Oh, when you're ready. All righty. Thank you, everyone, for joining us in our next session of the Piper Sandler Healthcare Conference. My name is Kelsey Goodwin. I'm one of the senior analysts here at Piper Sandler. With me, I have the Tango team out in the audience, as well as President of R&D Adam Crystal. Welcome, and thanks for joining.
Thank you so much for having us.
Of course. Let's start, for those maybe less familiar with the story, with a quick high-level summary of Tango and where we stand heading into 2026.
Perfect. So Tango Therapeutics is a small molecule precision oncology company focused on novel targets, which we have identified through our platform. Heading into 2026, we are focused on three clinical programs, the first of which is Vopimetostat, which until recently was known as TNG462. We believe this to be a potentially first-in-class, best-in-class MTA-cooperative PRMT5 inhibitor. We recently shared data from this molecule in October, which included over 150 patients' worth of data. And the key points of that data included a benchmark of an overall response rate of 27%, which compares favorably to a lead competitor, the BMS molecule, who established an overall response rate of 23%. Across these patients, the median PFS was 6.4 months.
We believe this molecule has positive differentiators to BMS, including across multiple metrics, including the observation that it hits target harder due to the exposures that we achieved at the FDA-aligned move-forward dose of 250 mg. In addition to the data across all patients enrolled, we disclosed two additional data sets. One was a focus on pancreatic cancer. Those included patients who are second-line only. And among those patients in second-line who are evaluable, the overall response rate was 25%, with a median PFS of 7.2 months, comparing quite favorably to standard of care chemotherapy, which is approximately two - three and a half months. Finally, we put forward a set of data in patients who are in what we're calling our histology-selective cohort.
These are all of the patients we enrolled, excluding pancreatic cancer and non-small cell lung cancer, because we are developing them independently, and also excluding sarcoma, because we demonstrated it does not work in those patients, and in these 34 patients, the overall response rate was 49%, with a median PFS in excess of nine months. This provides two key pieces of information: definitive demonstration of single-agent activity and optionality for development. The next key focus for us in 2026 is TNG456. This can be thought of fairly as a brain-penetrant version of TNG462. It is a little bit more selective and a little less potent, and we put it into the clinic primarily to focus on GBM, understanding that over 40% of GBM is MTAP-deleted, and there are about 8,000 such patients in the United States each year.
We are approaching active doses and look forward to sharing this in 2026. And finally, we have our molecule TNG260. We recently presented clinical data at SITC, demonstrating proof of mechanism and early proof of concept, and we continue to move that into expansion in the 10% of non-small cell lung cancer patients who are STK11-mutant and KRAS wild-type. The final thing that I'll emphasize is the size of the population our lead programs are pursuing. MTAP deletion is a biomarker that we use to select the patients. There are approximately 60,000 MTAP-deleted cancer patients in the U.S. each year. About 10%-15% of all malignancies are MTAP-deleted, including approximately 20,000 pancreatic cancer patients a year, 22,000 non-small cell lung cancer patients, and 20,000 who would fall into that histology-selective other cluster of patients.
Great. Very comprehensive. Maybe just diving in a bit on that last piece. For MTAP deletion specifically, how well is it currently screened? What does that look like?
Yeah, it's certainly not a standard of care because there are no approved agents that go after patients with MTAP deletion. However, it is part of all of the commercially available next-generation sequencing platforms, such as FoundationOne. It is widely done and available at academic centers on their NGS as well as their IHCs.
Okay, perfect. And then maybe just briefly touched on it a bit, but in terms of the areas of differentiation for Vopimetostat versus the emerging MTA-cooperative class of PRMT5 inhibitors, what are kind of the key points there?
Sure. So I think that the chief competitor is BMS-504. That molecule and our molecule have many similarities in terms of the characteristics of the molecule, but we believe when we compare key metrics, including how hard we hit target, our molecule tends to demonstrate superiority in many aspects. In terms of the safety profile, we're differentiated with less GI toxicity and less rash. And we also believe that strategically we are well differentiated from BMS-504. They continue to explore dose levels, and some of their studies open are comparing 200 - 600 mg in a randomized fashion. In contrast, we have alignment that 250 mg will be our dose for the upcoming pivotal study. There's a third molecule that entered the clinic at a similar time, which is Amgen's molecule. Amgen's molecule seemed to fall out of disfavor.
We don't believe it's competitive in terms of its PK and bioavailability characteristics, as well as safety and efficacy. There are two other molecules coming close behind, but still well behind, which include AstraZeneca and ZEON. We know very little about those molecules, but they do seem to be enrolling relatively well and are likely good molecules. We look forward to seeing that data, and after those molecules, there is a growing number of followers, but those remain about two years behind, and we believe that our job is to continue executing well so that that gap stays in place. The other thing that I would emphasize in terms of competition is that we do have a dose.
We also are unique in having a path to a second-line pivotal study in pancreatic cancer in 2026 and are the first PRMT5 inhibitor and presently the only PRMT5 inhibitor to have combined with KRAS inhibitors, with a partnership with Revolution Medicines, where we are dosing Vopimetostat with either daraxonrasib or with zoldonrasib, both in patients with non-small cell lung cancer.
Perfect. And a perfect segue to my next section in PDAC. I guess, so you've mentioned that's the lead indication, and you recently presented data. Just maybe walk us through what were the key clinical learnings from that phase I data set, specifically the second-line PDAC?
Yeah. The second-line PDAC is certainly interesting, and it's why we're pursuing a pivotal study. I think that the expectation for the class of molecules is that patients tend to do well over time and have continued shrinkage over time. So unlike, for example, TKIs, where a patient might achieve best response on first cycle, in contrast, patients tend to shrink as far out as cycle 9 or even cycle 11, obtaining a first PR. In pancreatic cancer, we have observed an overall response rate of 25% in the second line in those evaluable patients and a median PFS of 7.2 months. That stands in contrast to standards of care, where it is, as I said, two and a half - three and a half months. We are comfortable that in doubling that PFS, we have a high likelihood of success path to approval and uptake.
Understood. In terms of the overall response rate, you mentioned that the response is kind of deepening over time. What did you see in terms of median time to response and in terms of when you did the cutoff for time post-enrollment to be included in response rate? Maybe just walk us through the rationale there.
That's an absolutely critical point. For this class of molecules, overall response rate is a function of time. So why is that? When you look at the spider, you can see shrinkage over time. And as a result of that, less than half of the patients who eventually will achieve PR have done so at first scan, and about 70% after second scan. So if one is reporting those patients, they are significantly underreporting the eventual achieved overall response rate. What we observed if we included all of the evaluable patients was a 20% overall response rate. But if instead we looked at only those patients who had received their first dose at least six months before the cutoff, it had climbed over that time to 27%. And those are the overall response rates in waterfalls that we presented. To be clear, all patients are included.
In the event that a patient came on study six months ago and their first scan showed progression, that patient is, of course, included in the assessment as a zero over one.
Understood. And now that you've had time to discuss the data with KOL, it's been out for two months now. I guess, what feedback are you hearing? What stands out to them the most?
The investigators.
Yeah, yeah.
I think they continue to be impressed both by the durability of benefit that patients receive, as well as the degree to which they feel good on drugs. We have numerous examples of patients who have traveled far and wide with spouses and enjoyed their life, patients who continue long-distance running. Generally speaking, the tolerability profile is described by investigators as trivial to manage.
Okay, got it. In terms of the update for durability in 2026, how should we think about that? And could the data improve with longer follow-up, kind of given the dynamics we've seen?
Absolutely. So we will provide updates in 2026 for this molecule, both for the pancreatic cancer data, which we will present the mature version of, recognizing that the data that we presented is immature and will mature over time. The non-small cell data was much less mature and as a result, uninterpretable, and we look forward to presenting that in 2026 as well.
Perfect. In terms of the evolving second-line landscape, how do you think about the bar kind of alongside RevMed's daraxonrasib?
Absolutely. So pancreatic cancer is fortunately changing very quickly for patients. There have been very few advances in the field, and KRAS inhibitors will likely be approved next year, daraxonrasib specifically in the second line. And we believe that it will quickly advance to the front-line set. We plan our first pivotal study in second-line pancreatic cancer and believe there is value there. The first relevant bar is chemotherapy because that is the standard of care against which we will run in the pivotal study as the comparator. The bar there is low. Historical controls are two - three and a half months. An important point is that we expect our controls on our study to do even more poorly because all of them will be MTAP-deleted patients, and MTAP is a demonstrable negative prognostic marker.
We must be two to three and a half months or something even inferior to that, and our data is more than double that. The second bar is provided by daraxonrasib. Daraxonrasib has an excellent profile, as does ours. We believe ours is competitive and in the same ballpark. However, competing with daraxonrasib, who's likely to get there first and capture 100% of the market in terms of all patients being KRAS mutant, would present challenges. It's not our strategy to compete there, but our belief that daraxonrasib will rapidly gain access to the front-line space, at which time we will have a valuable position in the second line to treat and benefit those. Second line is not our ultimate goal.
We are really focused on getting to frontline, and we believe the preferred path to do so is in combination with the RAS inhibitor in a chemotherapy-sparing doublet.
Okay, understood. In terms of the initial pivotal phase III that you plan to run in second-line PDAC, remind us of the design there, the control arm, and what assumptions guided the trial design.
Sure. So it's fairly straightforward. One-to-one randomization of single agent Vopimetostat at 250 mg once daily. It will be one pill once a day versus four standard of care chemotherapy regimens. We must use four, very similar to the daraxonrasib pivotal study, in order to capture all eligible patients, regardless of what they got in the front line or the geographical region in which they are being treated. This will be an approximately 300-patient trial. And the reason many people ask that it is smaller than the daraxonrasib trial, which is about 450 patients, has to do with the statistical design. Our study uses a hierarchical design wherein we get a first readout of PFS, and in the event of positivity, progress to analyze overall survival.
Using this hierarchical approach means we do not have to spend additional alpha on a second primary endpoint of overall survival, which is, for many good reasons, what Revolution Medicines chose to do in their study.
Okay, understood. So you had said the last time, or when you presented this data, that you were awaiting alignment with FDA on the design. When do you expect to have that clarity? And I guess, have you provided any color of when you last spoke? Are you in contact with the FDA?
We've successfully completed our end-of-phase meeting and have alignment on the trial design as well as other key aspects. We don't anticipate any major.
Okay, perfect. And when do you anticipate starting this study?
We've got it to 2026, and we're focused on getting that up as quickly as possible, recognizing the competition that will be provided by an eventual divarasib.
Okay, understood. So just to confirm, the control arm would be for chemo options and not daraxonrasib?
Correct.
Okay.
The study already has alignment in the design from the FDA, and we will be up and running before their approval. At least that is the expectation. The important thing, though, is that we already have FDA alignment on that comparator, and I don't think.
Okay, that's great. In terms of evaluating Vopimetostat in combination with daraxonrasib, maybe just walk us through how you think about the efficacy bar for the combination based on what we've seen so far with daraxonrasib monotherapy and also chemo combo?
Sure. So just to flesh out what our study is, our study is examining two doublets plus daraxonrasib with Vopi, as well as plus Zelda with Vopi. We're doing this in non-small cell lung cancer and pancreatic cancer, and we began dosing in June. What we disclosed recently at our data update is that dose level one is completed and that both of those dose levels were tolerable, and efficacious exposures were achieved for all three molecules, and preliminary evidence of activity was observed. I don't think it will be the case that we will need more than two or three dose levels for either of these combinations to find the dose, which brings us to your question of what do we need to see in terms of efficacy.
I think that the bar is set by the need to demonstrate that the combination is demonstrably more active in either single, and for PRMT5 inhibitors in pancreatic cancer, I think it's fair to say that is in the 25% range, and for daraxonrasib in second-line pancreatic cancer, that is in the 30% range. We need to have a data set that is demonstrably better than 30% for the market to take notice and for us to be confident that there is a clear path into front line. The other bar which has been set is that in the initial data of daraxonrasib in the front line setting, and I think that if we can demonstrate that we are as good or better in the second or third line as daraxonrasib is in the front line, that could be very well received.
Understood. In terms of your development strategy for Vopimetostat, maybe just remind us how it compares to that of the kind of main competitor in the PRMT5 space with Bristol's asset?
Yeah. Bristol is moving into first-line pancreatic cancer, and they do not have a second-line strategy that we are aware of. And they have a study up that begins as a dose-finding exercise of three doses combined with Gem Abraxane. So that is Gem Abraxane plus 200, 400, or 600 mg of BMS-504. That study will then transition into a first-line pivotal phase III. However, we anticipate finding that dose will take some time, and I don't anticipate that pivotal phase would begin until at least the end of. It's worth noting that a combination with Gem Abraxane, while currently in the current landscape, might be quite attractive, recognizing the current standard of care. As KRAS inhibitors move to the front line, that may become a less important strategy, which is why our favorite strategy is in combination.
Okay, interesting. In terms of testing and moving into the front line, how do you anticipate kind of getting testing more prevalent for MTAP deletions? And what would be the turnaround time from when you run the test and when you get results and can use an actionable targeted therapy?
Yeah, it's a critically important question, particularly in pancreatic cancer, because in pancreatic cancer, there is an extraordinary value placed on starting therapy quickly. What typically happens in GI clinics is one meets a patient with metastatic cancer on Tuesday and starts them on chemotherapy six days later. Patients can wait a little bit longer, but not much, which means that turnaround time is absolutely critical. What we are using on the pivotal study is a companion diagnostic with IHC rather than NGS. In part, that is because of the faster turnaround time and easier use, as well as requirement for less tissue. The other reason is that, in short, IHC is more sensitive for correctly identifying MTAP-deleted pancreatic cancer than NGS. With IHC, 40% of patients are correctly shown to be MTAP-deleted, but NGS on tumor biopsy misses about.
Oh, okay, interesting. Okay, great. I want to make sure we have time to move on to some of the other indications. So maybe quickly for Vopimetostat in non-small cell lung cancer, remind us what we'll get in the first look at that.
Yep, so remember that 10%-15% of non-small cell lung cancer is MTAP-deleted. That is a large population with a lot of patients who could benefit. We enrolled 41 such patients at the time of the data cut to our study, but those were less mature than the pancreatic cancer patients, and what we will be doing is presenting those patients when mature in 2026.
Okay, understood, and have you guided to when in 2026?
We haven't. I would say there are four key data updates that will fit together in 2026. One is the Revolution Medicines combination data. The second and third are the pancreatic cancer maturing data and the non-small cell lung cancer data. The fourth, we intend to be the TNG456 data in a data set in which we hope to demonstrate activity in [group].
Okay, perfect. And a perfect segue to TNG456, the brain-penetrant PRMT5. Maybe just remind us why this might be particularly well suited in an indication that's obviously very difficult, like glioblastoma?
Yeah. I mean, let me start by saying Glioblastoma is not only a terrible disease but has been very difficult to demonstrate active drugs in. But we don't think this is any different than non-small cell lung cancer and melanoma were 15 -20 years ago, nor pancreatic cancer is now. And when we put the right drug in the right patient at the right concentration, those patients will respond. In GBM, 40%-50% of patients are MTAP-deleted. And MTAP loss, along with CDKN2A loss, is a truncal event. So the genetics say that an MTA-cooperative PRMT5 inhibitor should be active. TNG456 can fairly be thought of as TNG462 with brain penetration.
Understanding what we have learned so far from the ongoing dose escalation, it's our expectation that we will achieve concentrations in the brain which are quite active and hope to see activity in.
Understood. In terms of the data that we'll get, what could we expect, and what is the benchmark?
Sure. So we're still in escalation. We are approaching active doses, and when we find them, we will begin to add more patients. I anticipate sharing that data and hopefully data that demonstrates both CSF penetration as well as GBM. The benchmark in GBM is extraordinarily low. In this refractory setting, effectively nothing works. And there is both an opportunity for a single-arm accelerated approval if sufficient activity is demonstrated, very low overall response rate would be required, and a convincing PFS is quite short as well. Perhaps the best path for this molecule is not single-agent use in the relapse refractory setting, but moving it to adjuvant in place of a combination.
Okay, interesting. All right, with our less than one minute left, let's wrap up with cash runway and then just final thoughts as we head into 2026.
Sure. So our cash runway takes us into 2028 and through the first pivotal study, as well as covering all of the ongoing clinical trial activities and other activities. Key thoughts going into 2026 are that we are focused on many things, but I think the two things that are forefront that we are most concentrated on are executing the pivotal study and moving forward these RevMed combinations in a way that we think will provide a high probability of success past the front line.
Perfect. All righty. Two seconds is fair. Best one yet. Thank you guys so much for joining, and thank you for joining as well, and with that, we'll wrap up.