Good day, and welcome to the Tango Therapeutics Conference Call. At this time, all participants are in listening mode. After the speakers' presentation, there will be a question and answer session. To ask a question, you will need to press star one one on your touchtone telephone. Please note this call is being recorded.
I would like to turn the call over to Liz Hickin , 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're 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 and expansion strategy for vopimetostat and PDAC. 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, confirms 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 one plus one equals three type synergy with this combination, exceeding our expectations across all metrics. Second, establish an innovative and efficient registrational strategy. Based on recent FDA feedback, we are preparing to start a phase III 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 [audio distortion] since I became CEO.
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. 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 metastatic 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 toxic 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 III trial. Dr. Wolpin?
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. 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. 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. This slide provides some of the mechanism as background to vopimetostat, which is an MTA-cooperative PRMT5 inhibitor. 30%-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 MTA-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 that is MTAP null and KRAS G12D mutant, and you can see the benefit in this model to 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 plus daraxonrasib. We're going to focus on that aspect of the phase I 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 a 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 zero or one, 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 mg once daily or 250 mg once daily and daraxonrasib administered at 100 mg once daily. We will 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. 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. If we now look at the baseline patient characteristics for those enrolled to the study, you will 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. You can also see the KRAS mutation distribution at the bottom of the slide. 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%-75% of patients having liver metastases. If we now look at the waterfall plot for vopimetostat plus 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, the line of therapy for this treatment. 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. What we can see is that four of five patients with non-small cell lung cancer had an objective response to the combination. 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 swimmers 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. With all of the arrows to the right of the bars, we can see many of these patients, nearly all, remain on therapy and have continued opportunity for further durability. 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 for 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 the purple line is the combination, meaning all of the patients together.
Again, we can see very few progression events thus far as follow-up begins to lengthen. 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 mg of daraxonrasib and 200 mg of vopimetostat in patients with pancreatic cancer. The middle column, same doses, but now the patients with non-small cell lung cancer. Then to the right is dose level 2. So this is now an increase in the vopimetostat dose to 250 mg daily and daraxonrasib at 100 mg daily.
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. Similar 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. Then again, no grade four or five 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. 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 mg once daily, there's a very similar area under the curve as with single-agent daraxonrasib at 300 mg 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. Again, very stable, appropriate PK properties, as has been shown previously for both daraxonrasib and vopimetostat now in the combination.
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 clearer. 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 mg single agent. The dose reduction rate is 20%, also 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. Pre-clinical findings demonstrate that PRMT5 inhibition can increase MAP kinase pathway signaling, including phospho-ERK in 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 mg rather than 300 mg, 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 mg 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 III study to be a global randomized controlled trial evaluating 200 mg of vopimetostat plus 100 mg 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 II 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. The 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, pre-clinically, PRMT5 inhibition is synergistic with RAS pathway inhibition regardless of MTAP status. Although vopimetostat was designed to selectively inhibit PRMT5 in MTAP-deleted tumors, our data, some of which are shown here, demonstrate meaningful PRMT5 target inhibition in MTAP wild-type cells at exposures achieved with the 200 mg 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 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 mg. 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, 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- 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. This represents a capital-efficient opportunity to test our hypothesis with the potential to substantially expand the population of patients who could benefit from PRMT5-based combination therapy. We are particularly excited about the potential to pursue this study within our existing collaboration with Erasca.
With that, I will 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. With the evolving landscape of PRMT5 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. Most importantly, also in the first half of 2027, 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 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 development 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 datasets 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 will 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 am 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 one plus one equals three 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 an 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 medical chemists, and brought all the way to the clinic by our team here.
It is with that acknowledgment 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 in our mission to bring life-changing treatments to patients.
Operator, let's start Q&A.
Thank you. If you'd like to ask a question, please press star one one . If your question has been answered and you'd like to remove yourself from the queue, press star one one again. 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-changing for many, many patients. That is very clear. Maybe two questions from me. First, in terms of the collaboration with Revolution Medicines, is there going to be a supply agreement for the phase III study? Second, as per your agreement with the FDA on that first-line study, could you talk a little bit about what exactly you will 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 III study that we mentioned. RVMD and Tango are discussing at the moment. There are a couple of topics that deserve a resolution between the two companies, and it is our interest here at Tango to figure out the fastest way possible to bring the combination forward and to achieve a regulatory approval. That is very important for us here, and that clearly includes the continuation of the work with RVMD, but includes also other options.
For the second part of your question, can I turn it over to Adam?
Absolutely. The second part of your question was, after our interactions with the FDA, what are we needing to see in terms of our primary outcomes to achieve a regulatory approval? We have not disclosed the details of our statistical analysis plan, and those are not details that we intend to share for a number of reasons. 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, one-to-one study is the number of patients, which is 484 patients. 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. Congrats on the exciting update. Can you provide more color on the DDI, particularly as it relates to 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[audio distortion] Do you find any of the?[audio distortion].
You broke up entirely with the second part of the[crosstalk].
Is it better from a GI perspective?
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 re-ask the second part?
Sounds good. Thank you.
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 achieve in terms of key PK parameters, including AUC, are very similar to daraxonrasib 300 mg 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-ask the second part.
Yeah, sorry. I was breaking up on the road. Sorry if I was breaking up a bit. Yeah, 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 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. It may be a systemic effect in addition to or rather than a local GI effect. Again, not our data. It is speculation on my part. But I do think it is straightforward to envision that delivering 300 mg 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 a PRMT5 agent in the MTAP wild-type setting, and would you expect results to be as dramatic in these patients without a loss of function? Can you also give us some color on the toxicities that other PRMT5 inhibitors that are CNS penetrant are seeing that Vopi 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. I also think that the data support that it 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, in 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.
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 expansion arm of the study.
The second question was, I think, regarding the tox profile of other PRMT5 inhibitors.
Yes.
I think we can elaborate a little bit what we know.
Yeah. So in order to talk about the tox profile of other molecules, I will talk about the tox profile of our molecule first. It is 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 is 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 has a rash signal. It is a low-grade rash, but it is present. Navlimetostat has a little bit more GI tox, 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 will 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. If there is a CNS tox signal of other molecules, it could be a liability in pancreatic cancer.
Okay. Thank you. 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 agents do you think you are in PDAC with the RAS combos at this point?
I think, when you think about when we started our combination study between vopimetostat and daraxonrasib, that start was in end of June last year. I think we are minimum 12 months ahead of other combinations in the field. That is why I think we are very happy of having such an advanced data set. That is 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. I think we are determined to keep the headway attractive for patients and for Tango, to be honest. We are looking forward to starting the first-line study, as we outlined earlier, in the first half of 2027.
Great. Well, thanks, and congrats again. Appreciate it.
Yeah. Thank you, Andy. Thank you.
Thank you. Our next question comes from Brian Cheng with J.P. Morgan. Your line is open.
Hey guys, congrats on the data, and thanks for taking our questions today. First, I wonder if you can comment a little bit more about the durability of response here. The PFS curve looks a lot more stable than daraxonrasib alone in the second line back in the RASolute 302 study. So 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. Second question, just related to the partnership side. At this juncture, as we think about your partnerships with RVMD and Erasca, how do you prioritize each one today? Then moving forward that your combo strategy is pretty clear laid out with daraxonrasib. Thank you.
Brian, you want to speak to the durability?
Yeah. I would say, as you know, 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. 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 who are still on therapy.
Yeah. Thanks, Brian, and to your second question, Brian, with respect to the partnership between Tango and RVMD and Erasca, I think we are very happy that we are working with the two leading companies in the field of RAS inhibition. 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 RVMD 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 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. 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.
Yeah. 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 is 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? 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 is about to start, could you realistically run a phase III 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. 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 can get some copy number data from that. That usually has a turnaround of about 7-10 days. We also do tumor-based testing in two different ways, one of which is with next-generation sequencing. 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. As you know, immunohistochemistry has a quite rapid turnaround, right, within a couple of days, few days, you can get that information.
Next-generation sequencing tends to be in approximately two-week kind of timeframe. Generally within one-two weeks, we have data that we can use for both RAS mutation status and for MTAP deletion status. Thanks for that question.
Kelsey, to your second question of whether or not we can start a phase III study with the Erasca molecule as a combination partner. The answer is theoretically entirely yes. 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. I would say we are ahead of the curve with the daraxonrasib, vopimetostat combination. But in theory, it is totally possible to start a phase III 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.
Yeah. Thank you.
Thank you. Our next question comes from Michael Schmidt with Guggenheim. Your line is open.
Oh, hey 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, sort of the mid-80s for both cohorts or both subsets. Is there something going on there, or do you think that's just coincidence given the small sample size? Then I had a question on the phase III study. Anything else that's gating to starting the phase III? I'm just wondering, 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? How fast do you think you could reach this possible OR analysis in the phase III? Thanks so much.
You want to go?
Sure. The question regarding the overall response rate in second and third-line patients, they are very similar. We are at very high numbers, and perhaps it is hard to differentiate 80 from 85 when you are in that range. I do think it is 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%, 33% in second-line, and 47% in front line. We are sitting at about 80 in second and third-line. One could postulate it might be higher in front line. 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 is interesting to speculate how good a front-line Kaplan-Meier could look like in the eventual pivotal study. For the second question, I will go back to Malte.
Yeah. With respect to the gating factors, I think it is fair to say that the main factor is really operational execution right now. We have clearance from FDA regarding the protocol design as we mentioned earlier. The clinical operations team are a lot under the microscope here at Tango and they are working day and night to get this off the ground. To start a phase III study is a complex undertaking. We are running this study in three geographies, in the United States, in Europe, and in Asia Pacific. All of this needs to be orchestrated. We do not need any frontline data in pancreatic cancer to start the study. That is very clear.
With respect to your last question of when we could potentially have overall response rate in that study, we haven't really spoken about our forecasting or timelines of when certain endpoints would become mature. FDA doesn't really like the companies being ahead of themselves, of sharing forecasts and sharing details of when data will become available. Stay tuned, Michael, and we will share, of course, how good the progress is we make, and we will share with the public of when we intend to approach FDA for meaningful discussions regarding evaluating these endpoints.
Maybe just ask 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. 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 in second line. I don't know, Brian, if you want to add to that.
Yeah, sure. 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 Alethia Young with William Blair. Your line is open.
Hey, guys. Thanks for taking my question, and congrats on these data this morning. One for Dr. Wolpin. I guess these different grades, when it's Grade 1/2, I feel like not all grades are created equal. So I was just wondering if you could give us some color, maybe on even the Grade 1/2 events you're seeing in the combo versus what you see with Dara itself. My second question for the company is, obviously when you think about the totality of your announcements today, it seems you're certainly centralizing upon at least three indications and all in on pancreatic cancer. Can you talk a little bit about how these data increase potentially your confidence in what you're doing in glioblastoma and non-small cell, which have data events this year as well?
Sure. Thank you for the question. I would say overall, we certainly see a shift towards less high-grade toxicities with the combination. Again, we do have to keep in mind, these are still 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 being in front of a patient that you really only can do when you're 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.
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.
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 combinations. 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. We think we have a pretty good idea of how we develop these molecules.
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 or five patients had confirmed responses. The fifth was a stable disease with, I think, -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. 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 daraxonrasib or vopimetostat, and the doses to which patients were reduced? Are you seeing any effect from the reductions in interruptions on the magnitude of tumor reductions or duration response? Thanks.
Sure. The second part of the question, the answer is no. It would be hard for it to be yes, that there's an implication on the duration of response, because effectively, nearly all of the patients are benefiting. It's hard to stratify further. In terms of the dose reductions, 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- 80 mg, and in some cases, we dose reduced vopimetostat from 200- 150 mg. 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. Just one really quick one. For the potential accelerated approval path in second-line PDAC, have you already discussed a specific approach to the FDA already? Has 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 occurred yet, when do you expect to meet with FDA and discuss the phase II designs?
We did not have the detailed discussion, as you just mentioned. 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. We're looking forward to follow up with the agency on these ideas, and then as soon as we are in the position, we can update the public about 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 the strong durability data. My first question is, in this Vopi plus Dara PDAC cohort, it appears that there are no G12D patients. Do you anticipate the durability and ORR to be consistent between G12D and G12V patients?
You want to take this, Brian?
Sure. Yeah. Thank you for the question. I think as you saw from the design, that was mostly to allow for sufficient patients with G12D mutations to receive the zoldonrasib-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 mutant allele. 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 50% of these patients responding to the combination, which is a very encouraging sign, I think.
Yes.
Got it. Although we don't have any clinical data, what would you expect when you compare Vopi plus Dara versus combining Dara at 300 mg 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 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 mg of daraxonrasib. I think that the efficacy will be comparable, would be my guess. On safety, I think there are a lot of question marks. Will the higher dose of daraxonrasib result in more GI tox? Will the little bit of a skin signal with navlimetostat carry over into the combination to result in problematic overlapping toxicity?
Got it. Thank you for taking our questions.
Thank you.
Thank you. Our last question comes from John Newman with Canaccord Genuity. Your line is open.
Hey, good morning, and let me add my congrats on the really strong and impressive data here. Definitely, as Eric said, 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 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 tox.
Great. Thank you.
Thank you. This concludes the question and answer session. I would 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.