. As a reminder, in a Phase I study of 35 patients, safusidenib also showed a 17% confirmed ORR including 2 complete responses that lasted multiple years in a high-grade enhancing population. As we've discussed previously, larotrectinib is already approaching a $1 billion U.S. net revenue run rate, less than 2 years after its approval. This rapid commercial uptake underscores both the unmet need and the willingness of physicians to adopt targeted therapies in this setting.

While we acknowledge the inherent complexity and limitations of cross-trial comparisons due to differences in study design, patient populations, endpoints and sample size, recently published data in neuro-oncology and data from our Phase I study highlights the encouraging clinical profile of safusidenib and its potential to address significant unmet need in this patient population.

In parallel, we continue to learn more about safusidenib's safety profile. While the drug is generally well tolerated, we observed a distinct set of dermatological related adverse events, including alopecia arthralgia and skin hydro pigmentation. We believe the presence of these events may be due to a different pharmacological profile of saplusitinib, and we continue to investigate if saposetinib may inhibit targets other than IDH1.

Importantly, the drug-related discontinuation rate in the Phase II study, which was conducted at the pivotal 250-milligram twice-a-day dose remains low at approximately 8%. The patients who discontinued therapy were able to recover with interruption and appropriate management. Based on data generated to date, we announced in February that we started enrolling our pivotal Phase III study called SYGMA. This global randomized study is evaluating the efficacy and safety of safusidenib versus placebo for the maintenance treatment of high-risk and high-grade IDH1 mutant glioma following standard of care.

Specifically, the study population includes 300 patients with grade 2 or grade 3 astrocytoma who show certain high-risk features in all patients with grade for astrocytoma. As an important reminder, these patients have no FDA-approved targeted therapy options.

Considering the high unmet need and the exciting profile of safusidenib, we are optimistic about the speed of recruitment in this trial. Due to the sizable population being enrolled to support approval, and the use of PFS as the primary endpoint. We expect this study will read out in 2029. Importantly, we recently announced the initiation of a second nonpivotal cohort evaluating southside in patients with grade 3 oligodendroglioma, a patient population that is considered to be within the lower risk end of the high-grade glioma spectrum.

This grade oligodendroglioma study will enroll approximately 40 patients with measurable disease, including patients with residual disease following surgery for those with recurrent disease and will evaluate ORR as the primary end point. Given that we have 31 sites activated in the U.S. already, we estimate that we will be able to provide a full study readout in 2027.

Importantly, if we see significant objective response in this study, -- we will meet with the FDA to discuss the results and potential options for further development, aiming towards an accelerated approval pathway. Patients with grade 3 oligodendroglioma frequently seek alternatives through the cumulative toxicities associated with prolonged radiation and chemotherapy given the relatively young agent diagnosis and median life expectancy of 12 to 14 years.

Yet, there are currently no approved targeted therapies for this group either. While there are approximately 400 new grade 3 oligodendroglioma cases diagnosed annually in the U.S., we believe this represents a much larger prevalent population of several thousand patients who are underserved today and could meaningfully benefit from an effective, well-tolerated targeted therapy.

We view safusidenib as an ideal complement to IBTROZI as we now have an approved therapy and a late-stage program that both address unmet need for patients. We look forward to generating updates from our evaluation of saacipinib as quickly as possible.

Lastly, our drug conjugate, or DBC platform represents a novel modality in targeted cancer therapy designed to conduct 2 small molecules, a targeting agent and a warhead. While we discontinued development of our first DDC NUV-1511 in the fourth quarter, we were able to gather valuable insights into needing development and are already applying these learnings to move preclinical candidates in our pipeline. We hope to have updates on the next phase of our DDC program by year-end. We remain confident in our capabilities to successfully execute our program goals, build last and value and most importantly, serve patients.

With that, I'll turn it over to Colleen to provide more color on the launch of IBTROZI.

Thank you, David, and good afternoon, everyone. I'm excited to report that the launches of IBTROZI continues to build what we believe is market defining momentum in a rare disease indication.

From our approval in June through the end of 2025, we treated 432 new patients with IBTROZI, which represents a rate that is 6x faster than the 2 most recent TKI launches in ROS1-positive lung cancer.

As David mentioned, we continue to see patient starts from 3 distinct populations. Patients who have failed prior ROS1 TKI such as from patients currently treated with ROS1 TKI and newly diagnosed patients who are TKI naive. This momentum underscores that a significant medical need in ROS1-positive non-small cell lung cancer still exists. And it is clear to us that the efforts of our incredible team our tailored strategy and improve compelling efficacy and safety profile are well positioned to address this need.

By the end of the year, we had engaged all top-tier target accounts and our field-facing interactions reinforce that physicians are quickly gaining comfort prescribing IBTROZI for their patients. prescriptions have been written in 100% of our 47 sales territories by multiple repeat prescribers and per IQVIA data we are showing significant growth in market share of new patients treated with a ROS1 TKI.

On the market access front, payer engagement continues to be constructive and effective -- at this point in our launch, we have achieved broad coverage to label for patients across the country. Finally, our patient support program, Innovation Connect continues to help eligible patients receive support and access to IBTROZI, while reimbursement is secured.

Now I'd like to walk you through some of the key dynamics of our launch to further characterize where we are today and what lies ahead. As we've noted, acuity is being prescribed across both TKI-naive and TKI-pretreated patient populations. With our extremely high response rate in TKI-naive patients, we do expect an overwhelming majority of this population to be treated with IBTROZI for an extended period, which we are now starting to see.

Still, it is typical at the beginning of any oncology launch that the majority of patients who start therapy are in need of a third or even fourth medicine and the response and duration of treatment will unfortunately be lower.

While we expect IBTROZI to benefit these patients for a relatively shorter duration, meaning most will not remain on therapy for multiple quarters, we view this as an encouraging signal that providers are motivated to offer their patients a differentiated therapeutic option. While we have limited visibility into the characteristics of all IBTROZI patients, we do have some insight into the segment of patients that come through our Innovation Connect support program and specialty pharmacies.

Within this group in 2025, we know that about 75% of discontinuations came from later-line populations. We're encouraged that ITOs is providing another meaningful option for patients across lines of therapy and the patterns we've observed through this experience have given us 3 important insights.

First, discontinuation is strongly correlated with the line of therapy. If TRUs has been well tolerated by first-line or TKI-naive patients who have shown extremely high response rates in clinical trials. We also know that median DOR and PFS are much longer in this population than in the TKI pretreated population. Therefore, we expect to see far lower discontinuations as we move Etos upstream in the treatment paradigm.

Second, the fact that a significant share of our new patient starts at the beginning of launch were in the third-line plus setting helps explain the gap between an unprecedented number of patients starting IBTROZI and our net product revenue growth from the third to fourth quarter. As I mentioned, this late-line population unfortunately tends to discontinue therapy relatively quickly. And as a result, the majority of these patients are not treated for multiple quarters. which directly impacts near-term revenue trends.

By the end of 2026, we expect to see a more direct correlation between growth in new patient starts and growth in our revenue. As a larger portion of active patients treated with IBTROZI shipped to those who are newly diagnosed.

Lastly, first-line IBTROZI patients are the main driver to our long-term growth. And the reason we are so optimistic about our launch is because we continue to see a meaningful steady increase in first-line patients starting on IBTROZI on recent months. Our data, including the number of previously treated patients in the market suggest that we are expanding the ROS1 TKI landscape rather than simply competing for a fixed pool of patients.

We anticipate this will directly impact the number of active patients on IBTROZI over multiple quarters going forward. And we plan to elaborate further on this trend as we collect more data in 2026.

Switching to another key area of our launch dynamics. We continue to see use from providers in both academic and community settings nationwide. As of the end of 2025, approximately 70% of our new patient starts had come from the academic centers or IDNs and 30% from community centers compared to a 75%, 25% split at the end of the third quarter. It is typical in a rare oncology launch that immediate uptake occurs in the academic setting.

That said, this gradual shift towards the community is expected to increase over time, and in turn, will support prescription growth and momentum. This is important because the majority of ROS1 patients will be found and treated in community centers. Looking ahead, we are focused on deepening adoption and continuing to raise awareness of the importance of patient identification.

Today, DNA-based testing should identify roughly 3,000 advanced ROS1-positive non-small cell lung cancer patients annually in the U.S. And as the field shifts towards also utilizing RNA-based testing, which publication suggests may help to detect approximately 30% more ROS1 fusions, the annual addressable population could potentially expand to roughly 4,000 advanced patients in the U.S. alone. Because of IBTROZI's unprecedented durability, especially in the TKI-naive setting, this small incidence population turns into a substantial prevalence population, generating an opportunity to treat a meaningful number of patients over a period of several years.

Finally, I want to commend the efforts of our commercial team. We believe their hard work has positioned IBTROZI as the emerging market leader in this disease. There is still educational work that needs to be done, but I am beyond thrilled we have been able to deliver this therapy to so many patients in need.

With that, I will now turn it over to Philippe.

Thanks, Colleen, and good afternoon, everyone. For detail on fourth quarter 2025 financials, please refer to our earnings press release, which is available on our website. Now let's go over some important highlights of the quarter.

I'm pleased to inform you that in the fourth quarter, we generated $41.9 million in total revenue, including receipt of the milestone payments which bring our total revenue for 2025 to $62.9 million. These figures include $15.7 million and $24.7 million in IBTROZI U.S. product revenue in the fourth quarter and full year 2025, respectively.

As Colleen mentioned, we know a significant share of our product revenue was driven by patients treated with IBTROZI as a third line plus option. And unfortunately, these patients do not remain on therapy for very long. We do expect that over time, the bulk of our sales will be from first-line patients staying on drug for many years. This trend of more TKI patients benefiting from IBTROZI is what makes us extremely optimistic about our long-term growth.

As this occurs, we'll be able to see the true impact of our 15-month median DOR on revenue growth. Still, this dynamic will play out gradually over time, and we will continue to update you on emerging trends.

Our channel movements are stabilizing as we expected we would. And today, we believe our specialty pharmacy and distribution partners hold approximately 2 to 4 weeks of inventory on hand. This is standard and shows that our product revenue has been driven by true patient demand for pros. In addition, our free trial program continues to provide patients with IBTROZI before they are fully reimbursed -- and this prescription generate full commercial revenue in the patient's second month on therapy at the latest.

Our approach to access has been extremely successful and has resulted in broad coverage for patients across the country. As I mentioned on our last call, our level of growth [indiscernible] will naturally increase as we enter more contracts that allow us to cover more lives. As a result, our growth [indiscernible] now sits around 25%, and we would expect this to slightly increase before stabilizing long term. This is based on our balance of business with commercial, Medicare, Medicaid and 340B plans and the limited amount of free medicine provided to date.

The remaining revenue for 2025 came from our collaboration and license agreements, including milestone payments royalties, product supply and research and development services. In addition to ongoing royalty revenue from our partner in China, Innovent Biologics, with again receiving royalty revenue from our partner in Japan, Nippon Kayaku following regulatory approval and reimbursement in November, an event for which we received a milestone payment of $25 million.

We also continued our mission to bring IBTROZI to as many patients as possible outside of the United States. In January, we announced our strategic partnership with Eisai, covering Europe and select territories outside of China and Japan. As a reminder, commercial rights in China and Japan were previously out-licensed and when those deal values are combined with the Esai deal, this represents a total deal value of nearly $520 million for most territories outside of the U.S., but still excluding Latin America.

Under our agreement with Esai, we received an upfront payment of approximately $60 million and are eligible for a payment of about $30 million upon European approval. We will also earn at $140 million in milestone payments upon the achievement of certain sales level, in addition to double-digit sales royalties up to the high teens on net sales in [indiscernible] territories.

This partnership meaningfully strengthens our cash position allows us to reinvest in our own programs and allows us to precisely focus on our commercialization efforts in the United States.

Looking ahead, we expect to file IBTROZI for approval in Europe with Esai in the first half of this year. On the expense side, R&D expenses were $34.3 million for the quarter and $115.1 million or. We continue to invest in Itarsi and importantly, are focused on bringing safusidenib to patients as quickly as possible.

SG&A expenses were $40.3 million for the quarter and $151.6 million for 2025, primarily driven by support for commercialization. As discussed in prior quarters, we do not expect material increases in commercial head count going forward.

Turning to the balance sheet. We ended at 2025 with $529.2 million in cash, cash equivalents and marketable securities. This cash position has increased by approximately $60 million following the upfront payment we received from Esai.

As a reminder, an additional $50 million remain available to us under our term loan agreement with Sagard Healthcare Partners until June 30, 2026. Our robust capital position gives us a flexibility to invest [indiscernible], while also enabling the evaluation of additional business development opportunities that can create shareholder value similar to our acquisition of not.

Based on our current operating plan, revenue trajectory and disciplined expense management, we do not anticipate the need for additional external financing to reach profitability. We remain a well-managed and agile organization that is positioned to execute our 2026 objectives.

I'll now hand it back to David.

Thanks, Philippe. We take a step back and reflect on our 2025 what gives me particular confidence is the foundation we've built for what comes next, an increasingly durable commercial franchise, a pipeline with meaningful long-term potential and a capital position that allows us to execute with discipline and flexibility.

I'm incredibly proud of the team and grateful for the support of our investigators, partners, shareholders and most importantly, patients. as we continue this journey into 2026.

With that, I'll ask the operator to open the line for questions.

[Operator Instructions] The first question comes from the line of Farzin Haque with Jefferies.

Congress on the progress. So you're not providing any revenue guidance yet for 2026. But what are you seeing in 1Q in terms of first line and second line plus mix that gives you confidence in meeting the consensus market of $150 million?

Farzin, this is David. So we're -- as we said, we feel that the patients are out there. We think that the robustness of the first 2 quarters shows that we are able to capture a lot of -- a significant number of these patients. Just if you look at the number of new patient starts, we think the trajectory has been pretty good. As we did say, the majority of our NPS, our new patient starts to date have been later lines, as you would expect. But we are seeing increases in first line news.

But we've also made the point previously that we don't have visibility into the majority of these patients. because unless they come to the innovation, connect portal, we don't actually necessarily know what we need to know about what line of therapy they are. But what we've seen we do see a majority of our use currently in later lines of therapy.

Clearly, those aren't the ultimate price. Those patients, especially in the third-line study, have relatively short durations of response. And so that would lead to a much higher discontinuation rate. In fact, the vast majority of the discontinuations that we have seen are due to these late-line patients. But we are confident that over time, we're going to see growth moving toward to the second line and then to the first-line setting.

And so we think that the patients are there and we think that ultimately we will start to see first-line use a much longer durability and then the revenue stack that we've previously talked about.

Perfect. And then for safusidenib, can you provide an update on the current enrollment trajectory for the Phase III? And do you anticipate any interim analysis before the projected 2029 completion?

We haven't commented on our enrollment. Those patients are definitely there. As you know, there's absolutely nothing for high-grade disease or systems approved only in a subset of low-grade disease. So we think that, that trial will enroll well. But it is a PFS study. So it's going to take a while to get the number as we need to see it to see the results. So that's why we've guided to a 2029 readout for that.

But I would say that the patients are there. We feel very confident in the capabilities of our clinical operations and clinical development team. So we think that trial will enroll on target, we will not be any later than 2029 in reading that result out.

And also -- sorry, we don't have any plans right now for interim analysis. So -- I forgot to mention that.

The next question comes from the line of Leonid Timashev with RBC.

I just want to ask a little bit more about the IBTROZI trajectory. I guess, in the fourth quarter, there was potentially some seasonality, maybe changes in diagnosis has also been a historically weaker quarter for some lung cancer drugs. I guess how should we think about the seasonal bounce back we should see in the first part of 2026. Is any of those maybe weather-related seasonality is going to pull through into the first quarter? And any kind of payer dynamics that we should be thinking about in the first quarter as well?

The data set that we discussed, the seasonality was still based on just ROS1 TKI use in the last 4 years. So while there was a somewhat lower use in the fourth quarter. I would say, it's hard to know if that would necessarily predict what's going to happen going forward. We feel confident the patients are there.

We know -- we know that from -- just from our interactions with all the centers that we're at, these patients are there. We think that with -- while there's always way to improve the amount of genetic and genetic testing, we think that new patient diagnosis will happen. We know there's a prevalence pool of over 1,000 patients who are TKI experience.

Clearly, those are the ones that are the -- going to be the easiest ones to identify because they've already been on our ROS1 agent. And clearly, we've already captured a significant number of those. But so I don't really know if the seasonality will necessarily result in a bounce back. It could, but I can't tell. And as you know, we just had a significant blizzard recently. So that was a pretty significant weather event, but again, know if that will change anything.

The next question comes from the line of Michael Yee with UBS.

This is Matt on for Mike. I wanted to ask on your expectations just kind of further trajectory cadence of patient uptake for the year, especially with maybe a competitor entering the market in the second-line setting, later in the year. How do you expect to see kind of the market shake out? I know you guys talked about Trek as an important factor for you guys? Just kind of speak to the longer-term competitive landscape here would be great.

Sure. Well, you've already seen from the first 2 quarters that we're over 200 new patient starts per quarter so far, and we think that's going to continue. And I've already said that the majority of those are related line therapy.

So if you talk about second or third line, we've already captured a significant amount of the about 1,000 TKI experienced patients that we believe are out there. So by the end of the year, we think that we will have probably captured a significant majority of all those patients. And as I said, what we're looking for is growth in the first-line setting. And given our 50-month duration of response, which is unmatched and our tolerability profile, we would expect to claim the majority of that. So that's what we're really looking for. We're not really looking any more at later-line use because that's -- we've been there and we've got to capture much of that. But we're looking towards the first-line growth, and that's what everyone should be focusing on.

I think the one of the most compelling features of our drug is its durability. As you know, patients and doctors decide on therapy based on efficacy and by far, the most important metric for efficacy is how long that drug will work. We think that truck is an important factor in durability. If you look at the lorlatinib data, there is no TKI with longer median PFS that lorlatinib in the crown study, which is over 5 years. And lorlatinib has significant direct activity. And if you look at CNS control rate, it's really high. And as you know, for a cancer like ROS1 lung cancer, which is so CNS tropic where it starts in the brain more than 1/3 of the time and goes to the brain another 50% of the time. It's really important to have as robust control of the CNS as you can.

And we think that track will play a significant role there. And as I've discussed previously, if you look at our integration response rate and our second line setting up 66%, that's not been matched. There's nothing close to that.

So -- we think that the profile of this drug is extremely compelling, tolerability, efficacy, we're looking to move the first line, and we think that's where the unmet need will persist after we've already taken care of the later lines of therapy, which we are capturing. So we feel bullish. We feel we're just where we need to be and things are heading in the right direction.

The next question comes from the line of Barry Coleman with Clear Street.

Congratulations on the progress. For taletrectinib or IBTROZI. Just in general, how much adoption of TKIs any in the first-line setting? Have you observed following the NCCN guideline changes, especially in the community setting or community prices? And what factors or initiatives could further drive first-line use of prose there? And I have a couple after that safusidenib.

Sure. So we did note that if you look at the other TKIs that before we were approved, we actually did see an increase in scripts in the other TKIs after the NCCN guidelines came out. So I think those guidelines were helpful, and they did increase TTI.

Now since the introduction of IBTROZI to the market after our approval, we've seen clear growth from the little looms that we see we have been seeing increasing first light use, but it's -- again, our glimpse to that window is so limited at this point. I don't -- I can't really speak in detail about it, we'll need to wait until we have maybe a quarter or 2 more under our belt. But we feel that things are going in the right direction.

We think the NCCN guidelines are going to be a real benefit. Just the amount of IO/chemo, used before those new guidelines was significant. And even after the guidelines, we still think that's a challenge. But I think that now that IO is actually contraindicated, I think that's only going to help drive the appropriate therapy. And as I've said earlier, there is no other therapy that can match our metrics at efficacy or even tolerability.

So I think that we are well positioned to capture this. And I think the NCCN guidance will be a significant tailwind. But I think the greatest in the tailwind we have is just the strength of our label.

All right. That's helpful. And for the Phase III astrocytoma trial, what efficacy outcomes would be considered both clinically meaningful and commercially attractive. And -- what is the kind of estimated market opportunity or value that it can provide? And for the other cohort, what was the rationale for adding the oligodendroglioma patients as a separate cohort? And how might this become a value-generating program?

Yes. That's a great question. So when I think about glioma, I divide it into a pie about 50-50 low grade on 1 side and about 50% high grade on the other side. But within those subsets, you can divide them again. So each side, both the lower and high grade have a low-risk and high-risk features.

Currently, vorasidenib is only approved in 1 of those pieces of that buy. It's only approved in low grade, low risk. That means what remains for an opportunity is high risk, low grade, low risk, high grade and high risk high grade. So the Phase III study that we're doing targets 3 of those bots -- the pieces of that pie. Instead of the vorasidenib 1 piece, our Phase III trial targets 3 of those pieces.

So we think that's a very significant unmet nature patients. It's clearly a much larger commercial opportunity. And so we -- to get that drug approved in those 3 pieces of that pie, we have to do an overall -- we have to do a progression-free survival study, which is why -- we just need to enroll a certain number of patients. We have to follow them for a certain amount of time, and that's why the readout is 2029.

Now that said, -- we also think that it's important for us to get this drug out to patients as quickly as possible. And there is yet another piece of that pie that isn't currently being adequately addressed, which is -- if you look at all grade 3 oligodendroglioma patients, these patients are a little bit different because unlike the Phase III study patients, which I talked about, those patients have completed surgery and radiotherapy and somewhere between 6 and 12 cycles of temozolomide. So as a result, they don't tend to have measurable disease. When you don't have measurable disease, you have to use PFS. You can't use response rate. We'll clearly respond at a much faster readout than PFS.

So the grade 3 oligodendroglioma study is important because those patients have measurable disease. These are patients who have not had a resection or not a recent one, have, in general, significant measurable disease, and they just can't take because these patients can live 15-plus years, they just can't take chemotherapy or radiotherapy every day for the next 15 years. I mean it would just be impossible to tolerate that. So we think it's a huge unmet need. But because now these patients have measurable disease, we can use overall response rate, unlike the SIGMA Phase III study, which is a PFS readout -- this will be an ORR an overall response rate readout by RETEVMO 2.0 criteria.

So we think that if we can see a significant response rate in that study, and we've guided to reading that study out by 2027. Clearly, that's a much earlier readout. We know there are examples of other glia drugs being approved on a very small data set with response rate. We know that day 1 see drug was approved less than 80 patients with an overall response rate.

So clearly, we see a really robust response rate. We think that would that would justify a discussion with FDA as to what would it take to get this drug approved to get it to patients a lot sooner than a readout in 2029 for the Phase III study. So -- we think that it's important to do the study because, number one, it's a really important unmet need. These patients just cannot take chemo and radiation for 15 years. That's just not tenable. They need something that's much better tolerated, much more convenient.

And secondly, it gives us an opportunity to see the activity of this drug in an area where nothing else work [indiscernible] no responses in this highway population. The response was literally 0%. So we think that it will give us an opportunity to look at the response rate of this drug and potentially initiate a discussion with FDA to just figure out how to get this drug to patients even earlier.

We also think that generating data in this subset were nothing works and even worse has a 0% response rate will compel physicians and patients who think, "Hey, this is a drug that has activity where nothing else does, should assist a better drug. It's a more powerful drug. Is it to do things that other does can't do.

And we think that could potentially influence the [indiscernible] market and the practice of what position the patients decide to use or attempt for treating a disease that has relatively few treatment of that is still at the end of the day, an invariably release both disease. So we think that the second study is a very important study for all of those reasons.

The next question comes from the line of Mayank Mamtani with B. Riley Securities.

Congrats on the progress. I appreciate the level of detail on IBTROZI launch. Just maybe on the metric should we expect for you to provide the new patient start numbers in the coming quarters, like you have and expect to see this 200-patient quarterly run rate to sort of continue in the coming quarters, including perhaps when there's a competitor entrant later in the year? And also, what's the real world discontinuation you're seeing in earlier line? I know you gave the 75% discontinuation rate in later line. But I was just curious if you had something in frontline, I understand the sample size will be smaller? Then I have a follow-up.

So we have said since our very -- since the first quarter that we reported sales that we would continue to look at new patient starts. I think that's an important metric. It's particularly important in the first year where depending on the mix of patients and the duration of response or the rate of discontinuation. Your revenues will not necessarily track with your new patient starts, especially as an example of your a third-line patient you just continue in a month or 2, you're not going to have the kind of revenues that you would expect in the first line setting.

So we think it's important, and we said this since June 11, when we got approved, that we would focus on new patient starts at least for the first year because I think that's the best metric is our patients using this drug do physicians who want to prescribe [indiscernible]. And over time, what you'll see is that we've said there's only about 1,000 or so TKI-experienced patients. So if you see -- if you continue to see 200 patients per quarter. And we know that at some point, we're going to have captured the majority of that 1,000 patients. That means any growth at all in that 200 number has to be in first-line patients.

And while that revenue may not appear immediately because it takes you a year to get stacking. When you start to see that growth in first line, you will see over time revenue stacking. And you will also see a significant increase in revenue. It's just not going to happen immediately because those third-line patients are going to come off, some of them discontinue within a month.

And we think those first-line patients will be on for 5 months. So I think that for the next few couple of quarters, we still think NPS is important. But a year into our lot. So by third quarter of this year, we'll have been doing this for a year, and we continue to get 200-plus patients per quarter, and the majority of those are TKI experienced. That means we will have captured the majority of the TKI experience market. So any growth at all in that NPS number has to bite their position to be in first line.

So I think that's what you should be looking for. I think the revenues will catch up to built with a few more quarters. It's just not going to be right away, but that's what you would expect.

On the discontinuation on the earlier line.

Oh, yes, sorry. So 75% of our discontinuations came from late-line patients. So -- so very late.

For the patients that we know an as David said, it's a subset of patients, the one that we're going to the hub or patients going through the hub and discontinuing 75% of them were late line which gives a lot of confidence to us about the fact that, yes, the main patients will discontinue or pellet in patients.

If you go back to our clinical viral, the rate of discontinuation was very low, as you know, 6.5%, right? So -- this is really what we're going to see. We're going to see some of those later line patients. Unfortunately, as is expected in oncology, not responding very well to 1/3 or fourth line of therapy, that's the satin oncology. And what we've seen in our subset going to the hub is that those are the most discontinuations we see by far.

Understood. And then on the anemia cohort sigma study that David you just touched on, is there a threshold on ORR that you may have quantified or have in mind that will widen the state approval discussion. Sorry if I missed that.

I think that we've seen OR anywhere north of 20%. I mean this is a population, as you said, the biggest glioma drug in the world, [ vorasidenib ] has a 0% response rate in that population. So couldn't be lower, maybe, but certainly at 20% or higher, I think that would be extremely interesting.

The next question comes from the line of Greg Renza with Truist.

Congrats on the progress. David, just maybe on your current resource position. As you've commented on the current financial structure and also the path with the Troy launch, maybe providing that path to potential profitability. Just wondering if you could provide a finer point on maybe what that horizon looks like. And related to this, as you've spoken about business development, you've mentioned the complementarity that IBTROZI and [indiscernible] provide for the pipeline. How are you thinking about adding to that mix especially in light of that focus or that mention of profitability?

So you might recall that last year before we announced the Sagard Healthcare deal, -- we had said that at that point, we had enough cash to reach profitability. Well, since we made that statement, we raised $150 million with Sagard with another $50 million in debt. And then since then we've done a deal with Esai, where we got another $60 million, and we'll have yet another $30 million upon European approval submission or approval next year. So we stand by that statement. We -- we have certainly far more cash than we need to get to profitability.

Now if we do a significant business development deal that would certainly take some cash. But -- we're aware of the importance of getting to profitability without having to need additional financing. These are still difficult markets. I think that we, in general, we've been relatively conservative on that front. So we'll carefully weigh the upside of a deal.

And certainly, any deal we do would have to be what we consider a good deal as we consider [indiscernible]. We think that was a great deal for us. So any further business there would have to be a great deal for us, and we have to be -- we have to weigh the benefits and tons of using our cash cutting into our runway to profitability.

But we feel very, very confident that we'll get the profitability right now easily with what we have on hand, and we do believe that given what we have, we think that further business development is an important -- it's always been an important part of our company growth historically, and we think we will continue to look for opportunities that we think are particularly compelling for us, especially if they can capture some of the synergies that we already have within our company.

That's great. I appreciate that color. And maybe just one last one. If you could just comment on the DDC platform. I think I heard you mention maybe some updates in the year. Just maybe just remind us of your conviction on the platform as you invest at that area of the business?

So we are absolutely convinced that, that platform is real and has real potential. We that was a first-in-class compound as effective first in history can actually. So we learned a lot with 151 -- and it wasn't that we didn't see any responses at all. We did see responses with 5.11. They just weren't consistent enough for us to invest $100 million in a in a Phase III study.

We look at all our all our drug candidate gets asked, would this be worth spending $100 million on or should we make it better? And that's something you always have to balance in early-stage bots. So the answer for [ 1511 ] was probably not. And we learned enough to figure out how to make it better or to make a DDC better, and we are hard at work doing that. But we feel very confident that our DTC program will yield molecules that will go to the clinic and that we probably will take forward in development that we'll update you all hopefully by year-end this year.