Tango Therapeutics Inc Aktie

Good day and welcome to the Tango Therapeutics conference call. [Operator Instructions] Please note this call is being recorded. I would like to turn the call over to Elizabeth Hicken, Vice President of Investor Relations. Please go ahead.

Thank you. Good morning, everyone, and thank you for joining us on today's call. This morning we issued a press release describing the data we will present at ESMO, 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 make forward-looking statements on this call that are subject to important 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 registration process and expansion strategy for vopimetostat and PDAC, 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. Since I joined Tango as CEO in January 2026, we have developed a clear mission to deliver vopimetostat to patients with pancreatic cancer as quickly as possible. In order to achieve that goal, we need to accomplish three things. First, build on the body of clinical data. The updated clinical data that we are sharing today and that will be presented at ESMO this weekend confirm what we believe to be an unprecedented and potentially best-in-class safety and efficacy profile. This strong clinical profile may be attributable to some of vopimetostat's unique properties that have created a favorable drug-drug interaction with daraxonrasib that has yielded impressive clinical activity and a safety profile that, to date, appears to be superior compared to that of single-agent daraxonrasib. We believe we are seeing a 1 plus 1 equals 3 type synergy with this combination, exceeding our expectations across all metrics.

Second, establish an innovative and efficient registration strategy. Based on recent FDA feedback, we are preparing to start a Phase 3 study for this combination in first-line pancreatic cancer. Our discussions with the agency were productive and collaborative, and we now have a study design that is ready to go. We are committed to starting the study in the first half of 2027. In addition, we plan to seek FDA's guidance regarding a possible accelerated approval for the combination in second-line pancreatic cancer patients. Lastly, to support these efforts, we need to grow and evolve our organization to execute against these goals. We have evolved the organization significantly from a pre-commercial CRO.

We have an experienced leadership team in place, and we are laser-focused on operational excellence and execution as we enter late-stage clinical development and become a pre-commercial organization. But that is not enough. While executing against our pivotal study in frontline pancreatic cancer is our primary goal, the data and evolving landscape, along with a strong biological rationale, position us to further advance novel scientific approaches into the clinic. We aim to begin these efforts studying the combination in MTAP wild-type pancreatic cancer, supporting our ambition for vopimetostat to be a PRMT5 combination partner of choice for any RAS inhibitor. Over time, this may create the potential to evaluate combinations beyond RAS and to extend the impact of the PRMT5 program into additional tumor types and treatment settings. Tango is well positioned to move into the next stage of vopimetostat development and to continue on the path to creating meaningful benefit for patients and value for shareholders. On today's call, we are primarily focused on pancreatic cancer, and so I wanted to set the stage and outline the opportunity here. In the United States alone, each year approximately 60,000 people are diagnosed with pancreatic cancer.

And approximately 40% of those patients harbor an MTAP deletion. As standard of care evolves, we believe the percentage of patients receiving treatment at each line of therapy will increase, with treatment options that have the potential for greater patient benefit without cytotoxic chemotherapy. On the call today, we are very pleased to have Dr. Brian Wolpin of Dana-Farber Cancer Institute join us to present the updated clinical data for this combination. Dr. Wolpin is the director of the Gastrointestinal Cancer Center at Dana-Farber and will be the lead investigator in our planned Phase 3 trial.

Excellent. Thank you, Malte, very much. I appreciate the opportunity to present the data on behalf of all of the investigators and the patients and the team at Tango. So, to start out with, to think about how the standard of care in pancreatic cancer is evolving, really historically this has been a disease treated with chemotherapy. And in metastatic disease, the vast majority of patients really had limited options, and these options generally were multi-agent chemotherapy. However, in recent months with the approval of now the first RAS inhibitor for patients with pancreatic cancer, in particular metastatic pancreatic cancer, we see that the landscape starts to shift toward a more targeted approach toward treatment of patients with this disease. Now I think really as the next step comes additional options to add drugs to RAS inhibitors to create even greater durability, higher response rates, and ultimately more benefit for patients facing this difficult disease. So this slide provides some of the mechanism as background to vopimetostat, which is an MTAP cooperative PRMT5 inhibitor. 30% to 40% of pancreatic cancers have a biallelic deletion in MTAP. This deletion leads to an accumulation of the substrate for this enzyme, MTA. MTA then binds to PRMT5 and causes a partial inhibition of PRMT5 function.

Vopimetostat as an MTAP cooperative PRMT5 inhibitor then has a selectivity toward further reduction in PRMT5 function in tumor cells, therefore providing a therapeutic window for treatment in cancer cells compared to normal cells. There is now substantial preclinical data looking at the combination of PRMT5 inhibition and RAS inhibition across a host of different models and different scenarios. You can see on the left our data in a PDX model of a cell line, as MTAP-null and KRAS G12V mutant. And you can see the benefit in this model to both vopimetostat and to daraxonrasib, but then really the appearance of a synergistic benefit with the two of them together. On the right, you see a similar type experiment, again, another cell line-derived xenograft model, again, MTAP-null, in this case KRAS G12D mutant. And you see data for vopimetostat and zoldonrasib, in this case a G12D-specific RAS inhibitor, again, showing similar results with an apparent synergistic effect between a RAS inhibitor and PRMT5 inhibitor in these cell line xenograft models. Today, we'll show data for vopimetostat + daraxonrasib.

We're going to focus on that aspect of the Phase 1 dose escalation trial. Additional data with zoldonrasib will be presented in the poster at ESMO. As you can see, these are patients with second or third-line treatment of metastatic pancreatic cancer, they must all have MTAP biallelic deletion and RAS mutation. You can see from the key inclusion criteria that MTAP loss was defined either by next-generation sequencing or by immunohistochemistry, ECOG performance status of 0 or 1, and no prior therapy with similar agents. On the right of the slide, you can see the dose escalation range with vopimetostat given at either 200 milligrams once daily or 250 milligrams once daily, and daraxonrasib administered at 100 milligrams once daily. We'll talk about 34 patients in the safety analysis, 27 in the efficacy analysis, with those patients defined as patients who had at least 14 weeks since the initial administration of the combination. And you can see in the bottom right that MTAP status was defined largely by next-generation sequencing and also with a smaller proportion by immunohistochemistry with very high concordance between these two methods for defining MTAP loss.

So if we now look at the baseline patient characteristics for those enrolled to the study, you'll see in the first column is vopimetostat and daraxonrasib in patients with pancreatic cancer. In the middle, you see vopimetostat and daraxonrasib in patients with non-small cell lung cancer. And in the rightward column, vopimetostat and zoldonrasib in patients with pancreatic cancer. You can see relatively common characteristics to what you would expect for patients with metastatic disease. I think most notably is that many of these patients had two lines of therapy already prior to enrollment on the trial. And then you can also see the KRAS mutation distribution at the bottom of the slide. And then finally, liver metastases are very common in patients with pancreatic cancer, and you can see the percentage, which is very much in line with most studies in this setting, with 70% to 75% of patients having liver metastases.

If we now look at the waterfall plot for vopimetostat + daraxonrasib, again in patients with MTAP deletion and a KRAS mutation, this is in the second and third-line setting. You can see at the top line the response rate is around 80%. If we look at the waterfall plot, you can see within the bars are the dose levels, dose level 1 and dose level 2. The arrows indicate those patients who are still on therapy receiving treatment. You can see the darker bars are the partial responses and the lighter bars are those patients with stable disease. You can see again that many of these patients, actually the majority, were receiving this treatment as their third line of therapy.

And you can see at the bottom an indication for each individual patient, a line of therapy for this treatment. And importantly, the median duration of follow-up has now increased from the last report up to around seven months. If you look in the upper right, among the 22 patients with metastatic pancreatic cancer, the objective response rate was 82%, disease control rate was 100%, and all of these partial responses are now confirmed. If we now add in the patients who had non-small cell lung cancer, so this is a very similar plot to the prior one, the main difference is that the five patients with non-small cell lung cancer are now also included in the waterfall plot. They are the patients with the additionally darker bars that you can see. And what we can see is that four of five patients with non-small cell lung cancer had an objective response to the combination. And you can see the now overall response among all patients of both pancreatic and non-small cell lung cancer, again, is over 80%.

If we now look at the swimmer's plot for vopimetostat and daraxonrasib, again, the top-line result is nearly 90% at a nine-month progression-free survival rate. Again, we can start to see now with larger time for follow-up really some durable responses. And with all of the arrows to the right of the screen, we can see that the swimmer's the bars, we can see many of these patients, nearly all, remain on therapy and have continued opportunity for further durability. And again, to emphasize, the majority of these patients are receiving treatment in the third-line setting. If we then look at the Kaplan-Meier curves, progression-free survival, these are divided into three different lines. We can see the second-line treatment as the blue bar at the top. The third-line treatment is in the red, and then the purple line is the combination, so meaning all of the patients together.

And again, we can see very few progression events thus far as follow-up begins to lengthen. And again, a nearly 90% nine-month progression-free survival rate across these patients. If we now look at the toxicity and the events that we see with vopimetostat and daraxonrasib, again, the top line is that these agents together were well-tolerated. We can see, again, similar format that on the left, in the leftward column, is dose level 1, so 100 milligrams of daraxonrasib and 200 milligrams of vopimetostat in patients with pancreatic cancer. The middle column, same doses, but now the patients with non-small cell lung cancer. And then to the right is dose level 2. So this is now an increase in the vopimetostat dose to 250 milligrams daily and daraxonrasib. Again, we can see no new safety signals compared to the prior report and that very few grade 3 events with most of the side effects that have been seen being grade 1 or 2 and no grade 4 or 5 events.

If we now look at the specific toxicities as graded by CTCAE criteria, we can see, I think, some notable signals here. One is that for rash, there's no grade 3 rash events. So the rash that is identified has all been grade 1 or 2. For stomatitis and mucositis, no grade 3 events, and the events that have been identified were grade 1 or 2. We can also see that the only grade 3 events at dose level 1 were related to blood count suppression, anemia, and thrombocytopenia. We can see as we get to dose level 2, some increase in rash and stomatitis mucositis as one might expect with greater exposure to a RAS multi-inhibitor. And then again, no grade 4 or 5 treatment-related adverse events and a relatively low incidence of gastrointestinal side effects also, including nausea, vomiting, or diarrhea. If we then look at this in a way that is structured to think about some of the toxicities we see with pan-RAS inhibitors, again, we can see that stomatitis, mucositis, and rash are at lower levels than have been seen previously, and there's no grade 3 events, and again, the gastrointestinal toxicities also are relatively modest without grade 3 events.

To the right, you can see that the PK data, which we'll see on the next slide, for daraxonrasib in the combination, demonstrates that at the dose of 100 milligrams once daily, there's a very similar area under the curve as with single-agent daraxonrasib at 300 milligrams daily, which has been the dose that is now FDA approved in patients with metastatic pancreatic cancer. These are now the formal PK curves that you can see, and again, very stable, appropriate PK properties as has been shown previously for both daraxonrasib and vopimetostat now in the combination. So I'm going to pass this on to Dr. Crystal for the next part of the presentation.

Thank you, Dr. Wolpin, for joining us this morning and for your leadership in helping advance this combination toward pivotal development. As this data set has matured, the results have become increasingly compelling and the potential to transform the treatment of pancreatic cancer has become clear. These data validate that the addition of vopimetostat to daraxonrasib results in a marked improvement in overall response rate, to an impressive confirmed overall response rate of 82% in a mixed population of third-line and second-line patients. Perhaps more importantly, the potential durability of the combination is now apparent.

Across all patients, the median PFS has not yet been reached. The nine-month landmark PFS rate is 88%, and in seven second-line patients, zero progressions have been observed. Critically, with longer follow-up, the evidence that adding vopimetostat may improve the tolerability of daraxonrasib has become even more compelling. At dose level 1, we have observed no grade 3 or higher related rash or stomatitis. In addition, rates of rash, nausea, vomiting, and diarrhea are at least 20 percentage points lower than those reported with daraxonrasib 300 milligrams single agent. The dose reduction rate is also 20% lower than reported with daraxonrasib alone. Of course, these are cross-trial comparisons, and we recognize their limitations.

Nevertheless, the magnitude and consistency of the differences across the dataset are encouraging. Ultimately, what matters to patients is the clinical profile of the combination. However, we also have a compelling biologic hypothesis that may explain why combining two active anti-cancer agents could actually improve tolerability. Preclinical findings demonstrate that PRMT5 inhibition can increase MAP kinase pathway signaling, including [ phospho-ERK ]and MTAP wild-type cells. We hypothesize that this effect may partially counteract RAS inhibitor-mediated suppression of MAP kinase signaling in normal tissue, potentially explaining some of the improved tolerability we're observing clinically. We also believe that the lower oral dose of daraxonrasib, 100 milligrams rather than 300 milligrams, may contribute to the improved gastrointestinal tolerability. This, of course, cannot explain the change in systemic effects like rash, given that the exposure of daraxonrasib is equivalent to the 300 milligram single agent dose.

Importantly, what initially appeared to be a pharmacokinetic challenge, the DDI, may actually prove to be an advantage, contributing to a differentiated and potentially best-in-class clinical profile. Taken together, the PK, efficacy, durability, safety, and tolerability data give us increasing confidence that we have substantially de-risked the clinical development path for this combination. In the first half of 2027, we intend to launch a pivotal study in patients with MTAP-deleted pancreatic cancer in the frontline setting. The design of this study reflects both the strength of the clinical data set and our highly collaborative and productive interactions with regulatory agencies. We believe these discussions have helped establish a clear path toward pivotal development with shared recognition of the significant unmet need in pancreatic cancer. We are planning for the Phase 3 study to be a global randomized control trial evaluating 200 milligrams of vopimetostat plus 100 milligrams of daraxonrasib once daily versus standard of care chemotherapies. The dual primary endpoint of this study are overall response rate and progression-free survival with overall survival as a key secondary endpoint.

The study is anticipated to enroll 484 patients. In addition to the pivotal study in first-line MTAP-deleted pancreatic cancer, our first priority, we also intend to explore the possibility of an accelerated approval in second-line pancreatic cancer, which could be done through a small Phase 2 study, which would also allow us to assess contribution of components. We plan to discuss this further with the appropriate regulatory authorities. Together with the clinical data we announced today, we believe this development strategy will solidify our lead and position vopimetostat plus daraxonrasib as the first-in-class PRMT5 plus RAS inhibitor combination. The underlying biology led us to predict that combining PRMT5 and RAS pathway inhibition would produce synergistic anti-tumor activity. Emerging clinical data in pancreatic cancer have now provided compelling validation of that hypothesis, demonstrating not only remarkable anti-tumor activity, but also an unexpected improvement in tolerability compared with RAS inhibitor alone. We believe this combination of efficacy and tolerability creates an opportunity well beyond our initial indication, including in MTAP wild-type pancreatic cancer.

Critically, preclinically, PRMT5 inhibition is synergistic with RAS pathway inhibition, regardless of MTAP status. Although vopimetostat was designed to selectively inhibit PRMT5 and MTAP-deleted tumors, our data, some of which are shown here, demonstrate meaningful PRMT5 target inhibition, and are in MTAP wild-type cells at exposures achieved with the 200 milligram dose used in dose level 1. Importantly, we believe these findings establish the pharmacologic foundation for extending the synergy between PRMT5 and RAS inhibition beyond MTAP-deleted cancers. The critical question is, then is whether vopimetostat can inhibit PRMT5 sufficiently in MTAP wild-type tumors to enhance the activity of daraxonrasib or other RAS inhibitors. To answer that question, we evaluated the combination across 12 MTAP wild-type KRAS mutant pancreatic cancer cell lines using concentrations of vopimetostat achieved in our clinical dose of 200 milligrams. In each of these models, vopimetostat enhanced the anti-tumor activity of daraxonrasib. The graph on the right summarizes these findings, comparing the activity of vopimetostat alone to daraxonrasib alone, and the combination across all 12 models. Together, these data demonstrate that vopimetostat at clinically achievable concentrations consistently potentiates the activity of daraxonrasib in MTAP wild-type pancreatic cancer models.

In the first half of 2027, we intend to evaluate vopimetostat in combination with a pan-RAS inhibitor in approximately 25 to 30 patients with MTAP wild-type pancreatic cancer in the second-line setting. This study will test whether the compelling clinical activity we've observed thus far in MTAP-deleted pancreatic cancer can extend to patients whose tumors retain MTAP activity. A positive proof of concept result could open the door to developing the combination across the broader pancreatic cancer population while also supporting exploration of similar strategies in other cancers, including MTAP wild-type non-small cell lung cancer. This represents a capital efficient opportunity to test a hypothesis with the potential to substantially expand the population of patients who could benefit from PRMT5-based combination therapy. We're the potential to pursue this study within our existing collaboration with Erasca. With that, I'll turn it over to Matt to walk through our upcoming catalysts and financial highlights.

Thanks, Adam. 2026 has been a transformative year for Tango, and we have many meaningful catalysts ahead of us. Staying with pancreatic cancer, before the end of the year we plan to initiate our combination study with Erasca, and with the evolving landscape of pure MTAP inhibition and the multitude of opportunities it may provide, we are pleased to soon have multiple clinical combination studies underway that will enable us to learn more about the power of this combination approach and where different agents may fit into the treatment paradigm. As we turn to 2027, we plan to launch our proof of concept study in MTAP wild-type patients in the first half of the year. And most importantly, also in the first half of '27, we plan to launch our Registrational Study in First-line PDAC that Adam outlined earlier. Beyond pancreatic cancer, we are excited by the additional clinical data still to come with both vopimetostat lung cancer monotherapy, as well as with TNG456, our brain penetrant PRMT5 inhibitor, which we are studying in lung cancer and glioblastoma, as well as other tumor types. We believe those data and our developments in cancer are going to be very, very important. Strategies in both lung cancer and GBM could be meaningful value creation opportunities for Tango. In order to fully inform our strategy, we made a decision to enroll additional lung cancer patients in our study with TNG456.

These data will take a little longer to mature but are critical to our development strategy, and we intend to provide these data sets and our go-forward development plans at an investor conference in January. With so much opportunity to create near-term value for shareholders and patients with vopimetostat and TNG456, we have made a decision to heighten the focus of our efforts on these two lead programs and devote our resources to accelerating and expanding their clinical impact. To support this focus, we have made the decision to stop certain preclinical and research activities and dedicate our resources to our PRMT5 portfolio. We believe that these opportunities offered by these programs will benefit from our full attention and fully dedicated resources. Our ambitions are supported by a strong balance sheet, and we have a disciplined approach to capital allocation that allows us to efficiently de-risk the clinical hypotheses that Adam laid out while retaining financial capacity to accelerate our lead programs. I'll now turn it over to Malte for closing remarks.

Thanks, Matt. The clinical data for this combination that we first disclosed in June and now updated today has been a tremendous catalyst for Tango on several fronts. I believe that vopimetostat has the potential to be a novel treatment component for patients with pancreatic cancer in the near future. First, since those initial data, we have been laser-focused on getting this combination to patients, engaging with regulatory authorities, designing the clinical development plan, and building the organization to prepare for late-stage clinical development and commercialization. I'm tremendously proud of the team at Tango for what has been accomplished so far. This is important progress in our journey that has the potential to have tremendous impact for patients with pancreatic cancer. Second, the power of the combination and the 1 plus 1 equals 3 level of synergy we are seeing in MTAP-deleted pancreatic cancer has opened up a multitude of possibilities for vopimetostat as a backbone of cancer therapy, potentially across multiple cancer types. The first area we plan to evaluate is in MTAP wild-type pancreatic cancer, and we look forward to, in the future, sharing more details about our aspirations beyond pancreatic cancer.

Third, the early success of our PRMT5 programs and the opportunities we see ahead with vopimetostat and TNG456 have led us to focus our organization solely on those programs. Both vopimetostat and TNG456 were invented by the drug discovery team at Tango, built by our own medicinal chemists, brought all the way to the clinic by our team here. So it is with that acknowledgement of this potentially paradigm-shifting work in drug development that I extend my gratitude to the research organization at Tango and all who have contributed to it, past and present. I want to close by thanking the patients and their families who participated in this study, clinical investigators, as well as employees and partners who have worked tirelessly to get us to this inflection point. This is a very exciting time for the advancement of treatment for pancreatic cancer, and all of us at the company are united on our mission to bring life-changing treatments to patients. Operator, let's start Q&A.

Thank you. [Operator Instructions] Our first question comes from Eric Schmidt with Cantor. Your line is open.

Thank you and congrats on some truly exceptional data. This is going to be life-saving, changing for many, many patients, that's very clear. Maybe two questions for me. First in terms of the collaboration with Revolution Medicines, is there going to be a supply agreement for the Phase 3 study? And then second, as per your agreement with the FDA, on that first-line study. Could you talk a little bit about what exactly you'll need from either ORR or PFS or even in survival in order to file for approval? Thank you.

Yeah, thanks, Eric. Thanks for your kind words. For the supply agreement situation, we have an existing supply agreement for the ongoing studies. We do not have a supply agreement for the Phase 3 study that we mentioned. RefMet and Tango are discussing at the moment topics that deserve resolution between the two companies. And it's our interest here at Tango to figure out the fastest way possible to bring the combination forward and to achieve a regulatory approval. So that's very important for us here, and that clearly includes the continuation of the work with RefMet, but includes also other options. For the second part of your question, can I turn it over to Adam?

Absolutely. Yes. So the second part of your question was after our interactions with the FDA, what are we needing to see in terms of primary outcomes to achieve a regulatory approval? We haven't disclosed the details of our statistical analysis plan. And those are not details that we intend to share for a number of reasons. But a little bit of detail can be inferred from the details of the study design that we did share. A couple of notable pieces are that the primary readouts, the primary endpoints are overall response rate and progression-free survival, while the overall survival is a key secondary endpoint. There are implications of those and there may be opportunities to register on either of those primary endpoints. The second important piece of information that we did share in this head-to-head 1-to-1 study is the number of patients, which is 484 patients. And we are confident that the study as designed with those number of patients will give us adequate power to readily detect the signal required for approval.

Thank you. Our next question comes from Laura Prendergast with Stifel. Your line is open.

Hey, guys. We got some exciting updates. Can you provide more color on the DDI, particularly as early as two weeks? Seemingly to act more at the level of bioavailability than clearance. And then also, there's been some recent dialogue in the RAS inhibitor space, particularly regarding oral [ tox ].

You broke up entirely with the second part of the question. We simply couldn't hear it. Why don't I answer the first part of the question first and then give you an opportunity to react to the second part? Regarding the DDI, to start with the very important high-level details, we know that vopimetostat is a moderate CYP3A4 inhibitor and anticipated that it would increase the exposures of daraxonrasib in a manner similar to that which we observed. It increases the exposure approximately threefold, meaning that the exposures we achieved in terms of key PK parameters, including AUC, are very similar to daraxonrasib 300 milligram single agent. It also has no more variability than daraxonrasib single agent. There are many details important around this DDI. One could speculate, and it is reasonable to, whether this is absorption mediated or clearance mediated. It stands to reason that as the half-life is unchanged, much of this is probably not clearance mediated. Beyond that, the details are best spoken to by a clinical pharmacologist. Can I ask you to please re-answer the second part of your question?

Re-answer the second part. On the road, sorry if I was breaking up a bit. Yes, we were just referencing, there's been some dialogue in the RAS inhibitor space regarding the connection of oral RAS inhibitors to GI tox. Is there anything you can point to that you find particularly externally validating of this thesis?

There are a couple of pieces of information that I think are interesting. One is that, you know, we have not generated data on our own, but we have heard that the IV administration in dogs, for example, of RAS inhibitors can result in emesis and vomiting. So it may be a systemic effect in addition to or rather than a local GI effect. Again, not our data. It's speculation on my part. But I do think it's straightforward to envision that delivering 300 milligrams of any drug could result in local toxicity, nausea, vomiting and diarrhea resulting. And entirely consistent that giving a third of that dose to the GI tract would result in less nausea, vomiting, and diarrhea.

Got it. Thank you very much.

Thank you. Our next question comes from Andrew Berens with Leerink. Your line is open.

Hi, thanks and congrats on the quite stunning data. Maybe a couple questions from me. Adam, can you give a little more color on the scientific rationale for using our PRMT5 agent in the MTAP wild-type setting? And would you expect the results to be as dramatic in these patients without a loss of function? And then I guess, can you also give us some color on the toxicities that and other PRMT5 inhibitors that are CNS penetrant are seen. That [indiscernible] avoids?

Sure. Regarding wild-type, we certainly acknowledge that it is in some ways counterintuitive to the reason that MTAP cooperative PRMT5 inhibitors have been developed. But I also think that the data support that is a clinical experiment that has a likelihood of succeeding. Effectively, the first piece to recognize is that the synergy between RAS inhibition and PRMT5 inhibition is present regardless of MTAP status. So in MTAP wild-type cells, if you inhibit both of those targets efficiently, there is every expectation that they would be equally synergistic. However, with an MTAP wild-type cells, we are hitting PRMT5 less hard. But because the combination is so well tolerated and because we have data clinically that we are exerting pharmacologic activity on PRMT5 in MTAP wild-type cells, we ask the question if we are modifying PRMT5 enough to increase the activity of daraxonrasib. And we did not know what the answer to that question might be before we did the preclinical experiments.

But the preclinical experiment that we showed across 12 cell lines demonstrates clearly that it does increase the activity. The degree to which that will happen, if I had to predict, might be more measured than the increase of 32% to 82%, which we observed in deleted tumors. However, there is still a wide range of potentially positive results that could be detected with the capital-efficient technology expansion arm of this study.

The second question was, I think, regarding the tox profile of other PRMT5 inhibitors. I think we can elaborate a little bit what we know.

Yes. So in order to talk about the tox profile of other molecules, I'll talk about the tox profile of our molecule first. It's very well tolerated as single agent. As single agent, the rate of dose reduction at 200 is about 10%. We see on-target toxicities of anemia, fatigue, thrombocytopenia, low grades of nausea, vomiting and diarrhea. I think it's fair to say that it is well tolerated and an easy side effect profile to manage. It is differentiated from other molecules. If one compares the profile to the lead competitor, navlimetostat. Navlimetostat has a rash signal. It is a low-grade rash, but it is present.

Navlimetostat has a little bit more GI. And I think it will be interesting to see the safety profile of that molecule in combination with RAS inhibitors where GI tox and rash are so important. The other highlight I would point to, which we believe will become increasingly important over time, are the difference between PRMT5 inhibitors, which are brain penetrant, and those which are not. When one looks at the safety profile of brain penetrant molecules, you often see a real signal of dizziness and or confusion. This is not overwhelming. It tends to be grade 1, but it is present. And we believe this will differentiate non-brain penetrant molecules like vopimetostat from the emerging molecules which tend to be brain penetrant. The final thing that I'll say there is that we see very little benefit to CNS activity of our molecule in pancreatic cancer because CNS metastases are very rare, effectively in less than 1% of patients. So if there is a CNS tox signal of other molecules, it could be a liability in pancreatic cancer.

Okay. Thank you. And just one more maybe. I know at this meeting we have seen a number of competitors and some of them have pretty large data sets. How far ahead of some of these other agencies do you think you are in PDAC with the daraxonrasib combos at this point?

I think, you know, when you think about, when we started our combination study between vopimetostat and daraxonrasib, start was in end of June last year. I think we are minimum 12 months ahead of other combinations in the field. That's why I think we are very happy of having such an advanced data set. That's the foundation of today's presentation. And that also contributed to the fact that we have made really good progress in discussing the way to registration with FDA. And we are beginning discussions with other regulatory agencies around the globe. So, I think we are determined to keep the headway attractive for patients and for Tango, to be honest, and we're looking forward to starting the first-line study as we outlined earlier in the first half of 2027.

Right. Well, thanks and congrats again. Appreciate it.

Yes, thank you, Andy. Thank you.

Thank you. Our next question comes from Brian Chang with JPMorgan. Your line is open.

Hey guys, congrats on the data and thanks for taking our questions today. You know, just first, I wonder if you can comment a little bit more about the durability response here. The PFS curves look a lot more stable than the RAS alone in the second line back in the RAS 302 study. Curious how we should think about the durability of response over time and how we should think about that in the second line and eventually in the front line. And then second question just related to the partnership side. At this juncture as we think about your partnerships with RefMet and Erasca, how do you prioritize each one today and I'm moving forward that your combo strategy is pretty clear laid out with their RAS(ON) asset. Thank you.

Yes, you want to speak to the durability?

Yes, I would say, as you know, not not easy and straightforward to compare across data sets. However, I would say here the durability does look notable compared to what we see, whether it's with daraxonrasib alone, whether it's with chemotherapy, really against any of the prior treatments we've had available. Certainly that seems true in the second-line setting, where again there were not progression events thus far with the follow-up that's available. But also in the third-line setting, which generally is a very aggressive disease, with third-line pancreatic cancer, so to see that degree of durability with the combination in third-line patients also, I think, is notable. And obviously more follow-up will occur, but those, I think, are notable data thus far starting to show the durability for these individuals, most of which you are still on therapy.

Yes, thanks, Brian. And to your second question, Brian, with respect to the partnership, between Tango and RefMet and Erasca, I think, we are very happy that we are working with the two leading companies in the field of RAS inhibition. That's that was clearly, a very good decision on Tango's end to enter collaborations with these two companies. We are super happy where we are and with respect to the headway we have for the RefMet and Tango collaboration. That's the foundation of today's presentation, as said earlier. But we think Erasca is a very attractive molecule as well. There are probably going to be more data released soon. Adam spoke to the fact that the wild-type hypothesis, for example, is a moment of intensifying our collaboration with Erasca and there may be other opportunities as well.

So right now we are happy that we are collaborating with these two companies and we intend to pay a lot of attention of moving forward with these collaborations.

Great, thank you and congrats again.

Thank you, Brian.

Thank you. Our next question comes from Kelsey Goodwin with Piper Sandler. Your line is open.

Hey, guys, thanks so much for this call, and congrats on the update. That's great. I just have two questions. First for Dr. Wolpin, in practice, can you just remind us what the current turnaround time is for MTAP deletion testing? And then second, for the company, I think building on the last question with the combination plus [ ERAS-0015 ], I guess just kind of given where you stand with that combination and the fact that it's about to start, could you realistically run a Phase 3 trial plus 0015 in the front line? How do you think about that, just given kind of the dynamics of the evolving PDAC space? Thanks so much.

I can take the first part. Thanks for the question. So for patients with first-line metastatic pancreatic cancer, we generally try to obtain data from three sources, one of which is we commonly do circulating tumor DNA to rapidly get mutation status and also copy number data from that. That usually has a turnaround of about seven to 10 days. We also do tumor-based testing in two different ways. One of which is with next-generation sequencing. And then at my own institution, Dana-Farber, we also do immunohistochemistry testing on all new patients with pancreatic cancer, for MTAP as a part of our sort of diagnostic workup at this point. So as you know, immunohistochemistry has a quite rapid turnaround, right, within a couple days, few days.

You can get that information. And next-generation sequencing tends to be in the approximately two-week kind of time frame. So generally within one to two weeks, we have data that we can use for both RAS mutation status and for MTAP deletion status. So thanks for that question.

And, Kelsey, to your second question of whether or not we can start, a Phase 3 study with the, Erasca molecule as a combination partner. The answer is theoretically entirely yes, but I want to point out again the fact that we have made extremely good progress for the daraxonrasib and vopimetostat combination. Our discussions with FDA regarding the frontline study design were based on the data that we have shared today. So I would say we are ahead of the curve with the daraxonrasib, vopimetostat combination. But in theory, it's totally possible to start a Phase 3 study with vopimetostat and ERAS-0015 as a combination.

Okay, great. Thank you so much, and congrats again on the consistency of the data. That's really great.

Thank you. Yes, thank you.

Thank you. Our next question comes from Michael Smith with Guggenheim Partners.

Hi guys, thanks for taking my questions. Maybe just one more on the data. I noticed there was really no difference in response rate in the second or third-line patients, so in the mid-80s for both cohorts or both subsets. Is there something going on there or do you think that's coincidence given the small sample size. And then I had a question on the Phase 3 study. Anything else that's gating to starting the Phase 3? I'm just wondering, you know, the start next year, is it just purely operational to get the study up and running at this point, or do you still need to see some of the frontline PDAC data before commencing the study, and how fast do you think you could reach this possible ORR analysis in the Phase 3? Thanks so much.

So the question regarding the overall response rate in second and third-line patients, they very similar. We are at very high numbers and perhaps it's hard to differentiate 80 from 85 when you're in that range. I do think it's fair to say it works very well in both second and third-line patients. It is interesting to note the response rate of single agent daraxonrasib across the line, 20% in third line plus. 32% to 33% in second line and 47% in front line. We're sitting at about 80% in second and third line. One could postulate it might be higher in front line.

And you see hints of that in the PFS curve, where although they are small numbers, we have had three progression events in third-line patients and zero in second-line patients. If that trend continues, it's interesting to speculate how good a frontline Kaplan-Meier curve could look like in the eventual future. For the second question, I'll go back to Malte.

Yes, so with respect to the gating factors, I think it's fair to say that the main factor is really operational execution right now. So we have clearance from FDA regarding the protocol design as we mentioned earlier. So the clinical operations team are a lot under the microscope here at Tango and they're working day and night to get this off the ground. To start a Phase 3 study is a complex undertaking.

We're running this study in three geographies, in the United States, in Europe, and in Asia Pacific. So all of this needs to be orchestrated. And we don't need any frontline data in pancreatic cancer to start the study. So that's, with respect to your last question of when we could potentially have an overall response rate in that study, we haven't really spoken about our forecasting or timelines of when certain endpoints would become available. FDA doesn't really like the companies being ahead of themselves of sharing forecasts and sharing details of, you know, when data will become available. So stay tuned Michael and we will share of course you know how good the progress is we make and we will share with the public of when we intend to approach FDA for meaningful discussions evaluating these endpoints.

Maybe just as a quick follow-up, I guess in that context, does it even make sense to run a second-line study at this point, given that you might have an interim readout on the frontline study at some point?

I think we have a window of opportunity here for the second-line space. I don't know, I don't know, Brian can maybe also add to this. I think it depends, of course, on the timing of when a second-line approval would occur, right? Eventually, that window would close and the attractiveness of a second-line approval would go away. But right now, we believe that patients would benefit from a combination and second-line. I don't know, Brian, if you want to add.

Yes, sure. So I do think there are opportunities in the second line to improve what we're doing. I think the data for daraxonrasib have been really important to the field and important to patients. But there is still substantial room there for improvement and greater durability of responses. Also, certainly if it came with less side effects with treatment, that's a benefit to patients too. So I do see certainly a window of opportunity to improve care for patients in the second-line setting. And I think that that would be valuable to patients and to their treating providers.

Thank you.

Thank you. Our next question comes from Alethea Young with William Blair. Your line is open.

Hi guys, thanks for taking my question. Congrats on these data this morning. One for Dr. Wolpin. I guess, you know, these different grades, like when it's like grade 1, 2, I feel like not all grades are created equal. So I was just wondering if you could give us some color, like maybe on like, you know, even the grade 1, 2 events you're seeing in the combo versus like what you see with daraxonrasib itself. And my second question for the company is, you know, obviously, like, when you think about the totality of your announcements today, you know, it seems you're certainly centralizing upon at least three indications and all in on pancreatic cancer. So can you talk a little bit about how these data increase potentially your confidence and what you're doing in glioblastoma and non-small cell, which have data?

Events this year as well? Sure, thank you for the question. So I would say overall we certainly see a shift towards less high-grade toxicities with a combination. Again, we do have to keep in mind these are still small, relatively small data set. We now have quite large data sets with daraxonrasib. So the estimates there are a bit more stable. However, I would say we do see a shift towards less high-grade toxicity events. As you said, CTCAE is not, you know, being in front of a patient that you really only can do when you're, you know, taking care of patients. But I would say that these are less high-grade, and that really has been across the toxicities that have been most difficult in patients receiving daraxonrasib so far, right, particularly rash, mucositis, and then some of the gastrointestinal side effects too.

And obviously, I think this will be important as we go forward, not just for combinations with daraxonrasib. Some of these are class effects with RAS inhibitors. So seeing less toxicity, I think, will be beneficial to patients and providers.

And your second question, I think you are spot on in saying that we certainly have a reason to have increased confidence in the entire franchise and the entire portfolio of PRMT5 inhibitors. We are very happy that we have two big focus areas. One is in pancreatic cancer where we concentrate the development on the vopimetostat, daraxonrasib and Erasca combinations and the second area is clearly in non-small cell lung cancer and glioblastoma. For lung cancer, as Matt alluded to earlier, we're going to share our development plans and ideas in January of 2027 and it will involve both TNG456 and vopimetostat. So we think we have a pretty good idea of how we develop these molecules and we, and the confidence here at Tango is very high that we will make meaningful contributions for patients not only with pancreatic cancer but also with lung cancer and other tumors.

Just one quick follow-up. Is there anything to make of the combination data with lung? I know it's a very small number, but is there anything to think about there?

I think it's a very small number, but it's consistent with what we've been seeing with pancreatic cancer. The combination works better than either single agent. I think it is notable that four of five patients had confirmed responses. The fifth was a stable disease with, I think, minor shrinkage, 26%. All of those patients, it's fair to say seem to be benefiting from the drug. That's in contrast to single-agent daraxonrasib, which has a response rate of about 40% in a comparable group of non-small cell lung cancer patients. The other thing that I would say is that lung cancer is very different from pancreatic cancer in one critical way, which is that there are multiple different oncogenic drivers.

It's almost universally RAS in pancreatic cancer, but in addition to RAS, as we know in lung cancer, EGFR, ALK, and other kinases are important. One important scientific fact to recognize is that this synergy observed with RAS inhibitors isn't best thought of as a RAS synergy. It's probably best thought of as a MAP kinase pathway synergy. And it's our expectation, based on our preclinical data and others, that it would translate beyond the RAS inhibitor space to combinations with, for example, EGFR or ALK inhibitors.

Thank you. Our next question comes from Maury Raycroft with Jefferies. Your line is open.

Hi, this is James on for Maury. Congrats on the update and thanks for taking our questions. Going back to the data, can you provide more detail on the 40% dose interruption and 20% dose reduction rates at dose level 1, including the duration of interruptions and whether the modifications involved both daraxonrasib or vopimetostat? And the doses to which patients were reduced, and are you seeing any effect from the reductions and interruptions on the magnitude of tumor reductions or duration response? Thanks.

Sure. So the second part of the question, the answer is no. It would be hard for it to be yes, but there's an implication on the duration of response nearly all of the patients are benefiting. It's hard to stratify further. In terms of the dose reduction, there have been five at dose level 1. The majority of those were for rash or cytopenia. In some cases we dose reduced daraxonrasib, typically from 100 to 80 milligrams. And in some cases, we dose reduced vopimetostat from 200 to 150 milligrams. One important point I would note is that all of those doses are in the efficacious dose range.

So where we resulted in those cases was with both an effective dose as well as one which was more tolerable. And those patients restarted without further complication.

Thanks. And just one really quick one. For the potential accelerated approval path and second-line PDAC, have you already discussed the specific approach to the FDA already? And has the FDA indicated whether a single-arm study based on response rate durability, for example, could support approval or whether a randomized design would be required? If those discussions have not heard yet, when do you expect to meet with FDA and discuss the Phase 2 designs?

So we did not have the detailed discussion as you just mentioned. We, we mentioned to FDA that we would be interested in a detailed discussion, a follow-up discussion on the second-line accelerated approval pathway, and we are going to have a separate discussion with the agency on that topic, but the agency indicated that they are very happy to have that discussion quite soon, so we're looking forward to follow up with the agency on these ideas and and then as soon as we are in the position, we can update the public about how that how that discussion went.

Thank you. Congrats again. Thank you. Thank you. Our next question comes from Yuan Zhi with B. Riley. Your line is open.

Well, congrats on this strong durability data. My first question is, in this vopimetostat plus daraxonrasib PDAC cohort, it appears that there are no G12D patients. Do you anticipate the durability and ORR to be consistent between G12D patients?

And G12D patient? Do you want to take this, Brian?

Sure. Yes, thank you for the question. So I think as you saw from the design, that was mostly to allow for sufficient patients with G12D mutations to receive the zoldonrasib or vopimetostat combination. I think for the daraxonrasib combination, I would suspect we will see, although we obviously will need to see this in patients, but I would suspect we would see similar results. There really is not a biologic reason to suspect that the combination would perform differently in KRAS G12D mutant patients than it would in those that have a G12V mutation or other. So I would suspect we will see similar things, and that will have to play out in the future studies.

I think one additional comment we could make is that we have enrolled and treated six patients with G12R, which are notoriously very difficult to treat, and we've seen a lot of. 50% of these patients responding to the combination, which is a very encouraging sign, I think.

Got it. Although we don't have any clinical data, what would you expect when you compare vopimetostat plus daraxonrasib versus combining daraxonrasib at 300 milligrams with another PRMT5 inhibitor which has no drug interaction boost there?

Sure. As you point out, it is hypothetical. We have the data you've seen today and there's no data available for any other combination. I think that the efficacy we observe would fairly be expected to be seen with any other very good PRMT5 inhibitor. I think there are subtleties around the degree to which we hit target and the safety profile, which may play out to be differentiating, potentially positively differentiating, but again, data will prove that out. I think the first molecule we may see combination data for would would be navlimetostat. What I would point to there, I do not expect that there will be a meaningful DDI. My expectation would be that they'll be able to reach either 200 or 300 milligrams of daraxonrasib.

And I think that the efficacy will be comparable, would be my guess. I think there are a lot of question marks. Will the higher dose of daraxonrasib result in more GI tox? And will the little bit of a skin signal with navlimetostat carry over into the combination to result in problematic overlapping toxicity?

Thank you for taking our questions.

Thank you.

Thank you. And our last question comes from John Newman with Canaccord Genuity. Your line is open.

Good morning and let me add my congrats on the really strong and impressive data here. Definitely, as Eric said, a big benefit for pancreatic cancer patients. My question is, in terms of the doses that you would look to test for the MTAP wild-type study, I'm just curious if they would be similar to what you've tested in the past pancreatic cancer thus far. Thanks.

The very straightforward answer to that is it would be the same dose. We believe that this combination dose is the ideal dose to bring forward in development and that would be the same for MTAP wild-type. One of the reasons we expect that experiment to be rather fast to what could be a meaningful path.

Great. Thank you.

Thank you. This concludes the question and answer session. I'd like to turn the call back over to Malte for any further remarks.

Thank you. No further remarks from our end. Thank you to all the participants for asking questions and for following our call. Thank you very much.

This concludes the program. You may now disconnect. Good day.

This live transcript is auto-generated without human intervention or review.

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.