Tango Therapeutics Inc Aktie

Good day, and welcome to the Tango Therapeutics conference call. [Operator Instructions] Please note, this call is being recorded. I'd now like to turn the call over to Liz Hickin, Vice President, Investor Relations and Corporate Communications. Please go ahead.

Thank you, and good morning, everyone, and thank you for joining us on today's call. This morning, we issued a press release on the data, which can be found on the Investors and Media section of our website, www.tangotx.com. Before we begin, let me review our safe harbor statement. We will be making forward-looking statements on this call that are subject to risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. This call is being recorded, and a replay will be available on our website.

The agenda for this morning's call is as follows: Malte Peters, Tango's President and CEO, will share some introductory remarks. We are pleased to be joined today by Dr. Brian Wolpin, Director of the Hale Family Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute, who will present the clinical data. Adam Crystal, our President of R&D, will discuss our development strategy for vopimetostat; and then Matt Gall, CFO, will share some financial highlights and provide an overview of important upcoming events. Malte will then conclude the call, and we will open it up to Q&A. I will now turn the call over to Malte.

Thank you, Liz, and good morning, everyone. Today is a very important moment and a critical inflection point for Tango and the pancreatic cancer community. This morning, for the first time, we reported data from our ongoing trial for our PRMT5 inhibitor vopimetostat in combination with revolution medicines' pan-RAS inhibitors daraxonrasib and zoldonrasib in people with MTAP-deleted pancreatic cancer, which is an exceptionally difficult-to-treat malignancy. These data are the combination of years of research in PRMT5 inhibition with Tango leading the development of potentially best-in-class molecules and advancing the scientific understanding of this approach in patients with MTAP-deleted cancer.

The results from our ongoing combination trial dramatically exceeded our expectations. As of May 28, 2026 in efficacy evaluable patients with second- and third-line pancreatic cancer, vopimetostat with daraxonrasib demonstrated a 92% objective response rate. Six months PFS rate of 90% and a 100% disease control rate in heavily pretreated patients. This represents a clinical activity that is meaningfully greater than previously reported data for either agent alone or in combination with standard of care chemotherapy, both in second and first line treatment.

In addition, as we will describe on subsequent slides, the combination was generally well tolerated and no patients discontinued due to adverse events. We believe these data are extremely promising and have the potential to change the course of pancreatic cancer treatment and provide a path to development of potential chemo-free regimen in first-line pancreatic cancer. The RASolute 302 data presented by Dr. Brian Wolpin in the plenary session at ASCO are extraordinary. And we heard that the data was the beginning of a new era for patients with pancreatic cancer as well as a call to action to continue to build upon this data, and we feel that the combination data we are presenting today can be a meaningful part of that next step for many patients with pancreatic cancer.

When I started my role as CEO in January, the mandate was to accelerate the transformation of Tango from a research and early development focused company to one with the capabilities to successfully move programs through a registration and to commercialization. At that time, we were seeing some early clinical signals that were validating strong preclinical studies and the data has continued to progress in a very positive way. We are at a point now where we feel vopimetostat is ready to move to registrational trials, and we have an internal infrastructure ready to deliver. MTAP-deleted pancreatic cancer represents a potential blockbuster opportunity for vopimetostat. There are 60,000 patients with MTAP-deleted cancers, including approximately 20,000 pancreatic cancer patients. Of the pancreatic cancer patients, almost all harbor RAS mutation.

Additionally, we see meaningful development opportunities in indications beyond pancreatic cancer with large patient populations and unmet medical needs in areas such as lung cancer and glioblastoma, where we have ongoing clinical work, and we'll be sharing data later this year. On the call today, we will provide a look at the very promising vopimetostat combination data, discuss our updated strategy for developing the combination in frontline pancreatic cancer and highlight our capital allocation priorities and recent financial results.

We are very pleased to have Dr. Brian Wolpin of Dana-Farber Cancer Institute join us today to present the first clinical data which demonstrated the potential of PRMT5 RAS combination therapy. Dr. Wolpin is the Director of the Gastrointestinal Cancer Center at Dana-Farber and one of the investigators on our Phase I trial. In addition to being an experienced drug developer, he treats a large number of patients in his clinic, and he brings important perspective on the devastating disease burden and the evolving treatment landscape. With that, I'll turn it over to Dr. Wolpin.

Thank you, Malte. Thanks for the opportunity to be here and the opportunity to share some of the data of vopimetostat and RAS inhibitors, particularly in patients with pancreatic cancer. So I think as folks on this call know, traditionally and now for many years, we have treated pancreatic cancer with multi-agent chemotherapy. This is true, particularly in metastatic disease where most of what we've been able to use so far has been chemotherapy. However, we have known for some time that over 90% of pancreatic cancers harbor a mutation in RAS, particularly in KRAS and particularly in codon 12 of KRAS with G12D, G12V and G12R being the most common.

We have wanted for many years to want to target RAS and RAS that is mutated in pancreatic cancer, and this is finally now coming to fruition with now good data, including RASolute 302 showing that RAS inhibitors can be an effective therapy in patients with advanced pancreatic cancer and now showing in the second-line setting with RASolute 302 that it actually can be more effective and more tolerable than multi-agent chemotherapy.

However, we also know that will not be the answer by itself, right? Tumors will develop resistance to RAS inhibitors and really, the next wave of studies that will be coming will really be needing to combine second agents together with RAS inhibitors in order to really give our patients durable long-term responses that they deserve. So what we'll talk about today is a promising combination to do that, which is RAS inhibitors plus PRMT5 inhibitors. So a basic slide on mechanism of action for why a PRMT5 inhibitor is appropriate in pancreas cancer and actually in a number of other cancers. As Malte discussed, there's a host of different cancers that have biallelic deletion in MTAP when this gene is deleted, there's a buildup of its substrate MTA. And when there's a buildup of the substrate, that substrate displaces on PRMT5, the normal substrate that is used, which is SAM. And the goal or the function of PRMT5 is as a methyltransferase serving a number of different functions in the cell.

When MTA binds to PRMT5, you get a partial inhibition of PRMT5 function that is specific to tumor cells and not seen then in normal cells because normal cells do not have the MTAP deletion. This is a perfect opportunity then to bring in a drug that completes the inhibition of PRMT5 sparing normal cells and treating tumor cells. When drugs like vopimetostat then bind to PRMT5, you get a number of downstream consequences, including changes in RNA splicing and DNA repair that lead to cell death. And this is then the biologic basis for using a drug like vopimetostat in pancreatic cancer, where 35% to 40% of the time we see biallelic MTAP deletion.

So here's some data. The plots you see are data from Tango suggesting that there is a synergy between the use of RAS inhibitors and PRMT5 inhibitors in pancreatic cancer. I would also direct you to 2 independently done studies, both of which were published in Cancer Research last year that show a similar phenomenon, suggesting that this may be based on the preclinical data, a very promising combination to take forward in pancreatic cancer. We'll now show you today some of the first clinical data that suggest this to be true. So there's 2 drugs that we'll talk about today in combination with vopimetostat. You can see to the left is vopimetostat plus daraxonrasib. As Malte mentioned, this is a RAS on multi inhibitor. It binds to and inhibits the function of mutant RAS and wild-type RAS across a whole range of mutant alleles, including the main mutant alleles that we see in pancreatic cancer.

With the goal being inhibition of PRMT5 with vopimetostat, disrupting the methylation that the cell requires for normal function and daraxonrasib inhibiting RAS leading to a synergistic effect in cell killing in pancreatic cancer. You can see to the right, data will also show for vopimetostat, but in this case, plus zoldonrasib. Zoldonrasib is also a RAS(ON) inhibitor from Revolution Medicines. This is a KRAS G12D specific inhibitor with substantially less wild-type binding. This may also lead to synergy but there is data preclinically that using a PRMT5 inhibitor in a RAS mutant background within cancer cells can actually lead to compensatory upregulation of wild-type RAS and so it may be, and this we will have to see, but it may be that having a drug that also inhibits wild-type RAS such as what daraxonrasib does may even have greater synergy than a mutant allele-specific inhibitor. So here's the design of the study and the data that we'll talk about today.

So as we discussed, there are 2 arms to this study, both vopimetostat and daraxonrasib, this arm allowed patients with any RAS mutation because daraxonrasib is a multi-selective inhibitor or both vopimetostat plus zoldonrasib, in this case, patients were required to have a KRAS G12D mutation because this is a G12D specific inhibitor. You can see the key inclusion criteria, they must have had MTAP loss. This could be by NGS or immunohistochemistry. They must have had 1 or 2 prior lines of therapy in the metastatic setting. This is almost entirely chemotherapy in patients with pancreatic cancer. ECOG performance status of 0 or 1 and no prior exposure to either a PRMT5 or a RAS inhibitor and these patients all had metastatic pancreatic cancer or as we'll see a smaller number that had metastatic non-small cell lung cancer.

If we look to the right of the slide, you can see the dose escalation plan patients received either 200 or 250 milligrams of vopimetostat orally once daily in addition to 100 milligrams of daraxonrasib orally once daily. There was a prediction that was done prior to initiating the study that suggested with the addition of vopimetostat to daraxonrasib, 100 milligrams of daraxonrasib would actually lead to a similar exposure for the patient of 300 milligrams of daraxonrasib. For reference, 300 milligrams of daraxonrasib is what was used in RASolute 302 so it would be considered a standard dose in patients with metastatic pancreatic cancer. As we'll discuss, there are 25 patients evaluable for safety, 15 evaluable for efficacy, the ability to be evaluated for efficacy required that patients had at least 14 weeks since the start of their treatment, such that they would have had at least 2 CT scans to evaluate for efficacy.

And then as you can see in the bottom right, patients were evaluated for MTAP loss either by NGS or by IHC, although these measures are highly concordant. So here are the baseline characteristics of the patients who are enrolled. You can see 3 columns, in the first column is vopimetostat, daraxonrasib in patients with pancreatic cancer. The second is vopimetostat, daraxonrasib in non-small cell lung cancer and the third is vopimetostat and zoldonrasib, the G12D specific inhibitor. You can see focusing a bit more on the pancreatic cancer patients, median age in the mid-60s, the majority of patients received 2 therapies before they were treated on this trial. And then 70% to 80% of patients with pancreatic cancer had liver metastases. This is very common and what we generally see in trials of patients with metastatic pancreatic cancer.

So here, we can see the waterfall plot that provides some of the efficacy data for vopimetostat plus daraxonrasib in patients with metastatic pancreatic cancer. We can see on the top line, an objective response rate of 92% in 12 patients. If we look at the plot, what you can see is the line of therapy in the first row across, again, just to highlight many of these patients had received 2 prior lines of therapy prior to enrolling on the study. You can see the different dose levels, dose level 1 and 2 with the dose levels described below. And then the other thing I would call your attention to is the rightwards arrow at the bottom of each bar. These patients -- almost all of these patients continue on therapy so continue to have the opportunity for longer durability and deeper responses as they are followed on trial.

To the right, you can see the objective response rate was 92%, disease control rate was 100%. There were 9 confirmed partial responses and 2 unconfirmed partial responses, these patients remain on treatment so still have the potential to become confirmed with future scans. So this is a similar waterfall plot. Again, vopimetostat and daraxonrasib. The main difference here is that the eligible patients for efficacy for non-small cell lung cancer are also added to the plot. You can see 3 patients with lung cancer were added to the waterfall plot. These are the darker color. And you can see all 3 of these had partial responses. So again, really emphasizing that this is a relevant combination for pancreatic cancer and may also be relevant for other cancers, including non-small cell lung cancer and continues to be a very high objective response rate in the patients evaluated thus far.

So in addition to looking at objective response rate, it's also important to consider the durability of these responses. So here's a swimmer's plot to describe this and you can see all the way to the left, the indication shows you whether this is a patient with pancreatic cancer or non-small cell lung cancer, line of therapy, again, emphasizing many of these patients have received 2 prior lines of therapy already. And then you can see in terms of durability, the first set of patients now getting out almost 10 months on treatment. Most patients are now beyond 6 months and only 2 patients have had evidence of progression by RECIST criteria thus far. This then leads to for the pancreatic cancer patients, a 90% 6-month progression-free survival rate among these individuals. I would also highlight there's 9 additional patients who have not yet met that 14-week criterion for evaluation of efficacy, all are ongoing, no progressive disease events in those patients thus far.

This is a clinical example to show you a patient and what we are seeing on imaging studies among the patients that we're treating on the trial. This is a 72-year-old woman. She has MTAP deletion. She has a KRAS G12R mutation, and she has metastatic pancreatic cancer. This is vopimetostat and daraxonrasib in the third line setting, having received 2 prior lines of therapy before going on trial. We can see in the left, the CT scan representing at the red areas 3 liver metastases. And on the right and cycle 7, day 1 substantial reduction in all 3 of these liver metastases with now a confirmed partial response and by RECIST, best response minus 52% in the maximum diameter of these lesions and the response is ongoing.

Okay. So if we now turn to safety and tolerability of the combination for both vopimetostat and daraxonrasib. Again, 3 columns. You can see the column to the left is dose level 1. So 200 milligrams vopimetostat, 100 milligrams daraxonrasib. This is in patients with metastatic pancreatic cancer. The middle column also dose level 1 so the same doses of both vopimetostat and daraxonrasib, but this includes the patients with non-small cell lung cancer. And then to the right, this is dose level 2, that's 250 milligrams of vopimetostat, 100 milligrams of daraxonrasib.

If we first focus on dose level 1, we can see that almost all toxicity events are low grade, grade 1 or 2, and there are only a small number of grade 3 events, which were primarily thrombocytopenia in this population. If we move to the column all the way to the right in dose level 2, now a higher dose of vopimetostat, we see a higher rate of grade 3 adverse events, mostly related to a rash and mucositis, and also some increase in the lower grade toxicity, so grade 1 or 2. The DLTs in dose level 2 were rash and stomatitis. These are the common toxicities we see with daraxonrasib so not surprising toxicities to see. And I would say, overall, the safety signals that we're seeing in the patients treated thus far have really been very much within what we would expect based on what we know from vopimetostat and daraxonrasib. Based on these data and the efficacy data that were shown on prior slides, the plan is to advance dose level 1 to further clinical development.

If we now take a little bit more of a look and think about, well, what are the toxicities we know with daraxonrasib and how do those relate when we give daraxonrasib together with vopimetostat, it's a very similar toxicities, really the 4 main toxicities we see with daraxonrasib are the 4 that are listed at the top of the slide, rash, stomatitis, diarrhea and nausea, certainly not an increase. And if anything, actually a somewhat reduced incidence of these toxicities compared to what we see with daraxonrasib alone. If you look to the right side of the slide, if we look at the area under the curve using PK measurements from the patients on study for daraxonrasib, this was a very similar area under the curve to what is seen for single-agent daraxonrasib at 300 milligrams. Again, really emphasizing that the 100 milligrams as being used of daraxonrasib in this study when it's given together with vopimetostat, provides a very similar exposure for the patient to what you see in patients receiving 300 milligrams daily of daraxonrasib.

And there is some evidence preclinically that PRMT5 inhibition, as we talked about before, alter signaling through the MAP kinase pathway, and this may be part of what's to explain the potential for even reduced toxicity when they're used in combination. Okay. So if we now move on to talk about the data with zoldonrasib. So again zoldonrasib is Revolution Medicines' RAS(ON) inhibitor, a G12D specific inhibitor, much less wild-type binding. Again, very similar eligibility criteria. The only difference really is that required a G12D mutation. If we look to the right, the dose escalation schema, either 200 or 250 milligrams of vopimetostat orally once a day, and zoldonrasib is given at either 600 or 1,200 milligrams orally once a day. Evaluable patients for safety were 34 and efficacy for 27.

Again, the same criteria being used, we must have been followed for 14 weeks to be eligible for evaluation for efficacy to allow at least 2 CT scans for evaluation. And you can see again in the bottom right, NGS and IHC used for MTAP identification in terms of loss and high concordance between NGS and immunohistochemistry. So if we start by looking at the safety and tolerability of vopimetostat and zoldonrasib, again, we can see that most events are low grade, very few grade 3 or higher events and the grade 3 events that we're seeing were primarily due to blood count suppression.

In this case, as you can see, most commonly related to anemia. No DLTs were seen. Again, no unexpected toxicity events were identified and this, to be clear, this plot is actually for all the dose levels combined because the toxicities were quite similar across the different dose levels. If we now look at efficacy for vopimetostat and zoldonrasib, again, these are patients with MTAP-deleted KRAS G12D-mutated metastatic pancreatic cancer, they may have received 1 or 2 prior lines of therapy. We can see on the top line, objective response rate was 52% in patients -- in 27 patients. Again, you can see on the top line of the plot, the number of prior lines of therapy, you can see the dose level in the white print in the bar with the dose levels designated below. And then you can see, again, many rightward arrows in the bottom of the bars because many patients continue on therapy, and therefore, even have further opportunities for reduction in disease burden and durability.

Again, in the table to the right, you can see 27 patients, objective response rate, 52%; disease control rate 96%, 10 patients with confirmed PRs, 4 with unconfirmed PRs but still receiving treatment and a 74% 6-month PFS rate for the combination. Okay. To finish, this is now the combined waterfall plot for all patients receiving the combination of vopimetostat and a RAS(ON) inhibitor, again, either zoldonrasib or daraxonrasib. Again, I would call your attention to the high response rate, the high disease control rate and many patients still receiving therapy. So really indicating the durability thus far of this treatment and the promise for really durable responses with the combination. So I will pass it over to Adam Crystal, who will give some further information.

Thank you, Dr. Wolpin for joining us this morning and for your leadership on the trial. It's been a remarkable collaboration over the past several years, working with you and our other investigators to bring vopimetostat into the clinic and demonstrate the potential of PRMT5 targeted therapy. As you know, last year, we reported the first clinical data for vopimetostat. Those data demonstrated single-agent activity and a favorable safety profile. Together with the emerging preclinical data, which demonstrated synergistic activity with RAS inhibitors, these data prompted us to initiate the ongoing combination trial presented today. We believe the data presented today demonstrate that the observed preclinical synergy has indeed translated to the clinic.

These combinations have the potential to provide meaningful benefit for many of the nearly 20,000 patients with MTAP-deleted KRAS-mutant metastatic pancreatic cancer that die each year in the U.S. alone. Today's results, including the 92% objective response rate in efficacy evaluable patients treated with vopimetostat and daraxonrasib increase our conviction that the treatment of pancreatic cancer is being dramatically reshaped and that vopimetostat is well positioned to fundamentally change how this disease is treated. This combination approach may offer a first-line chemo-free option for patients with pancreatic cancer that could be both more active and more tolerable than current standards of care.

These results are particularly impressive given the patient population with more than half of patients receiving this investigational treatment regimen in the third line setting. Based on the strength of the data, and the evolving treatment landscape, we plan to prioritize development of the vopimetostat, daraxonrasib combination in the frontline setting, where we believe patient benefit will be maximized. Thus, as you can see on this slide, we plan to initiate a Phase III randomized controlled trial in first-line patients with MTAP-deleted pancreatic cancer. Additionally, we plan to expand the existing Phase I/II study, which generated the data discussed today to evaluate opportunities for second-line registration. In the coming months, we will share updated data with regulatory authorities and work with them to confirm the details of our development plans as we continue to accrue data to this ongoing study. I'll now turn the call over to Matt to share financial highlights and review our upcoming milestones. Matt?

Good morning, everyone. It's great to be with you. With approximately $380 million in cash on our balance sheet, we are well positioned to move forward with the planned frontline Phase III combination trial in pancreatic cancer, and we continue to expect cash runway into 2028. As we advance development of vopimetostat in pancreatic cancer, we will maintain a focused and disciplined approach to investment across our R&D portfolio while recognizing that we have several near-term catalysts ahead of us that have the potential to unlock additional meaningful opportunities, both as a monotherapy and potentially with further combinations.

We will prioritize our most promising opportunities to impact patients and our ability to cost-effectively generate compelling signals in a short period of time may allow us to efficiently derisk investment in additional indications for vopimetostat and TNG456 with clinical data. Ultimately, our goal is to realize vopimetostat's blockbuster potential while we continue to sustainably invest in additional compelling growth opportunities. We remain on track to generate multiple potentially impactful catalysts for the company, including sharing vopimetostat data in lung cancer and initial TNG456 data in glioblastoma in the second half of the year. With that, I'll turn the call back over to Malte for closing remarks.

Thank you, Matt. In closing, I want to highlight how we are positioning Tango to seize on these important data to deliver value to patients and our shareholders. Building on our scientific leadership, pioneering PRMT5 targeted therapies of cancer, we are reorienting ourselves to focus on late-stage development for vopimetostat. With the addition of highly experienced talent and enhanced operational capability, we are ready to efficiently execute a global pivotal trial in a competitive space. With promising combination data in hand and a derisked path in front-line pancreatic cancer, we believe vopimetostat's first and best-in-class potential has been strengthened. In addition, the optionality we have intentionally created to combine with other RAS targeted therapies in development further enhances vopimetostat's strong competitive positioning for the long term.

Finally, while the anticipated need for transformative therapies in pancreatic cancer alone represents a potential blockbuster opportunity for Tango. We also have significant upside potential in lung cancer and glioblastoma. In these indications, we believe we can also deliver important therapeutic benefit to patients with vopimetostat and our next-generation PRMT5 inhibitor, TNG 456 and we look forward to sharing additional updates to these programs later this year. Before we wrap up our prepared remarks, please allow me a personal reflection. As an oncologist who has treated many patients with gastrointestinal cancers during my academic career, I know firsthand how devastating pancreatic cancer is and how difficult it is to treat.

The fact that Tango is one of the companies advancing the field into what may be a fundamentally new paradigm with a potentially safe and effective chemo-free treatment is personally very gratifying to me. I want to close by thanking the patients and their families who participated in these studies, clinical investigators as well as employees and partners who have worked tirelessly to get us through this inflection point. This is an exceptionally exciting time for Tango, and all of us at the company are united in our mission to bring life changing treatments to patients. With that, operator, let's begin the Q&A.

[Operator Instructions] Our first question comes from Eric Schmidt with Cantor.

And congrats on these remarkable data, truly game-changing. Adam, I'm wondering if you had any opportunity yet to talk to regulators about the path forward in the frontline setting. Do you think you're going to require some experience in frontline patients before kicking off that study, how do you think about establishing contribution of parts in the front line, if at all? And then I'm also curious how we should think about a potential role for Revolution Medicines in running a future study.

Absolutely. So I would point to the data cut of May 28, only about a week or so ago, which has not given us an opportunity to discuss these data with either the FDA or other regulatory bodies. We are preparing to do so and look forward to doing exactly that over the coming summer to define exactly what our regulatory path forward will be. It's absolutely critical that we align with them. It is a changing landscape with a lot of open questions. And once we have done so and have a clear path forward into a Phase III first-line study with the study design at that point, we will bring it forward knowing that we have the endorsement of the FDA under our belt.

And then either for you or Malte on the collaboration with Revolution Medicines and their role here.

Yes. So I spoke to our collaboration many times. We have a very good collaboration. The project goes very well, we speak all the time between the 2 companies at all levels. And both companies have started discussions of how continued development of both the drug as a joint effort. And we believe that this joint opportunity is a very attractive and tremendous impact for patients and also for both companies. So I think that's how I would describe the situation with RevMed. At the same time, we spoke at the beginning of the year that we like the optionality we have built into our company here with the supply agreement that we started with Erasca. And that interaction goes also forward very well. So at the moment here at Tango, we like the fact that we work probably with the 2 best RAS inhibitors out there in clinical development.

Our next question comes from Michael Schmidt with Guggenheim.

Congrats on the data from me as well. Obviously, very impressive response rates and duration. I noticed that almost 2/3 of the patients were actually third-line PDAC patients. And I was just wondering if you had a chance to look at the efficacy data in second-line patients only, just curious, especially for the 12D cohort? And then just on dose selection, it sounds like you said you're moving forward with the 200 mg vopi combination dose and daraxonrasib maybe for Dr. Wolpin, do you feel that you have enough data to make that decision yet. And I know there are only a handful of patients treated at 240 mg -- 250 mg combination dose, but yes, just curious how the tolerability compares to daraxon monotherapy since a lot of the AEs were actually known AEs that have been seen with daraxonrasib.

Thank you for the question. Regarding efficacy in the second versus third-line setting, the numbers get quite small when we start subdividing, but our conclusion when we compare, for example, second line to third line patients in the daraxonrasib treated population is that there is no meaningful difference in activity. And perhaps the simplest way to say that of the 12 efficacy evaluable patients presented today, effectively all benefited and most continue to benefit with no difference between the second and third line patients and how they responded. In terms of the dose level 1, we do have a large number of patients treated in that in excess of 20 and very much like the profile in terms of PK safety as well as efficacy.

The one thing that I would note is that we have begun to explore other dose levels really to derisk the path forward. We considered the dose level 1 data we presented today, excellent and are very comfortable moving it forward. But in order to ensure that we can do so as quickly as possible, we're making sure that we understand possible alternatives so as not to slow things down.

Our next question comes from Laura Prendergast with Stifel.

Congrats on the very exciting data today. In monotherapy, PRMT5 inhibitors have shown about 6 months median time to response. Can you comment to how early you're seeing your responses and if you're seeing deepening with time. And then also regarding a Phase III, as far as inclusion of RAS mutations, is this something that you're going to need to wait to see what the daraxonrasib monotherapy label looks like first? Would you maybe do all comers in PDAC with an MTAP-deletion or a specific patient population? Any comments there would be helpful.

Okay. So add to the first question. Overall, the pace of tumor shrinkage is a little bit faster than with single-agent PRMT5 inhibitors, and we look forward to sharing a more full set of those data when we update these data as they mature with more patients later in the year. They do continue to shrink over time. Indeed, most of the patients in this cohort continue to shrink at the time of the data cut, but it is fair to say that the velocity of that shrinkage tends to slow by the third or fourth scan. The second part of your question.

Yes. I remember. Will we be testing for RAS in a Phase III. I think the simple answer for that is that we need to understand the daraxonrasib label as that likely approval comes to pass, and that will impact the discussion we have with FDA and other regulatory bodies as to the relative advantages or disadvantages of prescreening for KRAS mutation.

But we know from the RAS presentation that in each arm, there were only 8 or 9 RAS wild-type patients, respectively. So we assume that the label will not include testing, but that's our assumption. And of course, we need to wait for what the label will actually show.

Our next question comes from Kelsey Goodwin with Piper Sandler.

Congrats on the data this morning. Really impressive. Yes. I guess maybe 2 quick ones from me. First, in terms of the patient numbers for the daraxonrasib combo in PDAC, I'm just wondering, I think we had about 14 you had said as of December. I'm just wondering why did enrollment kind of not pick up in the first half of '26? And then maybe second for Dr. Wolpin, building on the plenary discussion and call to action to really evaluate more RAS inhibitors, more combinations? How do you see the landscape shaping out over the next few years?

Sure. So I'll take the first question and then on to Brian for the second question. The reason is straightforward is simply that we explored 2 dose levels with daraxonrasib and analyzed those data before expanding dose level 1 in contrast to with zoldonrasib where we explored 4 dose levels, which enabled patients to come on in escalation as well as backfill for a larger number of slots. And Brian, would you like to comment on the second question?

Sure. Thank you for the question. So I think we were all quite impressed with how RAS inhibition in RASolute 302 was able to lead to substantially higher response rates and durability than chemotherapy. I think as we also discussed and as you said, discussed and also mentioned, that doesn't mean these patients are cured. They will develop resistance to RAS inhibition and what we really need as a field now is to evaluate a number of options to improve the durability of response and increase further the response rate. I think there is a whole host of things out there that, that could potentially be. I think this, though, in terms of the data presented today is very much supported by preclinical data and now has a body of clinical data in patients suggesting that this may be one of those high-priority combinations for us to consider so I would consider this one of some high-priority combinations that we, as a field, need to explore to help our patients.

Our next question comes from Joe Catanzaro with Mizuho.

Congrats on the data here. Maybe 2 for me. First, forgive me if this was mentioned in the prepared remarks, but was rash prophylaxis implemented in the study? If not, are there any sort of considerations around utilizing that prophylaxis regimen that's being used with darax? And then second, I think there's some preclinical data out there that would suggest this sort of dual mechanism of RAS inhibition and PRMT5 inhibition could have utility in non-MTAP-deleted tumors. Wondering if you've explored this preclinically, whether any interest in exploring clinically? Any thoughts there would be great.

So the answer to your first question is yes. We prophylax these patients for rash much in the same manner as was done, for example, on RASolute 302 following the guidelines provided to us by our colleagues at RevMed. We have asked a very fair question of have investigators gotten better at prophylactically managing rash resulting in what may be a lower incidence here. It is possible, but it is also possible that the absence of Grade 3 events and slightly lower rate of Grade 1, 2 events is secondary to the impact on biology affected by the addition of the PRMT5 inhibitor. As to the second part of the question -- remind me the second part of the question, I apologize.

No problem. It's the idea of this sort of combo in non-MTAP-deleted tumors and whether you've looked at that preclinically, any interest in looking at that clinically?

We have begun to look at it preclinically. I can't say that we've generated any data that I'm ready to share today. I think it is an interesting question. If the data presented today holds up and continue to demonstrate that this drug makes pan-RAS inhibitors more tolerable. If it is the case that even in an MTAP intact patient, we get a little bit of efficacy from this molecule, which is possible given the concentrations we achieved. There may be a path to doing it. I would consider it speculative at this point, but certainly something we are thinking about primarily in a preclinical domain.

Our next question comes from Emily Shutman with Leerink Partners.

This is Andy Berens, I think Emily must have dialed in for me. But congrats on the update. Really a great day for MTAP and PDAC patients. Two for me. You gave some additional insights into the pathophysiology you're seeing the activity. Just wondering if you think HRAS or NRAS or Cyclophilin play a role. Just wondering if the pan-KRAS agents could possibly benefit from this synergy and have less tox. And then maybe if you could give us an update on where you are with this combination effort versus other efforts like your own with Erasca or collaboration of daraxonrasib with Mirati just trying to get a sense of how far you are ahead of any fast followers. Congrats again on this impressive data set.

Sure. Thank you. I'll answer your question -- your second question first. Our Erasca study, we are moving as quickly as possible with the intent of getting that study open this year. It is almost the second half, and that will be in the second half. It's worth noting that there are other molecules or other trials combining PRMT5 inhibitor with pan-RAS inhibitors. I think potentially the most interesting one from our perspective is the combination of daraxonrasib with BMS-504, the prior Mirati molecule. My understanding based on clinicaltrials.gov is that, that study is scheduled to start in July of this year, putting us at least 1 year ahead.

In terms of the role for NRAS and HRAS or Cyclophilin, I think that as KRAS wild-type may be upregulated by the treatment we've given here today. So too may be the case for HRAS and NRAS, I think more likely KRAS, but it could be important. I think that, that will be determined over time. In terms of Cyclophilin A, I think that -- that data set is emerging, and I don't think I would draw any conclusions on it based on what we presented today.

Just maybe one addition from my end on your first question. So we expect that there will be more than one RAS inhibitor approved going forward. And our vision here at Tango is that vopimetostat could ideally be the preferred PRMT5 inhibitor to be combinable with any RAS inhibitor available, right? That's a bit the vision and the dream we have.

Our next question comes from John Newman with Canaccord Genuity.

Let me add my congratulations as well. Just curious, obviously, you've got a lot of things going on here and you've discussed your priorities. But just curious about a potential path forward in lung cancer. I'm wondering at this point, if you just plan to expand the current study or if there are any thoughts kind of going forward eventually on a randomized study there?

Sure. I think that there are opportunities in non-small cell lung cancer for vopimetostat, I would guide first to the single agent data, which we are planning to share this year, which we are optimistic about. The most obvious place to put such a molecule for a short-term approval might be in the second line versus docetaxel. But I think for that data, we need mature PFS data, which establishes durability sufficiently strong that we would have high confidence that it could be docetaxel in such a setting. I also think that the overlapping population of MTAP-del and RAS mutation is a real population of patients of approximately 5,000 patients a year similar to the size of the ALK population in non-small cell lung cancer. And these preliminary data suggest that this combination could be meaningful there. We are determining the exact path forward, and we look forward to sharing that once we have developed it. But I think that there are opportunities, whether it be in the second or first line setting in that patient population for the combination.

Our next question comes from Maury Raycroft with Jefferies.

Congrats on the great data. I was just going to ask about the durability that you're seeing so far with the 6-month PFS. It seems like you're tracking better than RevMed's monotherapy data. Do you view this early durability signal as superior to daraxonrasib monotherapy? And could you show a PFS update later this year when you do your next data update? I'll start with that.

Perfect. So I think that here, we have 12 patients, and we have a 90% 6-month PFS rate. There are confidence intervals in the deck, which speaks to the likelihood that this may well be better than single-agent daraxonrasib, I'd also point out that ours is in more heavily pretreated patients than RASolute 302. So the data remain early, but thus far suggests that it could be better than achieved in RASolute 302.

Anything else.

That's all I have, I think.

And are you planning on doing a durability update later this year?

Thank you. I do think that when we present the data, an updated data set later this year, it will include more patients with efficacy there will be longer-term follow-up for many or most of those patients. And I would expect it would have a similar amount of patient-level data so that a PFS could also be extracted from that data set. We have one here, which is, of course, immature because so few patients have progressed.

Got it. And maybe 1 quick follow-up just with the data that you're seeing here and the debate around daraxonrasib potentially getting accelerated approval in frontline. As you communicate with FDA and figure out your next step plans, do you think you have enough to potentially go head-to-head versus daraxonrasib in registrational study?

We have not had these discussions in great detail. We are preparing to have the first discussions with regulators around the world, including FDA, but also EMA and the Japanese authorities. And once we have an opportunity of sharing the data and discussing next steps, we are ready to give an update. So that's, I think, probably the most realistic answer I want to give at this point.

Our next question comes from Yuan Zhi with B. Riley.

Congrats on the unprecedented combination efficacy. Maybe my first question is on the first line setting in PDAC, we don't know if dara 300 milligrams will beat the 200-milligram plus chemo. So how will that impact your Phase III design if dara plus chemo is better than the dara monotherapy?

I think that I would defer to in part what Malte said before, much of the finalization of our study design depends on upcoming interactions with FDA in this changing landscape, but we also intended to be the case that this study is up and running well before that Phase III first-line study reads out. And so the study design will be finalized before those results are known, but certainly accounts for the scenarios which emerge from that step.

Got it. And do you need any dose escalation to optimize the dose since the ORR is already at 92% in PDAC before your Phase III initiation?

Excellent question. We are very comfortable with dose level 1 in terms of PK, safety and efficacy, but recognize that there is often interest in dose optimization. For this reason, we have begun to explore other dose levels to ensure that the data package we bring forward supports a final dose determination for the Phase III.

Our next question comes from Kalpit Patel with Wolfe Research.

And many congrats on the results here today. One for Dr. Wolpin. How do you think about these results presented today versus the navlimetostat chemo combo data from Bristol-Myers, both from a tolerability and efficacy perspective. And then second question on the top line efficacy here between daraxon combo and the zoldon combo. Any reasons for why there's such a gap in the response rate? And then do you plan on prioritizing the daraxon combo going forward? I'm assuming that's the case.

Why don't I start with the second question, and then I'll ask Brian to comment on the first question. I think the first -- the second question is very interesting. Effectively, why is the overall response rate higher with daraxonrasib combination rather than zoldonrasib combination. I think that there are 2 credible explanations in terms of the data. One is what Brian spoke to earlier, the understanding that upregulation of wild-type RAS isoforms maybe activating and that daraxonrasib could effectively suppress that whereas zoldonrasib would be unable to. The second thing I would point out is that the zoldonrasib patients had an inferior ECOG status in this study, it may contribute to their -- to the lower overall response rate, but we certainly cannot be sure. Those are the reasons that I would point to. In terms of your first question on comparison to the other study, I'll defer to Brian.

I would say it's early days for comparisons across different PRMT5 inhibitors and across other combinations. I would say, focusing on what we saw today, this clearly looks like a promising combination. And I think it will need over time, further patient enrollment across a number of studies to really show what is truly best. However, this really does look like and in response to other questions that have been asked, this really does look like based on the data that's available so far like a competitive combination approach, whether that be with chemotherapy, other PRMT5 inhibitors or other mechanisms of actions of other drugs that this really does look to be a competitive combination for the field to be moving forward with.

Okay. And one, I guess, follow-up for the company. How should we think about the other tumor-agnostic indications because of the profound efficacy you've seen here in PDAC.

I think that it is something we are interested in. The data we shared towards the end of last year demonstrated a single agent overall response rate in that histology selected population of 49%. We believe that is meaningful activity and would highlight that in that population, there were some particularly interesting activity, for example, 3 of 3 patients with head and neck squamous cell carcinoma achieved confirmed PR. We have been adding more patients there. However, we have 2 primary focuses: one is pancreatic cancer. The second is non-small cell lung cancer. We are finalizing our plans in PDAC as we solidify our plans in non-small cell lung cancer. With those in hand, I do think that there are opportunities in the histology-agnostic population.

It's on our long list of questions we are going to discuss with the regulators.

And our last question comes from Robert Driscoll with Wedbush.

Adding to the congratulations here. Maybe just at a higher level and to follow on maybe a little bit. Does the synergy demonstrated here have read through to how you're thinking about development of 456 in GBM or how you may think about additional potential combinations outside of KRAS inhibition going forward?

It's a very interesting question, and I do think that it merits thought as to what this data means in other indications and beyond KRAS. I think the preclinical data speaks to this being through the MAP kinase pathway, and there are other targeted therapies, which drive their efficacy through inhibition of the MAP kinase pathway, those may provide opportunities. Specifically in GBM, I don't think that there is an obvious combination play because there are simply no other drugs, which are approved or even in advanced investigational development that might be efficacious in doing exactly that.

Thank you. This does conclude the question-and-answer session. Thank you for your participation. You may now disconnect. Everyone, have a great day.

Good morning, and welcome, everyone. I'm [indiscernible] I'm an associate on the health care team at JPMorgan in New York. Today, it's my pleasure to introduce Tango Therapeutics. With me on stage, we have Malte Peters, CEO; Barbara Weber, Executive Chairman and former CEO; and Adam Crystal, President of R&D.

Barbara, I'll pass it over to you. Thank you.

Thank you very much, and thanks for the opportunity to be here today. As you just heard, until last Thursday, I was the CEO of Tango Therapeutics. And I just want to mention that we will be making forward-looking statements today, and this is our disclaimer.

As of last Thursday, Malte Peters is our new CEO. And I just want to mention a few words about him, and then I'm going to hand it over to Malte for the presentation. Malte and I have been friends and colleagues for a long time, worked together at Novartis. And in 2018, I asked him to join the Board of Tango Therapeutics. He's been a thought partner for me and part of building Tango since then. And he has most recently served as the Chief R&D Officer at MorphoSys, where he did quite a lot of development work that's relevant to what Tango needs to do next.

So as I let the Board know at the beginning of 2025 that I was looking to step down as we got to the end of this year, showed that vopimetostat was really an important drug moving forward, and the company would be well capitalized. It was clear after a significant search that Malte was the right person to take over for me. And I want to introduce Malte today, who will tell you more about where we are at Tango Therapeutics. Thank you.

Thank you, Barbara, for your very kind introduction. I'm very excited and honored to take over the leadership at Tango at this really exciting time. The company is moving very rapidly into its next phase of growth. And we are moving and developing and evolving the company from a phase of successful clinical validation into a phase of late-phase drug development, regulatory activities and potential approvals, of course, with the attempt to have a commercial product. My single focus at Tango as CEO will be to translate the clinical achievements into significant value for patients and for shareholders.

Now let's look a little bit into the pipeline and into the science that had brought Tango to where it is today. MTAP deletion is one of the most common genetic alterations observed in patients with cancer. 60,000 patients are diagnosed each year in the United States of America with tumors related to MTAP deletion. And you can see the frequencies are displayed here, non-small cell lung cancer, pancreatic cancer and GBM are amongst the most frequently mutated tumors.

Tango has developed a very exciting pipeline addressing these indications and are designed to attack cancers with MTAP deletion. You'll see here our current pipeline, and we are very excited about where we are. Vopimetostat is in dose expansion studies, a combination study of vopimetostat with RevMed's RAS inhibitors is in dose escalation. And we have a molecule called 456, which is a blood-brain barrier, penetrant molecule that's also in dose escalation. And we have an HBS1L degrader molecule, which is ready to enter Phase I clinical trials this year.

Now the year 2025 was a very successful year for Tango. Tango has developed a clinically validated PRMT5 pipeline with the best-in-class potential, both from an efficacy perspective, but also from a safety and tolerability perspective. In addition, there is a unique opportunity of combining PRMT5 inhibitors from Tango's portfolio with RevMed's RAS inhibitors. Strategically, we are focusing our work and development activities on indications with a high unmet medical need in difficult to treat cancers and potential fast-to-market opportunities. Moreover, the company is well capitalized with a cash runway into 2028.

Now what are we going to do in the year 2026 moving forward? We are going to deliver on 4 critical milestones. First of all, we are going to launch a second-line pivotal trial in pancreatic cancer. Secondly, we will complete our vopimetostat RAS inhibitor combination studies to potentially support activities moving directly into frontline development activities in pancreatic cancer. Thirdly, we will expand our knowledge base in patients with lung cancer and potentially other indications to investigate if vopimetostat has a role for treatment of patients with other indications. And lastly, we will evaluate TNG456 efficacy in patients with glioblastoma.

Now we have a very attractive competitive angle or advantage that allows us to do our work. First of all, we have a plan -- we have a pivotal trial protocol, which has received a lot of support from FDA. Secondly, we have a potentially best-in-class molecule based on MTAP selectivity and also potency. Thirdly, we have a potentially best-in-class safety profile, which is very important when you think about combining vopimetostat with other molecules, and I'll come back to that in a moment. And lastly, we are the first company combining a PRMT5 inhibitor in a clinical trial with a RAS inhibitor and in our case, we're using 2 RevMed RAS inhibitors.

Now diving a little bit deeper into the pipeline. I spoke already a bit about vopimetostat. Vopimetostat is targeting a patient population of approximately 60,000 patients each year. We have a potentially best-in-class molecule in our hands from a safety perspective but also from an efficacy perspective. TNG456, our brain-penetrant PRMT5 inhibitor, remember, 45% of patients with glioblastoma have MTAP deletions and we are currently in dose escalation with this molecule. Our HBS1L degrader TNG961 has produced very exciting single-agent and vopimetostat combination activities in multiple preclinical models, and this molecule is ready to start clinical trials this year.

Now let's take a short look at the data, the clinical data situation, and we're very excited about what we are seeing. Vopimetostat demonstrates a clear monotherapy activity across multiple tumor histologies. You see here a waterfall plot displaying 94 patients with different tumor histologies. All patients had active doses with a follow-up of 6 months or longer. In this population, we are observing a response rate of 27%, a median progression-free survival of 6.4 months and we have seen very good tolerability with no discontinuation at drug-related events at 250-milligram doses.

Now if you think about this from a time-dependent endpoint perspective and look at Kaplan-Meier curves, that show you median progression-free survival, you see a doubling of the median progression-free survival Kaplan-Meier curve of TNG462 or vopimetostat compared to standard of care or historic treatment regimens that patients would get with pancreatic cancer when they are treated with chemotherapy regimens. We're seeing a response rate of 25%, 7.2 months of medium progression-free survival. And it's interesting to note that the patient populations that we're displaying here for the standard of care are MTAP unselected patients, right? So they are wild-type patients and mutated patients. And because we know that MTAP mutation confers poor prognosis to treatment with chemotherapy, we think that the curves that you see here for the standard of care is actually an overestimate. So the true median progression-free survival for standard of care treatment with patients with MTAP deletion may actually be lower than what you see here.

So based on this data, we have designed a pivotal trial in second-line pancreatic cancer. It's a very straightforward design, 2-ARM study with vopimetostat and standard of care control. 300 patients will be enrolled in the study. We have discussed the design of this trial with FDA and got a lot of support regarding the trial design, the statistical analysis plan, the dose selection and the overall study design. We believe that we are in a very good position for a very rapid enrollment given the high unmet medical need in this patient population and a sheer high number of patients that are unfortunately available with this disease.

Now I want to show a couple of data points related to our combination activities of vopimetostat and RevMed's RAS inhibitors. You see here preclinical data of an experiment where we treated a CDx model with suboptimal doses of vopimetostat and zoldonrasib. And you see that there is almost no activity, but when you combine both components, there's a striking combinatorial activity of both compounds. Pancreatic cancer is a RAS-addicted cancer and almost all MTAP deleted pancreatic cancers have also a RAS mutation. And roughly 40% of MTAP deleted pancreatic cancer is RAS G12D mutated. Now based on this information and based on this data, we have designed the study that you see on display here. It's a dose escalation. The study is currently in dose escalation. And we are combining vopimetostat with daraxonrasib and with zoldonrasib. We are very happy with where we are in terms of enrollment. 30 patients have been dosed to date. Both combinations are very well tolerated, and we have achieved active exposures for all components in this study, and we have seen no unexpected adverse events. We are very pleased with the early signs of clinical activity.

Now if you think a little bit about this combination strategically, a couple of points are important. First of all, I said it already, RAS -- more than 90% of patients with pancreatic cancer are RAS driven. And RAS inhibitors are likely to transform the way of how pancreatic cancer patients will be treated in the future. Now looking at the combination that I mentioned before, combining a PRMT5 inhibitor of vopimetostat with a RAS inhibitor, we can say that this could be a potential path to justify and support a frontline study with a combination of vopimetostat and RAS inhibitor, potentially giving access to a chemo-free treatment regimen for patients with pancreatic cancer early on.

Now we're very often asked when we speak to investors and analysts, what activity are you actually looking for? what would you be excited about? Our answer is that we always first look at the baseline -- at the baseline of what the RevMed's RAS inhibitors deliver, we know that second-line pancreatic cancer patients treated with these molecules have a response rate of roughly 30%. And of course, we are interested and excited to potentially significantly increase that response rate, hopefully, with a clinically meaningful durability of response.

Now that's not all we are excited about. There is one more piece of data related to vopimetostat. We have observed a 49% response rate in a histology selective cohort, that involves multiple different histologies. In this population, we have seen a median progression-free survival of 9.1 months. And we are excited about this data and are committed to enrolling more patients with all different histologies to find more data points that could guide our thinking in terms of what indications are also potentially benefiting from a treatment with a PRMT5 inhibitor vopimetostat.

Now here again is a comparison of the PFAS curve of what I just described to you in this tumor -- in this histology agnostic patient population with standard of care -- with standard of care treatment. And you see that, again, we are doubling the median progression-free survival compared to standard of care treatment.

Now let's switch gears a little bit and speak about TNG456, that is a compound -- that's a PRMT5 inhibitor, which has a very good blood-brain barrier penetration. The potency is very good. The MTAP selectivity is even better, and we have observed preclinically very comfortable CNS exposure. Based on this data, we have designed a Phase I/II clinical trial in patients with MTAP deleted solid tumors. And in this study, we were clearly focused on patients with glioblastoma. Remember 45% of patients with glioblastoma have an MTAP deletion. This study is ongoing, and we are very happy that just a couple of days ago, we put the first patients with glioblastoma on the study.

Now the last component of our pipeline, which I want to mention briefly is TNG961, our HBS1L degrader. So FOCAD deletion and HBS1L are synthetic lethal pair, and FOCAD deletion occurs in 1/3 of MTAP deleted cancers. So basically, in patients or in tumors that are FOCAD deleted, you need HBS1L for ribozyme lifetime. And if you delete or abolish HBS1L that process can no longer be done and cells die.

We have delivered or shown very strong xenograft activities across multiple lineages. And this program is now in -- has now completed IND-enabling studies so that we are ready basically to start a clinical trial with TNG961.

Now in summary, in the year 2026, we will deliver a couple of very important clinical milestones. First of all, we will start a pivotal trial in second-line pancreatic cancer. Secondly, we will show data of our combination of vopimetostat with RevMed's RAS inhibitors. Thirdly, we will expand our knowledge base of vopimetostat clinical activity in lung cancer and in other cancers. And lastly, we will show the activity of TNG456 in patients with glioblastoma. All of this is possible because we are well capitalized, and we have a cash runway into 2028.

So with this, I stop, and I guess there are maybe 1 or 2 questions that we hope we can answer. Thank you.

Great. Thank you very much, Malte. We'll open the floor for any questions that you might have.

The initial hypothesis for the PARP inhibitors was based on a synthetic lethal approach with BRCA. But ultimately, it's been found that there's a utility and benefit for patients beyond BRCA mutations. Have you guys ever tested or do you have any plans to test the PRMT5 inhibitors in non-MTAP deleted tumors, say those with low levels of SDMA for non-MTAP deleted reasons?

Adam, do you want to take that question?

Sure. It's an excellent question. Thank you. The mechanism of this molecule as well as the other PRMT5 inhibitors relies heavily on the accumulation of MTA to establish the therapeutic index. So that suggests that in the absence of MTA accumulation, secondary to MTAP deletion, one would lose the therapeutic index, the molecule is built to create. We also have looked extensively preclinically to determine whether or not baseline SDMA levels may predict responsiveness whether it be an MTAP deleted or MTAP wild-type cells. And in our hands, the answer to that question has been no.

Anyone else? Otherwise, I have one. Malte, stepping into your new role as CEO, what are your key priorities?

So my key priority is really to help moving the company very rapidly into a phase of late-phase drug development and to make sure that we are well equipped to enter meaningful discussions with regulatory authorities. So that we have a team in place who is experienced in clinical development, clinical operations, regulatory affairs, so basically executing very rapidly into a late development organization. Our goal is clearly to get this drug approved. I think I showed you that we have options of doing this. We can, of course, do this based on our pivotal trial as monotherapy, but we've shown you how excited we are about the combination potential. So all of a sudden, we have multiple ways of doing this. So that's the goal really of finding the best way of getting vopimetostat to patients.

Okay. Anyone else in the audience? Otherwise, I have another question about the pivotal study. Can you narrow the guidance when you plan to start the study for that?

Yes. So we hear this question a lot. And we have deliberately decided not to be more specific than what I said. So we will do it this year. And we are well on our way and on track of doing this. But it will -- we will not be providing more details of when this is going to happen.

I want to discuss more about the revolution strategy because it is also exploring maybe the combination with PD-1 and extremely increased the ORR. And so what about our strategy is that benefit more about the OS or also the ORR?

So I think in terms of the end -- so you are referring to the endpoints of the clinical trial. Okay. So the endpoints that are meaningful for regulators of granting approval are different -- are deferring based on -- from one indication to another. So of course, when you develop a drug in pancreatic cancer, you have to meet the standards of how the drug would get approved based on knowledge and based on discussions with FDA. So you have to have an agreement between the sponsor, the company and the regulatory agency that the endpoints that you are selecting are accepted by the agency to give you an approval. We have done this for our pivotal trial. And we are very confident that FDA will be supportive in case the data allows the agency to give a potential approval.

Anyone else in audience, otherwise, I have one last question. You provided an enrollment update for the combination study, and you mentioned that you would disclose data for that later this year. What amount of data would you need to disclose that? And would this be in a medical meeting?

Yes. So that's a very good question. So we are very happy where we are with the enrollment. At the moment, the excitement is really very high. With the company now moving into a more, I would say, late phase thinking or time, we are committed to share data when we are 100% convinced that the data is robust and mature enough to make a statement regarding its implications for moving forward. So at this moment, I cannot say when this is going to be. We are not tied to any medical meeting. If it falls into place with a medical meeting, then of course, we take that opportunity. But if it's outside of a medical meeting's calendar, we will do it independent from a medical meeting.

Great. If there's no more questions from the audience...

Any comments on the leadership transition?

Barbara?

Well, as I mentioned before, I'm the founding CEO of Tango. I started the company with Alexis Borisy at Third Rock in 2015. It became a private company in 2017, and I've been the CEO ever since. We're very proud of what we've accomplished over that period time going literally from a very high-technology genomic target discovery platform into being ready to start pivotal studies with our first compound. It was really a good time for a leadership transition. I think that both my skill set and sweet spot is around early development. And it was really time for somebody who had the focus on the next phase of what Tango needs to do, which is really to get its drug approved and moved forward with the company in that direction. It was with that in mind, as I mentioned, that we selected Malte for his experience. But there are a couple of other things that are really nice about that, which is that he's been very involved in the company, particularly in the last couple of months with the full development team, and it makes for a very smooth transition. He's familiar and comfortable board, with the executive team and with the people who are executing on what we need to do. So I think it's -- for me, it's a perfect time, and he is the right person.

Yes. Maybe one addition from my end. I think Barbara said it extremely well that I was involved in -- as a Board member with a company's strategic direction since 2018. So what you see in terms of where the company is at the moment, strategically, that was with my contribution in some shape or form. So I don't think you can expect a massive strategic change because I have already been involved in bringing the company to where it is today. So I just wanted to add that, that we are committed to execute what we have in front of us, and we have enough on our plate to be busy.

Great. Thank you for these closing remarks.

Good day. Thank you for standing by. Welcome to Tango Therapeutics Clinical Data Update Conference Call and Webcast. [Operator Instructions] Please note that today's conference may be recorded. I will now hand the conference over to your speaker host, Liz Hickin of Investor Relations. Please go ahead.

Thank you. Good morning, everyone, and thank you for joining today's call to discuss the vopimetostat clinical data.

This morning, we issued a press release on the data, which can be found on the Investors and Media section of our website, www.tangotx.com. On today's call, Tango Therapeutics President and Chief Executive Officer, Dr. Barbara Weber; and President of R&D, Dr. Adam Crystal, will walk us through the data. At the conclusion of prepared remarks, we will open the call to Q&A and will be joined by CFO, Daniella Beckman.

Before we begin, let me review our safe harbor statement. On today's call, we will be making forward-looking statements that reflect our beliefs as of today and are subject to risks and uncertainties as outlined in our filings with the SEC.

And now I will turn it over to Dr. Barbara Weber.

Thank you, Liz, and welcome, everyone. Today, we are pleased to provide a clinical update on TNG462, our lead PRMT5 inhibitor, now formerly named vopimetostat.

As a brief background, we launched Tango in 2017 based on the idea that the genetic concept of synthetic lethality offered an opportunity to discover and develop cancer drugs targeting genes that are frequently deleted in human cancers and to contribute to building the arsenal of novel cancer drugs that have changed the lives of so many people with cancer over the past 20 years.

Vopimetostat is an example of such a drug, specifically designed to work in cancers with MTAP deletion, largely sparing normal cells. Vopimetostat is an oral once-daily PRMT5 inhibitor we are developing for multiple cancer types with MTAP deletion, one of the most common genetic alterations in human cancers found in 10% to 15% of all solid tumors.

Our initial development focus is on pancreatic cancer with approximately 20,000 MTAP-deleted cases annually in the U.S. The data from our Phase I/II study support plans for our first pivotal study starting in 2026 in second-line MTAP-deleted pancreatic cancer, providing a path for vopimetostat to be the first MTAP selective PRMT5 inhibitor to market.

In considering plans for development in first-line pancreatic cancer, we believe that RAS inhibitors will change the treatment paradigm in the coming years. Thus, we started the trial last summer of vopimetostat in combination with the RAS(ON) inhibitors, daraxonrasib and zoldonrasib, in collaboration with Revolution Medicines.

These combinations provide a potential path to a chemotherapy-free first-line treatment of MTAP-deleted pancreatic cancer, a tribute to our friend and colleague, Dimitris Papoutsakis, who died of pancreatic cancer just before his 50th birthday in 2021 and just a little bit too soon to benefit from the remarkable progress now being made in this disease.

MTAP-deleted lung cancer is another important development focus for us, representing approximately 22,000 patients in the U.S. annually. We anticipate a data update from the monotherapy cohort of our Phase I/II trial as those data mature in 2026.

Finally, the data we will review today provides the basis for developing vopimetostat in the 13 different cancer types represented in the histology-agnostic cohort of our study. This group of multiple difficult-to-treat cancer types account for another 20,000 MTAP-deleted cancers in the U.S. each year, bringing the total population of MTAP-deleted solid tumors to more than 60,000 patients per year in the U.S.

As a reminder of the study design and to provide context for the data we will present today, the dose escalation cohort included any solid tumor with an MTAP deletion. For dose optimization, we enrolled patients in 3 cohorts: pancreatic cancer, lung cancer and a group we are calling histology agnostic. Today, we will provide data from the study as a whole as well as an analysis of the pancreatic and histology-agnostic cohorts.

While we have enrolled more than 40 patients in the lung cancer cohort, enrollment to this cohort has taken longer than the others due to the large number of competing lung cancer trials. Thus, these data are not yet sufficiently mature and will be presented in 2026.

The details of our disclosure today are shown here. Following this update, we have a strong cadence of disclosures planned for 2026. These will include initial data from our ongoing combination of vopimetostat plus the RAS(ON) inhibitors from Revolution Medicines in second-line plus pancreatic and lung cancers; initial data from a planned cohort of first-line pancreatic cancer patients, along with a more fulsome update on the second-line plus cohort; clinical data from the monotherapy lung cancer cohort as it matures and initial data on TNG456, an MTAP selective PRMT5 inhibitor similar to vopimetostat in potency and selectivity that is brain penetrant. TNG456 is being developed in glioblastoma, another indication of high unmet need, representing approximately 7,000 MTAP-deleted patients per year in the U.S.

Now I would like to introduce Dr. Adam Crystal, our President of R&D, who will provide the data update.

Thank you, Barbara. I'd like to begin by highlighting key data that underscore our strong conviction in vopimetostat as the potentially first-in-class and best-in-class PRMT5 inhibitor.

The observed overall response rate is 27%, which compares favorably to published competitor data. The FDA has agreed with our selected go-forward dose of 250 milligrams and that we have satisfied the conditions of Project Optimus. In second-line pancreatic cancer patients, the median PFS is 7.2 months and the overall response rate is 25%, more than double the historical standards of care, supporting our planned pivotal study. In the histology-agnostic cohort of heavily pretreated poor prognosis cancers, the overall response rate is 49% with a median PFS of 9.1 months.

Finally, vopimetostat has a best-in-class safety profile and tolerability profile to date with no drug-related discontinuations and a dose reduction rate of 8%. With vopimetostat, as with other PRMT5 inhibitors, overall response rate is a time-dependent variable. This effect is demonstrated here. When all evaluable patients are assessed for response, the overall response rate is 20%; and with additional follow-up, the overall response rate increases to 27%.

For this reason, the overall response rate analysis presented today are derived from patients enrolled more than 6 months before the data cutoff regardless of outcome in order to avoid underreporting response rates. As noted, the overall response rate for vopimetostat across all histologies is 27%, currently best-in-class across published datasets.

Notably, the majority of partial responses occur after the first scan with the longest time to first response being 8 months in a patient with lung cancer. There are several other key data points worth highlighting. The median PFS is 6.4 months, an increase of almost a month compared to our update in November 2024 when we reported a median PFS of 5.5 months. This demonstrates that durability also continues to improve with increasing follow-up.

Finally, almost 40% of patients remain on study, remarkable with a median follow-up of 9.4 months in heavily pretreated patients enrolled in a Phase I study.

This spider plots of all evaluable patients treated at active doses further demonstrates the durability seen in patients with partial response and those with stable disease, even those with more modest tumor regression. While the median PFS is 6.4 months when evaluating all patients, median PFS is almost 1 year in patients with partial response and a very substantial 7.3 months in patients with stable disease.

Here, we provide an update to our previously disclosed safety and tolerability profile at 250 milligrams daily, now with 84 patients and more than 6 months median follow-up. Drug-related adverse events are uncommon, most occurring in fewer than 10% of patients and most of those being grade 1. No related grade 4 or 5 events have been reported. GI events were infrequent and low grade, and there is no rash signal.

Importantly, only 8% of patients at 250 required dose reduction to 200 milligrams. None required further dose reduction and no patient has discontinued for a related adverse event. Dose reductions have primarily been for anemia, a well-described on-target effect of PRMT5 inhibition in normal bone marrow cells. And this safety profile, including the anemia, has been described by investigators as "trivial to manage."

Finally, this safety profile suggests that vopimetostat is likely to be readily combinable with either chemotherapy or targeted therapy agents, which we are already seeing in the first cohort of the RAS inhibitor combination study.

A total of 64 pancreatic cancer patients have been enrolled. Enrollment was sufficiently robust that earlier this year, we began recruiting only second-line patients in order to provide direct support for our planned pivotal study in this indication.

Notably, more than half of the 64 pancreatic cancer patients were treated at the go-forward dose of 250 milligrams. Here, the Kaplan-Meier analysis is presented comparing second line to third line plus patients. As has been seen in other recent pancreatic cancer datasets, the durability in second-line patients is meaningfully better than third-line plus patients.

In the second-line patients with a median follow-up of 7.8 months, the median PFS was 7.2 months and the overall response rate was 25%, a notable improvement over standard of care. Additionally, the median PFS of 7.2 months exceeds the median overall survival typically seen with standard of care chemotherapy in this setting.

To compare vopimetostat to current standard of care chemotherapy, our median PFS data are plotted versus historical trial data demonstrating that vopimetostat more than doubled the median PFS reported in these studies. Of note, the control arm of our upcoming pivotal study may be shifted to the left as several recent studies have shown that MTAP deletion is a negative prognostic marker associated with inferior overall survival across indications, including in pancreatic cancer.

While we will not power the study for this effect, it may increase our likelihood of success because in our control arm, all patients will be MTAP-deleted in contrast to these historical controls.

Our proposed study design is straightforward, randomizing patients to vopimetostat or a choice of 1 of 4 standard of care chemotherapy regimens in second-line MTAP-deleted pancreatic cancer. Allowing both Gem/Abraxane and 5-FU-containing regimens in the control arm ensures that patients may be enrolled regardless of the first-line therapy they receive, and it allows for utilization differences between the U.S., Europe and other areas of the world.

We expect that this trial will enroll quickly given the experience with our first-in-human study and the high unmet need in these patients. This study has generated considerable excitement, and we are proud to be the first to evaluate the promising combination of a PRMT5 inhibitor and RAS inhibitors in both pancreatic and lung cancer.

The first dose cohort is complete. Exposures were in the active range for each compound and both combinations have been well tolerated to date. We are backfilling both combination arms and investigator enthusiasm is high, driving rapid enrollment.

Cohort 2 is enrolling, and we anticipate backfilling this cohort at the completion of the DLT observation period. Once go-forward doses have been determined, we plan to open a cohort of first-line patients to gather data needed to enable a pivotal study in this setting.

As RAS inhibitors transform the care of people with pancreatic cancer, these combinations have the potential to support a chemotherapy-free first-line pivotal study with competitive time lines.

As noted previously, lung cancer patients can be challenging to enroll in clinical studies in general due to the multiple trial options available. Thus, these data are less mature than pancreatic cancer with only 12 of 41 patients having reached the 6-month follow-up threshold. Emerging data are consistent with expectations, and we will provide an update on this cohort in 2026 as the data matures.

The histology-agnostic cohort is a collection of multiple late-line difficult-to-treat cancers, representing approximately 20,000 MTAP-deleted patients per year in the United States. Many of these patients were enrolled early in the study, providing a substantive number of patients with mature data.

The 9 sarcoma patients enrolled in the study and included in the overall analysis on Slide 8 are excluded from the analysis of this cohort because there is no evidence of vopimetostat activity in this cancer type. The overall response rate was 0%, and they will not be included in any further development times.

In this cohort, the overall response rate is 49% with a striking median PFS of 9.1 months, an indication of activity not previously reported with this class of drugs. As indicated by the black dots, 21 of these 37 patients are ongoing, a measure of remarkable durability in this group of late-line difficult-to-treat patients.

Additionally, as indicated by the color coding in the graph, the activity observed in this cohort was seen across the 13 histologies represented with no single cancer type driving the overall response rate. In order to evaluate the activity of vopimetostat versus standard of care treatments for this diverse group of cancers, we plotted the results of several trials representative of the enrolled cancer types and lines of therapy.

As was the case with second-line pancreatic cancer, median PFS is more than double the available treatment options. These data provide further evidence of the robust single-agent activity of vopimetostat and provide us with development optionality beyond pancreatic and lung cancer.

In summary, the data we've shown today demonstrate that vopimetostat has the potential to be both best-in-class and first to market for multiple large patient populations with high unmet medical need. We are planning our first pivotal study of single-agent vopimetostat in second-line MTAP-deleted pancreatic cancer next year.

The ongoing combination study of vopimetostat with daraxonrasib and zoldonrasib in collaboration with Revolution Medicines puts vopimetostat in the lead to take advantage of the impact RAS inhibitors will have on standard of care in pancreatic cancer.

Finally, the potentially best-in-class safety and tolerability profile of vopimetostat to date suggests that as development advances, vopimetostat will be readily combinable with other agents.

And now I will turn it back to Barbara for closing comments.

Thank you, Adam. Before we open to Q&A, I want to say that I believe the data we are presenting today represent a potential turning point for patients with multiple hard-to-treat cancers. And as an oncologist, I am tremendously proud of all the work that led up to today and the people who made it happen.

In summary, these data provide the basis for a $225 million financing announced this morning, reinforce our insertion that vopimetostat has the potential to be the best-in-class and first-to-market MTAP selective PRMT5 inhibitor, support our strategy to start a pivotal study in second-line pancreatic cancer in 2026, give us the confidence in our plans to move into first-line pancreatic cancer in combination with RAS inhibitors with competitive time lines and highlights the remarkable single-agent activity of vopimetostat in our histology-agnostic cohort.

This provides a potentially important opportunity for these patients in an environment where pursuing individual approvals in each of these indications is not feasible. In closing, I want to thank the many, many people at Tango, our founding scientists and collaborators and most of all, the patients who put their trust and their lives in our hands in choosing to participate in our first-in-human study of vopimetostat.

Vopimetostat is one of the things I'm most proud of in my long career, which has seen many fundamentally important advances in cancer treatment. And I, along with the rest of the Tango team, are committed to realizing its potential for as many patients as possible.

And now we'll take questions.

[Operator Instructions] Our first question coming from the line of Eric Schmidt with Cantor Fitzgerald.

Congrats Tango team on a seminal moment for vopimetostat's development and just some remarkable tolerability and activity data.

Barbara, it sounds like since we last spoke, you've maybe reached some alignment with your friends at Revolution Medicines on this first-line cohort that is in planning combining RAS inhibitors with MTAP -- sorry, with PRMT5 inhibition. Is it true that that's kind of a new development? And what would be the next steps after that cohort? Do we have further alignment on other activities and actions?

Thanks, and thanks, Eric, for your comments on vopimetostat. There's been no change in our collaboration with Revolution Medicines. I think we've always thought that this was a potential path to first-line therapy in pancreatic cancer, and that hasn't changed. That will, of course, be dependent on emerging data, and we look forward to disclosing that for the first time next year.

And then a quick follow-up, if I could. What is sort of rate limiting for starting the pivotal second-line study in 2026?

We plan an FDA interaction on that study this year, and we're working on study start-up actually now at risk. So it's really an operational time line at this point.

Our next question coming from the line of Michael Schmidt with Guggenheim.

Yes, congrats on the update. I have to say I'm a tiny bit confused about some of the patient numbers that are mentioned throughout the slide deck. And I just wanted to confirm, so the 27% overall response rate across all patients, is that based on 94 patients that were evaluable or 85, which is listed on Slide 7? And then similarly, I guess, how many patients were efficacy evaluable in total in the pancreatic cancer cohort?

So first of all, thanks, Michael. I appreciate the comment. And I'm going to turn it over to Adam to go through the numbers because they are a little bit confusing.

Sure. So the disconnect you're seeing, Michael, between 85 and 94 comes from the fact that, that table was an analysis we did about a month before the final data cut. So the 27% is the same, but an additional 9 patients-or-so mature to the following waterfall plot, which was 2 weeks later. Therefore, there are 94 patients represented on the waterfall plot and the 27% overall response rate is actually the same in both of those.

In terms of the total number of evaluable patients in pancreatic cancer. If you turn to the slide which speaks to the patient numbers, there were 8 patients in the second line assessable for tumor evaluability. And in the later lines, there were many more. I don't remember the exact number. 29 of the 34 patients were -- had reached the 6-month threshold of evaluability and somewhere in the neighborhood of 24 to 25 of them were evaluable for tumor.

Okay. Great. And then yes, just a follow-up around the longer-term development strategy. And yes, how do you think you are positioned in pancreatic cancer longer term? I know the daraxonrasib combination obviously holds a lot of promise. But in the near term, you have Bristol doing a first-line PDAC study with chemotherapy and you have presumably daraxonrasib on the market prior to your second-line study reading out. And so, yes, how do you think about the evolving landscape in PDAC in that context?

Yes. Thank you, Michael. And it is a complicated space right now, which, of course, is really exciting for patients after such a long period of no further development. But in terms of our thinking about our path forward, first of all, as we mentioned, we're going to start the second-line study as soon as possible, which we believe will be valuable both for patients and for the company going forward for patients post chemotherapy and post RAS inhibitors until there is a PRMT5 inhibitor in first-line pancreatic cancer.

Our plans are that, that would be us, vopimetostat, likely in combination with the RAS inhibitor. Now in terms of the Bristol study, I can only, of course, comment on what's on clinicaltrials.gov, but what is there is a plan for a 6-arm dose-finding study scheduled to start later this year and the readout of a pivotal study of Gem/Abraxane plus BMS504 that would read out in 2029 or 2030.

As I mentioned in our remarks, we believe that RAS inhibitors will change the paradigm of treatment in first-line pancreatic cancer, and therefore, are moving forward, as we said, with competitive time lines to the Bristol study, not with the combination of chemotherapy and vopimetostat, but with a RAS inhibitor and vopimetostat.

Our next question coming from the line of Maury Raycroft with Jefferies.

I'll add my congrats on the data update. Wondering if you could talk more about the combo study. How many cohorts do you project you'll need? And can you generally comment on what you're seeing so far in Cohort 1 on efficacy and safety and how doses could shape up there?

Thanks, Maury. In terms of the cohort planning, of course, it's a dose escalation study, so it's difficult for us to comment until we have data from each individual dose cohort moving forward. But as the exposure of all 3 compounds was well within the active range in the first cohort, I don't expect that it will be very many dose escalation cohorts.

In terms of additional data or color that we can provide, we're not disclosing any additional information from what's on the slides.

Got it. And maybe just a quick follow-up. If you can comment on the 3.5 months median time to response versus Bristol's 5 months and just what could be driving that?

Well, we do believe that vopimetostat has substantively better target coverage at 250 milligrams than BMS504 does at 400 or 600 milligrams. So it's possible, but that is partly what's driving it. It's hard to say for sure with the limited data that we have available to do a comparison of the individual patients, but that's certainly a possibility.

Our next question coming from the line of Peter Lawson with Barclays.

Great. Congrats on the encouraging data. Maybe just on the pivotal trial design for the second line. And why don't you kind of walk through the final elements that are still under discussion with the FDA and if there's anything around control regimens or anything you can talk about [indiscernible] and I assume OS is going to be the primary endpoint?

You're talking about the second-line pancreatic cancer study?

Yes.

Yes. So as I briefly just mentioned, we have an FDA interaction scheduled and coming up. So anything I say here is a bit speculative until we've had that meeting. But the size of the trial is estimated to be about 300 patients, which should be sufficient to detect the differences that we've described. And in terms of the chemotherapy regimen, the selection of them are similar, if not identical, to the design used by Revolution Medicines of the three 5-FU containing regimen and Gem/Abraxane as options for investigators.

So it's not a full investigator's choice. It will be from that menu. And that has been acceptable to the FDA, as I mentioned, in the Revolution Medicines study.

Got you. And then the histology-agnostic responses, really strong response that you saw there. And as you think about taking that forward, is there particular indications you would exclude? Or have you got a good sense from the FDA kind of what indications you have to include in the number of patients?

Yes. So first of all, I just want to remark that our pancreatic cancer development path is our first priority, and we have to remain focused on that. As it has been highlighted a few times, those are very competitive time lines, and it's important for us to move that forward as quickly as possible.

Having said that, we also are very excited about the data in this histology-agnostic cohort, but we have not yet had an interaction with the FDA on that. It certainly is well -- the data, both the overall response rate and the median PFS are well within the range of multiple histology-agnostic studies that have been approved by the past. But bear in mind, we're probably histology-agnostic may not be the best name for this cohort because we're not trying to include all cancers, we're trying to include the cancers that are in this cohort.

That means it wouldn't include pancreatic or lung cancer, which are being developed separately, and as Adam mentioned, wouldn't include request to have sarcoma included in the label because we just don't see any activity in sarcoma. I would briefly mention, we do think there's a biologic reason for that, which is MTAP deletion is heterogeneous in most sarcomas, therefore, likely not a truncal mutation the way it is with all other solid tumors that we're aware of.

Our next question coming from the line of Robert Driscoll with Wedbush.

Adding to the congratulations here on all the progress and the data. I want to ask about the MTAP deletion screening rate for the patients that you've attempted to roll in the study in pancreatic cancer. Is it matching the nonprevalence of MTAP deletion?

Well, overall, the estimated incidence of genetic screening for patients in the U.S. is about 40%, but it is not uniform across cancer types, and there's a heavy bias towards lung cancer in that number. Certainly, at the beginning of our studies, getting patients screened for MTAP deletion was a challenge. We don't see that anymore at all as causing any delays in enrolling patients.

But I think it will, as it has always been in targeted therapies, continue to be a challenge to increase the screening rates in these cancers because that's critical for getting the patients both on studies and later commercially on drug.

Our next question coming from the line of Kelsey Goodwin with Piper Sandler.

Congrats on the data. Maybe actually building on testing rates. I guess, do you have a sense in frontline PDAC, how long it would take from the time of testing to get the results? And I guess, would physicians have time to start a targeted therapy? Or would they put patients on chemo to wait until the results come? I guess maybe the dynamics there would be helpful.

Thanks, Kelsey, and it's a great question. What we are moving forward with for companion diagnostics is actually 2 different assays. And particularly in pancreatic cancer, we're working on a companion diagnostic based on immunohistochemical screening. I always kind of cringe at that as a geneticist, but in fact, in this setting, IHC for MTAP deletion is very clear black and white.

It's either -- it's because it's a homozygous deletion, it's either there or it's not. And that IHC staining is something that can be done with 24- or 48-hour turnaround in essentially any hospital in the United States and Europe. So I think that will facilitate the enrollment of those patients rapidly.

And then in addition to that, we'll be working on a NGS assay with Foundation Medicine that allows that -- the use of that assay as well. So people will have the option of either one of those assays. And I don't -- other than just the uptake and getting physicians to send the test, I don't anticipate any special problems with screening for MET MTAP deletion as any other genetic alteration for targeted therapy.

Okay. Great. And then just one follow-up on the Phase III. I saw the trial has 300 patients. I know Resmed is targeting closer to 460, but they have some other hierarchical statistical analyses going on. Maybe just a comment on the delta there and what gives you confidence in 300 patients?

Sure. It's actually powered equivalently. The difference is that the Revolution Medicines study has formal co-primaries of PFS and overall survival, which requires them to increase their patients enrolled by about 50% to 450. In contrast, our intent is to pursue a hierarchical design study, which first reads out PFS and then if and when it is positive, overall survival. Doing it in this fashion does not require spending alpha, additional alpha on a co-primary, thus enabling us to enroll less patients, which will be faster to accrue.

Our next question coming from the line of Yuan Zhi with B. Riley Financial.

Congrats on the data. I was surprised no one is talking about safety here. So maybe, Barbara, you can comment on the safety profile observed so far. What's the DRT here? And why not dosing higher than 300 or 250 milligrams here?

Yes. Thanks. Dose-limiting toxicity in the dose escalation portion of this study was actually thrombocytopenia, that was at 600 milligrams a day. We then decreased back down to 300 milligrams a day and explored 3 dose cohorts, 200 milligrams, 250 milligrams and 300 milligrams a day.

There was a trend towards increasing activity across those doses, but there was a big distinction between 250 milligrams and 300 milligrams in terms of the bone marrow suppression. So the amount of anemia and thrombocytopenia at 300 milligrams a day that was seen in those patients, although they felt well and were not symptomatic, about 50% of those patients required a dose reduction because of that.

At 250 milligrams and at 200 milligrams, that dose reduction rate is 8% and lower. And so that was the discussion with the FDA who has agreed that we have satisfied the requirements of Project Optimus with this dose optimization cohort that the sweet spot between optimized efficacy and really good tolerability was at 250 milligrams a day.

Got it. And maybe a quick follow-up here. In terms of the combination, any overlapping toxicity profile with pan-RAS or G12D inhibitors that would prevent dosing TNG462 higher than 250 milligram or at 250 milligram?

Well, in terms of vopimetostat, we don't have any intention of increasing the dose beyond 250 milligrams. In fact, that is the second dose cohort is increasing vopimetostat to 250 milligrams because we wouldn't expect that it would be more tolerable in combination with the RAS inhibitors than it is a single agent. And we've already determined that 300 milligrams is a higher dose than we plan to go forward with because of the dose reduction rate.

In terms of the RAS inhibitors, both of them are very well tolerated as well and with non-overlapping toxicity in general. So as we continue to enroll patients, we're optimistic about the safety and tolerability profile, and we'll be updating you with that in more detail in '26.

And there are no further questions in the queue at this time. I will now turn the call back over to Dr. Barbara Weber for any closing remarks.

Thank you all for your time this morning. And if you have any additional questions, please reach out to us directly.

This concludes today's conference call. Thank you for your participation, and you may now disconnect.

Hello, everyone, and welcome to Annual Goldman Sachs Global Healthcare Conference. My name is Karishma Raghuram. I'll be moderating this session. It's my pleasure to introduce Barbara Weber, Chief Executive Officer of Tango Therapeutics. Barbara, welcome.

Thanks for having us.

So maybe for those who are less familiar with the company, could you start by perhaps providing a brief overview of Tango, your synthetic lethality discovery platform, how it's differentiated versus competitors in the market?

So the basis for Tango really, as you pointed out, is synthetic lethality. And the whole idea of that is that most of the drugs that have been developed in the last 15 years in oncology have been inhibitors that were targeting activated oncogenes. Every cancer has also associated with that tumor suppressor gene loss and you can't directly target tumor suppressor genes because they're gone or inactivated. So the whole idea was to be able to find a way to unveil a whole new category of targets against tumor suppressor genes to supplement all the work that had been done so successfully in activated oncogenes.

And this wasn't a new idea, but it wasn't really possible until CRISPR became widely used, and that was the basis for founding Tango. Now that was in 2017, so fast forward now quite a few years, and we are now well into the clinic with our first target and have a pipeline coming behind that based on synthetic lethality. Just one interim point to make is that really the harbinger for the value of synthetic lethal targets is PARP inhibitors, and that was really the first discovery that was clinically relevant.

Great. Very, very helpful and informative. I guess what are some of the current challenges in the synthetic lethality field? And how can Tango address these challenges?

So I don't think we all really, meaning us at Tango and the community as a whole, understood this as we started out. But the way synthetic lethal targets act is very different from activated oncogenes. I'd say, first of all, there are a large number of synthetic lethal targets, but they are not all equally efficacious against the target. I think Chris Lord has talked about this as penetrants. That's sort of a version of a genetic concept, but it basically means how active in a cell is that inhibitor even though it may be fully inhibiting the target. And so there's a range, whereas hitting an oncogene that a cell is essentially addicted to will essentially always give you a strong effect. Synthetic lethal targets can give you a range of effects depending on that target.

The other thing that we're seeing now specifically with PRMT5 inhibitors, and it's somewhat true for PARP inhibitors as well, although less dramatic, is that the really striking thing about that is a PRMT5 as a target is the durability as opposed to what people are used to, which are response rates. And so I think that's taken some time for us and other people to fully understand that this is what is special about these targets and will make a very important and unique contribution.

Got it. So maybe digging a little bit more into the pipeline and your lead program. Can you give us an overview of TNG462 and then your next-generation brain penetrant asset, TNG456?

Yes. So TNG462 is our lead asset. That is a PRMT5 inhibitor, which is synthetic lethal with MTAP deletions. And MTAP deletions are among the most common genetic alterations in cancer. In particular, lung and pancreatic cancer frequently have MTAP deletions. And so our focus with 462 as we're nearing the end of our Phase I/II study is development plans going forward for both pancreatic cancer and lung cancer, where we think PRMT5 inhibitors in general and 462 in particular, will play a really important role going forward.

Great. And can you maybe help us understand the investigator enthusiasm here? And how much data in terms of patient numbers, follow-up we might expect for the update second half of this year from the Phase I/II?

So for our update later this year, what we plan to present in addition to the full dose escalation expansion study cohort and the data that support our selection of 250 milligrams a day as the dose to go forward with, we will also have a real focus on pancreatic and lung cancer. We will have more than 20 lung cancer patients with 6 months of follow-up and well more than 20 pancreatic cancer patients with more than 6 months of follow-up.

And we will, particularly in pancreatic cancer, also have a reasonable sized cohort of second-line pancreatic cancer patients. It's those patients in particular, that are really intended to support our plans for our first pivotal study, which will be in second-line pancreatic cancer. And I think that -- those data will all be available with our update later this year.

What is getting investigators excited about this, I think, is the combination of the efficacy measured in particular by durability. I mean it's pretty remarkable. We have a number of patients with difficult-to-treat tumors, including pancreatic cancer that have been on for more than a year. I mean I've been an oncologist for a long time. That's just not something that we've really seen before. And the BMS data that was just presented at ASCO supports that as an effect of this target. But on top of that, the patients tolerate the drug really well.

And 462 in particular, we think has a best-in-class tolerability profile. So now you're talking about patients with esophageal cancer, pancreatic cancer, advanced difficult-to-treat cancers, and they not only are staying on drug for very much longer periods of time than standard of care, but they feel really good as opposed to the chemotherapy options, which they have that are not very effective and really not tolerable at all.

Great. And you recently announced the dosing of your first patient for 456. Can you remind us of some of the preclinical data to date and which elements will ultimately correlate in your view to clinical success?

Yes. So you can sort of think of 456 as 462 with brain penetrants. And the reason why that's particularly important to think about with MTAP-deleted cancers is because glioblastoma, almost 50% of glioblastoma have MTAP deletions. And as you know, that is probably the single most difficult to treat solid tumor now that there's been advances and even now with pancreatic cancer and really moving into that much more treatable space. So making a PRMT5 inhibitor that can get enough brain exposure for those patients to have a chance and a meaningful response is important. And that's what we think we might be able to do with 456.

Fantastic. And noting that this is somewhat of a successor to your previous efforts with 908, what learnings have you at Tango derived from that investigation that you hope to leverage and perhaps improve upon or implement with 456? And what aspects or property of this molecule are perhaps differentiated from 908, which ultimately will drive your confidence going forward?

So 456 is markedly more potent than 908, but the real difference that we think should matter in terms of glioblastoma is that we've tripled the selectivity for MTAP deletion. And what that means is that we think we can deliver significantly more drug into the brain because of that, you can just give more drug, so you can get more of it into the brain. So 908 is a reasonably brain-penetrant molecule. The problem is you have to stop dosing as you hit toxicity. Because of the increased selectivity of 456, we expect that waiting for the first PK, of course, but PK dependent, we expect that there will be -- we'll be able to dose 456 into the range where we're getting above the efficacy threshold in the brain.

And people say, well, glioblastoma is a hard cancer. It is. I mean there are some unique things about it. It's a growing tumor inside a very enclosed space. But there's nothing magic about it. And I think you get the right drug in there at the right exposure and glioblastoma will respond like other solid tumors does.

Great. Now maybe taking a step backwards, noting that you have these 2 assets looking at the same target in your pipeline, help us frame and contextualize how you view the positioning of each molecule in the broader treatment paradigm? And what is your criteria to perhaps call one of these programs?

So we are very focused on moving 462 forward in all solid tumors with the exception of glioblastoma. It's, I think, a really excellent drug. The 456 program is really focused on glioblastoma because 462, we know just will not get there. And it's a big market in its own right. I think the other thing that's important is the flip side of that, which is that most brain-penetrant molecules will have some CNS toxicity. And there are cancers like pancreatic cancer that virtually never metastasize to the brain. So having a really active and well-tolerated PRMT5 inhibitor that isn't brain penetrant has significant value in all these tumors that are not likely to metastasize to the brain and then having another one that is when you need it, I think, could be a very important strategic distinction.

Now you brought up lightly Bristol's data. So there are obviously some other PRMT5 MTA cooperative programs in the space. We've seen data from Bristol, formerly Mirati, Amgen, there's others in the clinic from AstraZeneca. How do you view the competitive landscape here and maybe some of the differences between molecules? And given the clinical data that is out there and that the Street, as we all know, is very likely to make cross-trial comparisons, how are you talking and framing maybe expectations for your data from a response rate perspective, durability, safety, et cetera, compared to the others?

Yes. And it's -- as you say, it's a complex field that been generating a lot of interest for a while. So there's a number of players out there. But I think in the lead are Tango, BMS and Amgen, all those molecules started in the clinic sort of in the initial wave. I would say there are qualities to the Amgen molecule that may hold it back. The public data right, it has a slightly more difficult tolerability safety profile and the durability overall has been less than what BMS and we have already published on. So we really think about BMS as our prime competitor, and it's a good molecule. We think that from the standpoint of the PK properties and the tolerability, 462 is better. I mean, just head-to-head data comparison.

We think in the end, because we can hit the target harder because of the PK properties and the tolerability, that will ultimately translate into at least the same, if not better efficacy. And so for us, the BMS data was really a very positive thing. Now going back to your question, we'll come back to the BMS data, but going back to the competition, about a year behind that first wave is AstraZeneca. They haven't put out a lot of data, but presumably, that's a good molecule. And then a year behind them are BeiGene and a number of other molecules. And so I think that it's on us, but we have a significant lead over all of those molecules.

Great. And how are you approaching combinations? What have you seen so far preclinically? And what is your strategic development plan here with potential consideration for co-occurring mutations like EGFR or KRAS G12C?

Yes. Great question and something we've been thinking about for a while. And our combination strategy is sort of divided into 3 camps. So the first part are tolerability combinations that you have to think about for first-line studies if you have to combine with chemotherapy, knowing that you'll eventually have to combine with pembro, those things. So that's one bucket. And that's not a big priority right now for us because they're not on the critical path, and our real focus for time and resources is on 462 in pancreatic cancer. The second set of combinations that people have been talking about for a long time are the MAT2A inhibitor, PRMT5 combinations. There is synergy, biologic synergy between those 2.

The first study was the IDEAYA Amgen study, which never read out, but I think has been talked about in terms of why that, that was a difficult study to do because of the tolerability of that combination. There are others out there, and it's something that we think is a question that needs to be answered. But based on our preclinical data, we believe that a good PRMT5 inhibitor will be -- will always be a MAT2A inhibitor single agent and the combination may just give you a more complicated path forward.

So we're leaving that to other people to answer that question, but we're obviously interested in the outcome. The real focus of our combination strategy and what we think is going to be really exciting over the next year or 2 are co-occurring oncogenic mutations. And the most exciting and important one right now are the RAS mutations. The reason in part for that is not just the excitement around Revolution Medicines and the new class of RAS molecules, that's really important, and that's clearly central to pancreatic cancer and lung cancer development.

But also because the frequency of RAS mutations is such that all -- essentially all MTAP-deleted pancreatic cancer is also RAS mutant. So we are now just about to start a study where basically every MTAP-deleted patient with a RAS mutation, so more than 90% of them are eligible to go on the study either in combination with daraxonrasib, the pan-RAS or zoldonrasib, the G12D inhibitor from RVMD. Given the strength of the single-agent data from both of those -- all 3 of those molecules and the really amazing preclinical data from that combination, we have high hopes for that combination that's really game-changing for pancreatic and lung cancer patients.

Great. And you've kind of touched on this a little bit throughout our conversation, focused on tolerability. Are there any overlapping toxicities with these combinations that you're watching out for? And do you think potentially dose lowering in either drug in these combinations would be advantageous?

Well, all 3 molecules have really good safety profiles. I would say daraxonrasib maybe have rash issue and a little bit more GI toxicity, but overall, very well-tolerated drug. And so we expect that the combinations will be very well tolerated. Now we'll see, right? Things sometimes happen in combinations you don't expect either good or bad, right? But I think if you just look at the safety profiles of all the molecules involved, and you think about the fact that they're completely nonoverlapping pathways, I think they should be very well tolerated.

Great. Maybe taking a little bit of a pivot here. Can you talk about TNG260, your KRAS inhibitor, which is being developed in STK11 mutation patients? Obviously, a large opportunity, which represents roughly 15% of non-small cell lung cancer. What's the status of the dose escalation? And when might we expect an initial update here?

Yes. So this is a really, I think, innovative program that is sort of a riff on synthetic lethality, which is starting with the original data that we discovered in animal models and at the same time -- almost at the same time was published in retrospective analyses in patients that had been treated with -- who had lung cancer treated with pembrolizumab that STK11 mutations in tumors, which are inactivating mutations really render cancers immune resistant, right? So those -- the mice that have STK11 mutant cancers or the people that have STK11 mutant cancers really just are not sensitive to anti-PD-1 agents.

And what we did was an in vivo CRISPR experiment to try and find targets that reverse that setting of STK11 mutants and then made them be responsive to anti-PD-1. As I said, it's sort of a rip on synthetic lethality to say, if you have an STK11 mutation, this will work. If you don't, you wouldn't expect to see any effect. That study now is in dose expansion. So we've released the data on proof of mechanism, and we've shown that in patients, exactly what we predicted based on the animal models would happen happens in patients. So PD-1 expression goes way up, cytotoxic T cells come into the tumors, all the things that you would expect to have a tumor become sensitive to checkpoint inhibitor all occur in those patient tumors. And what will happen later this year is an update on those study -- on that study looking at clinical proof of concept.

Great. Extremely helpful. And how does 260 compare to other therapies that have been tried before, including LSD1 and pan-HDAC inhibitors?

So they are all functionally related to each other because it's the CoREST complex that we think is driving this, and they are components of the CoREST complex. But 260, which we call an HDAC inhibitor because -- I mean, a CoREST inhibitor because it does bind to a complex that contains HDAC, but it really only acts when that is part of the CoREST complex is like 200x more selective against this than an HDAC inhibitor. And the pan-HDACs that have been in the clinic have been generally not well tolerated. They don't really have a therapeutic index. There's no patient selection strategy. So it's really a pretty big difference between what's been tried before and TNG260.

You've shown some preclinical combination data here with an anti-PD-1. What's the path forward here as a combination? Could you give us a sense?

Well, one thing that's really important is that the combination with PD-1 was engineered in from the beginning, literally the in vivo CRISPR experiments were done with an anti-PD -- a mouse anti-PD-1 to say, okay, what -- if you knock out which genes in the presence of an anti-PD-1 will cause a response. And what we found as one of the top targets was, in fact, the target of 260, which is the KRAS complex. And so only in those STK11 deficient mice did we see that virtually all the mice got durable complete responses, and they were essentially immunized against their own tumor by this effect. So there is no path forward with 260 as a single agent. That was never an intent and it isn't the biology, right? So even in the Phase I study, every patient has been getting pembrolizumab in combination from the beginning.

Great. Now perhaps more broadly, do you think that there's anything that the Street is underappreciating with regard to Tango more broadly that we should be maybe paying more attention to on the forward for the balance of the year?

Well, to be fair, I think we've probably been underestimated on pretty much every level, right? I get that. It's a tough time out there. But I think maybe the biggest things were really almost more on PRMT5 as a target. I don't think that investors have been really convinced until maybe pretty recently that PRMT5 was going to be an important target. So if you don't believe our lead program is really going to be important, that's a big problem. I think there were other sort of rumblings around that.

Well, maybe it's an important target, but Tango is way behind or it's an important market, but Tango is not going to have the money to compete against BMS. I think none of those things turn out to be true, right? It is a really important target. I think it's going to be a cornerstone of pancreatic and lung cancer therapy going forward. I think we are absolutely not behind. I actually think we're in the lead for a couple of different reasons we could talk about. And we have a lot of strong supporters. So I have no doubt we'll have the resources we need to do this.

Great. Really quickly, maybe touch upon capital allocation strategy for the balance of the year.

So I really strongly focused on the pancreatic cancer development plan because our plan based on the data that we expect to present later in this year will be to start our first pivotal study next year, and that will be a study -- a monotherapy study of 462 in second-line pancreatic cancer versus chemotherapy. And so that is our primary focus. And all of our -- we've made actually some changes at Tango to really make sure that our capital allocation is solely focused on that -- well, largely focused on that going forward.

Great. Well, thank you so much, Barbara, for being here today. And to everyone else on the line, thank you so much. Have a wonderful rest of your day.

Thanks for having us.