Hello, and welcome to Relay Therapeutics conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you will need to press star one one on your telephone. You would then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. I would now like to hand the conference over to Peter Rahmer. Sir, you may begin.
Thank you, operator, and good afternoon, everybody. Thanks for joining. We are excited to share these initial data for RLY-4008, now known as lirafugratinib, in FGFR2 altered solid tumors with you. You can access the press release from today, the slides we are reviewing, and the replay of this call by going to the investor relations section of our website. As a reminder, during this call, Relay Therapeutics will make certain statements that are considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including express or implied statements regarding our strategy, business plans, objectives, the expected therapeutic or clinical benefit of our products, the potential of our platform and our product candidates, and progress and timing and execution of our clinical trials.
Such forward-looking statements are not guarantees of future performance, and therefore you should not put undue reliance upon them. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect. We refer you to our SEC filings available on the SEC website and on our website for discussing the risk factors that could cause our actual results to differ materially from those discussed today. The forward-looking statements in this presentation speak only as of the original date of this presentation, and we undertake no obligation to update or revise any of these statements. Today, on the call with me are Sanjiv Patel, our President and CEO, and Don Bergstrom, President of R&D. With that, turn the call over to Sanjiv.
Thank you, Pete, and thank you for those of you joining the call this afternoon. We're excited today to be talking about RLY-4008. Our research team designed it using a combination of leading-edge experimental and computational approaches to overcome challenges that others could not overcome using traditional approaches. We created the first highly selective FGFR2 inhibitor. In September of 2020, we dosed our first patient, and today, approximately three years later, we've enrolled more than 450 patients into our ReFocus study. Today, we announce that we fully enrolled our first pivotal cohort with more than 100 cholangiocarcinoma patients. This is testament to the continued excellent execution of our clinical team. Moving to Slide 4. Our clinical experience has shown the exquisite selectivity of 4008 allows us to inhibit FGFR2 at very high levels.
As we've shown in the past, this translates into activity levels in cholangiocarcinoma FGFR2 fusion patients not previously achievable with the non-selective inhibitors. Today, we're thrilled to show this activity also translates across tumor types and alteration types, and this opens up a much larger patient population that is currently underserved. Don will review the data in much more detail later. Moving to Slide 5. 4008 is one of four clinical assets that we have designed using our in-house tools, using our Dynamo platform. Given the breadth of our clinical and preclinical pipeline, and today's data showing the potential for 4008 to be in a much larger patient population, we have some choices to make as a company as we focus our team's execution capacity.
For RLY-4008, we have taken the decision to focus on the larger tumor-agnostic opportunity as our first regulatory approval pathway and align the timing of accessing the cholangiocarcinoma opportunity to this. As you know, the IRA favors accessing larger opportunities initially versus the conventional approach of speed to market with smaller indications. This clearly pushes out our investment on commercial readiness. We've also continued to expand our PI3Kα mutant selective efforts to target the very large breast cancer opportunity, with the goal of being able to treat larger patient populations sooner in the life cycle of the PI3K assets. With this goal in mind, we are accelerating the exploration of triple combinations with CDK4/6. We plan to initiate the first RLY-2608 triplet this year. To enable all of this clinical execution, we'll pause our CDK2 program at IND.
All of this will enable our team to focus on the highest value opportunities and significantly extends our cash runway by an additional year into the second half of 2026. All of these actions ensure we can generate meaningful clinical data on these key clinical programs and not be reliant on the capital markets. Slide 6 clearly shows the broader tumor-agnostic opportunity versus the cholangiocarcinoma one. There are more than 40,000 FGFR2 fusion patients globally each year. Over the next year, we will generate data from the fully enrolled cholangiocarcinoma pivotal cohort, and with the limited investment, we'll also follow the tumor-agnostic signal and share further data in 2024 and a regulatory update on these cohorts as we determine the optimal path forward to help these patients. On Slide 7, you can see the PI3K mutant selective opportunity is also very large.
PI3K is the most frequently mutated kinase in solid tumors and significantly larger than several multibillion-dollar franchises relating to alterations such as EGFR. It's also a very concentrated one, with PI3K alpha mutations prevalent in more than 150,000 hormone receptor-positive, HER2-negative breast cancer patients in the U.S. alone. The goal of this program is to enable PI3K alpha to be selectively inhibited to avoid the off-target toxicities that have unfortunately plagued the non-selective inhibitors. This will potentially allow us to serve patients in earlier and earlier lines and in combination with CDK 4/6 inhibitors and also in combination with future targeted combination therapies. We believe our initial clinical disclosures have gone a long way towards showing 2608 is potently inhibiting mutants, selectively PI3K alpha, while maintaining a very good tolerability profile.
We're excited to start the triplet trials of RLY-2608 with fulvestrant and CDK4/6 inhibitors later this year. On Slide 8, you can see we have a lot going on in the clinic with our PI3K alpha franchise and look forward to a very data-rich next year, which should allow us to determine the next steps for these important programs. On Slide 9, you can see our broad portfolio of precision medicines, and in 2024, we'll be excited to unveil the next set of exciting programs. Moving to Slide 10. We have a team that has an execution culture that we've always been able to hit the challenging goals we've set for ourselves.
We have the focus and capital to continue doing this, and we look forward to generating meaningful clinical data across a range of programs over the coming years. With this, I'll hand it over to Don to talk us through the data from today in more detail.
Thanks, Sanjiv. Moving to Slide 11. As you've heard us say in the past, pan-FGFR inhibitors are not selective for FGFR2 and potently inhibit FGFR1, FGFR3, and sometimes FGFR4, resulting in toxicities related to inhibition of other FGFR family members, including hyperphosphatemia and diarrhea, while achieving limited inhibition of oncogenic FGFR2 alterations. Consequently, there remains significant need for better therapeutic options for patients with FGFR2-altered tumors, including in late-line patients, where the recommended therapies per NCCN guidelines typically have less than a 15% overall response rate. Moving to Slide 12. Lirafugratinib has been evaluated in over 450 patients in the ReFocus study. The part one dose escalation is now complete, and 70 mg was selected as the recommended phase II dose, based on safety, PK/PD, and anti-tumor activity. The part two dose expansion is ongoing.
Today's presentation at the Triple Meeting focused on the three expansion cohorts in the ReFocus trial for patients with FGFR2 altered tumors outside of cholangiocarcinoma. These include cohorts in FGFR2 fusions or rearrangements, FGFR2 amplifications, and FGFR2 mutations. On Slide 13, you can see that 124 participants with solid tumors were enrolled across FGFR2 alterations, representing 18 non-cholangiocarcinoma tumor types. Patients were heavily pretreated, with most having three or more prior lines of systemic therapy. The safety population consists of all patients receiving at least one dose of Lira. The efficacy population consists of 84 FGFR inhibitor-naive patients with at least one post-baseline imaging assessment. Moving to Slide 14, we show radiographic tumor regression and response per RECIST for patients with FGFR2 fusions or other rearrangements.
Most patients had tumor regression, and the majority had disease control per RECIST, and the overall response rate was 35%, with responses observed across five distinct tumor types. Slide 15 shows the swimmer's plot for patients with FGFR2 fusions or other rearrangements, where you can see most patients who responded have a duration of response in excess of six months. Slide 16 shows tumor regression and response for patients with focal amplification of FGFR2. Again, the majority of patients had tumor regression, with 24% of patients achieving a response per RECIST. Responses were most frequently observed in breast cancer, but were also seen in gastric cancer and colorectal cancer. The overall disease control rate was 62%. Slide 17 shows the swimmer's plot for patients with focal amplification of FGFR2, with good duration of response, especially in patients who responded with breast cancer.
On Slide 18, you can see tumor regression and response for the 10 hormone receptor-positive, HER2- breast cancer patients with any FGFR2 alteration enrolled in the ReFocus trial. These patients are very heavily pretreated, with a median of 7 prior lines of therapy, with all 10 patients having been treated with prior CDK4/6 inhibitor therapy. The overall response rate in these patients is 40%, with 70% achieving disease control. Slide 19 shows the swimmer's plot for the HR+/ HER2- breast cancer patients, demonstrating very encouraging durability of response, with all 4 responders having response duration longer than 6 months. Three of the 4 are ongoing, with one ongoing longer than 1 year now, which is very significant in this heavily pretreated breast cancer population. Slide 20 highlights lirafugratinib's activity in a heavily pretreated breast cancer patient with hormone receptor-positive, HER2- disease.
The CT scans on the right show significant regression of multiple liver metastases. The patient remains in confirmed response that is ongoing at cycle 19. You can see the summary response table by FGFR2 alteration type on Slide 21. The overall response rate was the highest at 35% of patients, in patients with FGFR2 fusions, as shown in the second column. In amplifications, the overall response rate was 24%, and we saw a 13% overall response rate in mutations across all solid tumors. Slide 22 shows the breadth of lirafugratinib efficacy in non-cholangiocarcinoma solid tumors with FGFR2 fusions or amplifications. The overall response rate across these 60 patients was 28%, with responses seen across eight tumor types, including non-small cell lung cancer, ovarian cancer, and pancreatic cancer, in addition to the responses seen in breast cancer and gastric cancer.
On Slide 23, we show NCCN-recommended therapies for heavily pretreated patients across the indications where Lira has shown promising clinical activity in the ReFocus trial. For these patients, late-line standard of care is typically chemotherapy, with response rates typically well less than 15%, highlighting the need for more effective targeted therapies for patients with FGFR2 alterations across a broad range of solid tumor types. As shown on Slide 24, safety data remains consistent with the previously reported profile of Lira. With that, I'll now hand it over to Pete to wrap up.
Thanks, Don. As you've heard from many of our peers, the IRA has flipped the script of the typical, typical drug development approach of starting in small populations and expanding over time, given this first approval now starts the nine-year clock to price controls. As a result, we, along with other peers, are now prioritizing pursuing the larger populations first. So as Sanjiv mentioned, rather than continue to pursue the CCA opportunity first, we are shifting our focus to align this with the larger tumor-agnostic opportunities that we've outlined today. Given the promising early data in these populations, we will continue enrolling the ongoing tumor-agnostic cohorts to enable us to collect more data. We expect to share initial potential regulatory development path and updated data next year. Our updated pipeline slide is reflected here on 26, and it reflects the changes that we talked through today.
We continue to have a robust and deep pipeline, which is now more focused on pursuing the most significant opportunities and ensuring we have the capital to see those efforts through. Lastly, moving to Slide 27, echoing what Sanjiv started with, a key theme throughout the remainder of 2023 will be continued clinical execution, particularly with our lead clinical programs. For 2608, we plan to initiate the first triplet combination this year with the goal of moving into earlier lines of therapy, which is where we believe the true value of having a selective inhibitor like 2608 lies. The 5836 first-in-human study continues ongoing, and we will make an additional PI3K alpha inhibitor clinical data disclosure in 2024.
We have achieved our anticipated milestones of RLY-4008 in the second half of 2023 of full enrollment of our pivotal cohorts in the FGFR2 fusion-positive, cholangiocarcinoma population, and with today's exciting initial clinical data from the ongoing tumor-agnostic cohorts. We have an execution-focused team, sufficient capital, and a growing track record to continue advancing our key clinical programs, and we look forward to updating you on our progress as we go. With that, I'd now like to open the call up to questions. Operator?
Thank you. Ladies and gentlemen, as a reminder, to ask a question, please press star one one on your telephone and then wait to hear your name announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Salveen Richter with Goldman Sachs. Your line is open.
Good afternoon, thanks for taking my questions, and, congrats on the data here. Could you provide more detail on what is involved and the steps and timelines associated around a tumor-agnostic label with regard to not only the FDA discussion, but how you'll design a trial here?
Thanks for the question, Salveen. Maybe I'll hand that one over to Don.
Yeah. So I think, as Pete alluded to, I think the first thing we want to do is, get some more patient experience and greater duration of follow-up with some, additional enrollments in the ongoing ReFocus trial. I think we then need to have an FDA interaction to clarify with them what the anticipated, path forward would be for a tumor-agnostic population. I think the question there will be a question, both of what data is required, as well as what the patient populations would look like in the distribution of solid, of tumor types that the FDA would expect to see. And I think with that, information, then we'll be able to provide more guidance for what the timeline would be for a likely, path forward for, for a filing in a tumor-agnostic indication.
Can I just follow up there, and do you think you'd be able to include more than one alteration, or do you have any sense of what could be allowed here?
Pete, maybe do you want to take that?
Yeah. So it's really gonna be a data-driven question in concert with the regulators, as to what is possible here. So there's not much precedent for, you know, tumor-agnostic, alteration-agnostic, even if you just combine, say, fusions and amplification. So we'll follow the data and have a constructive conversation with the agency as to the best path forward.
Thank you.
Thank you. Please stand by for our next question. Our next question comes from the line of Brad Canino with Stifel. Your line is open.
Great. Hi, team, and thanks for the disclosures, and congrats on the showing at Triple. I want to ask, because you're getting better durability in the fusion patients and even some durable, stable diseases compared to the amplifications, and do you have any data that correlates that differential in efficacy to maybe higher co-alterations in the amp patients? Just trying to see if, if you're seeing a difference in what's driving the tumor in those two different cohorts. And then a broader regulatory question, if that level of activity in amp, you know, around mid-20% ORR that you're seeing continues to be consistent at the later cuts, do you anticipate that it could be sufficient to be included in that broader tumor-agnostic NDA package that you've now outlined? Thank you.
Thanks, Brad. Maybe, maybe, Don, maybe you can start, and then we hand it back over to, to Pete to take that second half of that question.
Yeah. So, you know, I think we have a robust translational medicine program in this RLY-4008 overall development program. And I think one of the things that still needs to be done is fully characterizing what the baseline mutational status of the patients look like, and understanding if there are any baseline molecular correlates that show an association with either the likelihood of response or durability of response. That being said, I think we are very encouraged that when we do look at the amplified patient population, while on average, you know, or overall, I think you're seeing fewer patients with greater than six months duration of response.
We have seen some patients, especially the breast cancer patients, where the duration of the response we're getting is really, really promising, including that vignette we showed where the patient's now out in cycle 19 of treatment remaining in response. So I think, you know, there will be further work that we'll do to try and understand what some of those molecular correlates are. But I think we are encouraged both by the signal we're seeing is manifested by response rate, and then within both the fusions and the amplifications, the potential to get very good quality responses with long duration.
Okay, Pete, you take the second question about regulatory.
Yeah. On the regulatory side, Brad, I mean, it's a good question. Look, the one thing that the FDA made clear in the draft guidance last year around this topic is they, in a tumor-agnostic context, want to see a good diversity of tumor types represented and consistency of signal across tumor types. I think that'll probably hold, that concept will hold even when you think about, you know, trying to pool alterations. I think the context will matter as the data mature. It'll be, again, a data-driven decision in consultation with the FDA as to what the options and paths forwards are.
Thanks, Brad.
Great. Thank you.
Thank you. Please stand by for our next question. Our next question comes from the line of Dane Leone with Raymond James. Your line is open.
Hi, thanks. Could you just give us a sense of what your expectations would be for continued enrollment in these cohorts, and then what the future weighting of gastric would be specifically? And how you think you and maybe the regulatory bodies would interpret, you know, a certain tumor histology that seems maybe out of line with what you're seeing across other histologies, taken in weighting to the total outcomes of the study?
Thanks, Dane. Again, Pete, do you want to take that one?
Yeah, I think it, it's a good question, Dane, and I think it's one, you know, here, one of the things that we didn't do thus far in the tumor-agnostic portion of the ReFocus study is we were not proactively trying to enrich or control for any one specific tumor type. I do think going forward, we will- we'll, we'll keep the gastric portion, gastric cancer patients capped at the current number that we have in there as much as we can, and try to get, you know, as you allude to, more diversity of tumor types in that amplification population. 'Cause you're right, I think we're gonna need, you know, if you want to have a tumor-agnostic conversation, especially in amplifications, we're gonna need a greater diversity of tumor types in that patient population.
And we have—w e'll continue to enroll and build out these arms. We have more headroom in these cohorts, and we'll continue to do that and generate, hopefully, more and more diverse tumors, especially in the amplification setting. But obviously, in the fusions, we're very happy with the distribution of tumor types and the consistency of the signal we're seeing there.
Thanks, Dane.
Thank you. Please stand by for our next question. Our next question comes from the line of Yaron Werber with TD Cowen, and your line is open.
Great. Yeah, thanks for taking my question. So a couple of things. Are you thinking that 30% in 6 months durability is sort of still the magic numbers? Given you're talking about now multiple tumors, you know, multiple types of mutations. I mean, I imagine the mutations themselves might be out. It's going to be amplifications and fusions. But you know, the standard of care, obviously, in many of these is much lower than that. I'm just trying to figure out how much flexibility do you think the agency has? And then secondly, why terminate or why deprioritize right now or halt the CDK2 and ER degrader programs? Is it for cash reasons, or is it just because of just the landscape, you know, outside?
And then finally, there are so many other—y ou know, the way we look at it, your, your platform is now validated with both the first two drugs. I'm just talking about validation of the program in terms of able to hit the target selectively that you want to. Have you considered, you know, FGFR3, for example, or, you know, achondroplasia or other targets outside of oncology, where you can potentially find a lot of prominence? Thank you.
Thanks, Yaron, for the three questions. Let's take them one at a time. The last one, I think, as you know, we have a deep pipeline, 10+ preclinical programs. I think, you know, we're excited about revealing the next one of those programs next year. And so you're exactly right. Like, we're—that's our focus is on precision oncology and disease targets that our platform can really target that others can't. So obviously, you know, we're not gonna name the future targets today, but maybe that takes us to the second question around why deprioritize and pause our CDK2 and our ER alpha programs. And I think it comes down to clinical execution. Our focus very much is on, you know, all of the things that we have in front of us.
And one of the things that we've been very true to is executing well in the clinic. And we've learned from, you know, all of the great precision oncology companies that have come before us to knowing that's how important that is. And so the focus over the next year in the clinic is obviously following the cholangiocarcinoma pivotal cohort patients, continuing to enroll these patients outside of cholangiocarcinoma across the various mutation types and alteration types. And then obviously, our 26-08 and 58-36 trials continue. And as we said today, we're obviously running both the doublet and obviously, before the end of the year, a triplet trial. So I, I think we remain very focused on making sure that we can execute optimally to generate that data as rapidly as possible.
At the right time, we'll go back and assess whether it's the right time to bring those programs forward. And maybe on the final question around the standard of care in patients outside of cholangiocarcinoma, that we showed data on, so I'm going to hand that on to you, Pete.
Yeah, I mean, you know, your, your question there, your own was, is 30% ORR and roughly six months durability, still the, a, a good rough benchmark? I think it is, too, as you allude to, somewhat context-dependent. You know, I think the 30%, number comes from the—y ou, you've seen the FDA reference a number of times that in these patient populations where there is no alternative therapy, they're generally looking for a dataset that can exclude 15% in the lower bound of the 95% confidence interval. If you have, you know, the 75-100 patients, that would, at a 30% response rate, that would do that. So I think that's where that comes from.
It's probably an okay general benchmark, but I think it will always be somewhat context-dependent based off of the patient population you're talking about.
And look, I guess the final thing, going back to the CDK2 ER alpha question, is it—y ou know, obviously, we announced today the extension of our cash runway into the second half of 2026. Obviously, in the capital environment that we're in, we think that's a prudent thing to do to make sure that we can always keep independent of the capital markets and generate the data that we need to in both of these key programs, 4008 and 2608. Thank you.
Thank you. Please stand by for our next question. Our next question comes from the line of Eric Joseph with J.P. Morgan. Your line is open.
Great, thanks. And, let me add my congrats on these data, guys. Just two quick questions from us. First, just thinking about next steps, could you clarify whether you think the data so far in ReFocus would be eligible for a potential sort of registration-directed study? Or is the thinking there that you may to pursue a tumor-agnostic label, start a different trial altogether? Then secondarily, just in thinking about the scope of the tumor-agnostic label, how should we be thinking about it by sort of line of treatment, right? So far here, we're looking at a rather heavily pretreated patient population. There are IRA considerations as well.
How should we think about the potential to kind of look at incorporating use in earlier lines of treatment with 4008? Thank you.
Thanks, Eric, for the question. Yeah, Pete, do you want to take that one?
Yeah. I, I think, Eric, in, in the context of, you know, the—i s this trial designed in a way that could be, registrational? And the answer there is similarly to the cholangiocarcinoma arm, yes, we can. Based off of the conversation and interaction with the FDA, we could align on you know, expanding the end and converting these to a potentially registrational single-arm study, in, in any one of these arms. And then, to the other question on the, diversity of tumor, diversity of tumor types, I, I think it's gonna be important to continue to, follow the data. And, and, and there's probably, like, as I said in the, in previous comments, you know, there's gonna— you're gonna need a diversity of tumors represented most likely in this conversation.
Really, I was asking, just trying to get a line of treatment, you know?
Yeah, I think if you continue to consider an accelerated approval path, that would likely be, you know, not too dissimilar to what we've seen in kind of the TRK, RET, BRAF/MEK types of labels, which are for lines that generally say, have exhausted all other standard of care and/or, you know, giving the physicians a little bit of discretion of no alternative treatment. I think that's generally the type of label in that context that we would anticipate. Again, you know, we have to generate a bit more data here, have a conversation with the regulatory authorities before we can get too far down that road of speculation.
Okay, great. That's helpful. Thanks again.
Thank you. Please stand by for our next question. Our next question comes from the line of Peter Markey. Your line is open.
Great. Thanks. Thank you for my question. Thanks for the depth of data. In breast cancer, you had three patients that responded that had a concomitant treatment therapy, so kind of in Slide 19. I wonder if you could kind of talk through that, why they had that, and it looks like one was for just a single treatment. If you can talk about the other two patients, that'd be great.
Thanks, Peter, for the question. As you know, these patients were heavily pretreated, maybe Don will get into the actual detail.
Yes. Yes, so the ReFocus trial for the hormone receptor-positive population does allow at investigator discretion, the continued use of anti-estrogen therapy in combination with RLY-4008. Again, these patients were extraordinarily heavily pretreated. The patients to which you're referring, you know, have at least six lines of therapy, one is as many as eleven lines of therapy. And as you point out, there's one patient who did just receive a single dose of fulvestrant, and then was not treated with any additional fulvestrant while they were on therapy. The other two patients who received either an AI or other anti-estrogen therapy were patients who were also, you know, had seen multiple prior lines and/or had an ESR1 mutation.
I think it's unlikely that the depth of activity and the duration of activity that we're seeing here in this trial would be attributable to the anti-estrogen, and I think what we're seeing really is the true effect of 4008 in these patients with FGFR2-driven tumors.
Got you. What gives you the confidence around the fact that that concomitant treatment doesn't? Just like the extensive lines of treatments that the patients have already had, or just any other details around that would be great.
Yeah. These patients, these patients have already seen multiple prior lines of therapy, including multiple prior lines of anti-estrogen therapy. They have 6, 11 and 8 prior lines of therapy. Two of the three patients have ESR1 mutations, and they're being treated, you know, with regimens that are not highly active in patients with ESR1 mutations. I think it's the total clinical picture gives us the confidence that what we're seeing is the 4008 activity is not confounded by any exposure the patients may have to an anti-estrogen therapy.
And the durability of these responses, Peter, far exceed anything you would ever anticipate to gain from single agent estrogen therapy in a patient of these status.
Perfect. Thank you. And then just kind of a follow-up around the CDK2 ER programs that have been paused. Is that something you're on, or it's too early to think about that?
I think at the moment it's too early. I think, as you know, it's driven by both the clinical execution and, you know, the cash runway. I think there could be a time that we come back and continue to advance these if we need to use them. As you know, both assets were created to combine with our PI3K alpha mutant selective portfolio. And so at the right time, we'll either access them through using, you know, the available therapies that are in development or our own. So I think it's probably too early to make that choice. But if we ever did decide to partner them, you know, I think they're both great assets, and so I think they're highly marketable.
Important to remember that ER alpha was the subject of a collaboration with EQRx, which, as you know, recently underwent an acquisition by RevMed and is discontinuing all their programs. The nature of that partnership was they were supposed to take the baton at DC, and it was not something that we had anticipated having to shoulder the development of. It's also part of the decision making here. We are very happy about the ability to generate a degrader with our platform, and it has brought a new modality into our armamentarium as we think about how to pursue additional novel targets.
Thanks. Thanks for the reminder as well. Thank you so much.
You're welcome, Peter.
Thank you. Please stand by for our next question. Our next question comes from the line of Jason Gerberry with Bank of America Securities. Your line is open.
Hi, guys. Thanks for taking my questions. First one, just on the fusion solid tumor, Slide 14, the waterfall. Just—c an you just remind me, the patients sort of achieving a 40% tumor reduction, why they're scored as a stable disease versus a PR? Was this like a— was there a non-target lesion, or are these unconfirmed PRs? Just wondering kind of what went into that designation. Secondly, just on a regulatory question. You know, as you hold up the CCC, ultimate filing, you know, we kind of thought about CCC or cholangiocarcinoma as a first or second line opportunity. The tumor agnostic, as you kind of alluded to, is probably a third line slot.
Would those ultimately just be two separate filings as you kind of think it through from today, what you know today? Thanks.
So maybe, Jason, thanks for the questions. And so maybe, again, Don, you can take one on the status of the stable disease patients and the regulation.
Yeah. So in general, and if you look, actually on the tumor plot, you can, you can also see, the data that the patients who have more than 30% tumor regression, but are labeled as stable disease, generally had a first scan, that was a PR, that then was not confirmed in the subsequent scan. So for RECIST 1.1, those patients have gone into the, into the numerator as a stable disease. And you raise a good question, Jason, that, you know, it's just one that we can't answer without having an interaction with the regulatory authorities, and how they think about the path forward in the context of the CCA data that we already have in hand.
Okay, thanks.
Thank you. Please stand by for our next question. Our next question comes from the line of Matthew Biegler with Oppenheimer. Your line is open.
Hey, guys. Thanks for the question. We're wondering if you're seeing any correlation between amplification level and response in that amplification cohort. I guess it begs the question of going forward, you know, do you think you have the right cutoff on ISH? Thanks.
Thanks so much for the question. Maybe Don?
Yeah. So we're not seeing a strong correlation between amplification level and response. We have been using a relatively stringent threshold of eight copies of FGFR2 to be eligible for enrollment in this cohort, and we anticipate we'll continue moving forward with that eight-copy threshold.
Thank you. Please stand by for our next question. Our next question comes from the line of Silvan Türkcan with JMP Securities. Your line is open.
Hello, and congrats on this large update. I have a question. Could you please comment on the pancreatic responders? You seem to have a large number of those that responded. You know, it's a very difficult tumor type. And then I have a quick follow-up on Relay 2608 and the ReDiscover trial. So that triplet, just to double check, is that in an earlier line now versus your doublet that you're studying? And is that signed off by the FDA yet, that you can go in earlier line, or do you just anticipate enrolling later line patients with a triplet and then move up? Thank you.
Silvan, thanks for the question. Maybe we'll take one at a time. Obviously, we were thrilled to see the signal in pancreatic patients, too. Maybe, Don, you can just confirm.
Yeah. Yeah. So I mean, I think, you know, it is clear that there are a subset of pancreatic cancer patients, FGFR2-driven tumors. The biology looks different, for example, from KRAS mutant pancreatic cancer. These patients tend not to have a concomitant mutation in KRAS. I think it's consistent with what we've seen for the genomics across fusions for FGFR2, where FGFR2 tends to be the dominant oncogene driver in the background of a relatively quiet genome with regard to other oncogene alterations.
And then just on the protocol of the patients involved in the triplet trial.
Yeah. So for the ongoing ReDiscover trial, just as a reminder of what the doublet patient population has been, these have been patients who have seen typically a prior AI. They've seen prior CDK4/6, up to one prior chemotherapy and no prior PI3K inhibitor. As we go into the triplets, we do anticipate we may get patients who are less heavily pretreated. Although we anticipate initially we'll see a lot of patients who are maybe being rechallenged with CDK4/6 inhibitor after progression on the frontline CDK4/6 inhibitor. I mean, we have, you know, submitted the protocol and have gone through regulatory review on the protocol.
Thank you.
Thank you. Please stand by for our next question. Our next question comes from the line of Michael Schmidt with Guggenheim. Your line is open.
Hey, guys. Thanks for taking my question. I had a follow-up on the breast cancer cohort. Just confirming that you're kind of treating breast cancer as a separate cohort now, as opposed to part of the tumor-agnostic cohorts. Is that correct, first of all? And then, any reason why FGFR2 inhibition would not be active in triple-negative breast or HER2-positive patients, versus just the HR-positive, HER2-negative cohort? Thanks so much.
Thanks, Mike, for the question. Don, you can confirm both.
Yeah. So, just to clarify, the breast cancer patients are being enrolled in the three cohorts that are defined by alteration. The data that we're showing is data being presented across the breast cancer population, across those cohorts, but at this point, it is not a discrete cohort in the ReFocus trial, and breast cancer patients are eligible for enrollment in any of the three different FGFR2 alteration cohorts. With regard to the second question, you know, we have enrolled 14 breast cancer patients total, of which the majority are hormone receptor-positive, HER2 negative. And I think obviously that's consistent with that just being the most common subtype, but also potentially being consistent with the fact that it would appear from the literature that FGFR alterations could be a mechanism of resistance to hormonal and CDK4/6 therapy.
So you may see some enrichment for FGFR2 alterations in that patient population. With regard to the other four patients we've enrolled, three of the four patients were triple-negative patients. The fourth patient, we don't have hormone receptor status on. We have no reason to believe that RLY-4008 wouldn't be active in those patients. I think at this point, we just have a small N, and we need to get some more experience.
Thank you.
Thank you. Please stand by for our next question. Our next question comes from the line of Akash Tewari with Jefferies. Your line is open.
Hi, guys. This is Amy on for Akash, my strategic assistant. So just two from us. In terms of the tumor-agnostic approach, what efficacy endpoint do you think the FDA would be looking at? Would it be primarily ORR? And if so, what would that bar look like? Or would they want, you know, more durability? And then number two, can you just help us size up the FGFR2 market? It looks like breast cancer may be making up the biggest population. I guess in particular, how many of these breast cancer patients are HER2-negative and HR-positive? Thanks so much.
Thanks for the question. Maybe both of those questions, Pete, can you take the sizing question and then the bar question from the approval for our tumor-agnostic?
Yeah. In the context of an accelerated approval pathway and tumor-agnostic or even, you know, solid tumors in general, the FDA has stated guidance that they would consider overall response rate in combination with a relevant durability metric, so, you know, median duration of response, and consider the two in concert with each other. In the question on sizing here, the HR-positive, HER2-negative metastatic breast cancer patient population with FGFR2 alterations is approximately 7,000 patients or so in the U.S. per year. So you're right. As you look at it across all alterations, it's a sizable part of the opportunity.
Thank you.
Thanks so much.
Thank you. Please stand by for our next question. Our next question comes from the line of Christopher Liu with Leerink Partners. Your line is open.
Hey, guys. Congrats on the data. Just a few questions from me. So I was wondering, with the data readout by tumor type, gastric cancer historically has seen a lot of robust responses with other inhibitors. Just wondering what your thoughts were on kind of the responses we saw in gastric in this data set. And then in terms of the dose reductions, just wondering what adverse events were causing those dose reductions.
Chris, thanks for the question. Maybe, Don, you can take both of them.
Yeah, I mean, I think we are actually very encouraged, you know, with the data that we're seeing in gastric cancer. You know, there aren't that many datasets of FGFR inhibitors in FGFR2-altered gastric cancer. We've probably seen the most is for bemarituzumab, the monoclonal antibody originated from Five Prime, now being developed by Amgen in FGFR2 overexpressing gastric cancer. In the monotherapy experience with that agent, the responses that we're seeing in gastric cancer were very similar, both in terms of response rate and durability to what we're seeing with 4008. I think we, again, have been encouraged by the activity we're seeing.
It's clearly an active drug in gastric cancer, and I think there's opportunity for further development in gastric cancer, you know, potentially, either alone or in, or in earlier lines of therapy, potentially in combination. With regard to the question around AEs, I think the AE profile, again, has been very consistent, with what we've shown in the past. The AEs that we're seeing, are, we believe to be on target on FGFR2-related AEs, and the AEs that are typically resulting in dose modification are the AEs that we're seeing most frequently, including the nail tox, stomatitis, and PPE. Again, I think those are directly related to inhibition of FGFR2.
Of note, the overall rate of dose modification that we're seeing tends to be lower than what's been described for some of the other inhibitors in the development that's been done outside of cholangiocarcinoma. And we're also seeing a very, very low rate of discontinuation due to treatment-related AEs. So I think we're encouraged by the overall safety profile we're seeing. We're encouraged to see that we are continuing to avoid clinically significant hyperphosphatemia or diarrhea, and we have a profile ultimately that's related to inhibition of the target and is being well managed by our investigators.
Got it. And then I guess just one more question, if that's all right. Historically speaking, with tumor-agnostic approvals, like with RET or TRK, how many different tumor types do they have to show? And, you know, during the conference, they talked a little bit about anchor tumor types. Just wondering how many anchor tumor types you might have with your different tumor types, as well as how many we might need to see just based on historical experiences.
Thanks for the question. Maybe Pete can comment on that.
Yeah. If you look across the 7 tumor-agnostic approvals that have happened over the past, I think they've really been all in the past 5-6 years, you generally see three tumor types that make up anywhere from half to two-thirds of the patient population, and then a long tail of additional tumor types representing the rest of the population. You know, there haven't been really too many approvals, the most recent one on the tumor-agnostic side was selpercatinib, as you referenced. And again, there you saw three dominant tumor types making up 50% of the patient population, and then a smattering of single-digit tumors represented. So I think that's, you know, that's generally the direction that one should anticipate, and obviously some consistency of signal across those different tumor types.
And I think that's kind of what we heard referenced in the session today. As others have highlighted, you know, how do we treat and use the CCA data that has already been generated and being generated in the previously pivotal cohort, will be a subject of discussion with the agency as we continue to generate these data.
Thank you.
Thanks.
Ladies and gentlemen, at this time, I would now like to turn the call back over to Sanjiv for closing remarks.
Thank you for all the questions, and thank you for spending the evening with us, hearing our updates. As you heard, we have a very data-rich year ahead of us, and so I look forward to catching up with each one of you as we continue to generate that data. Thanks. Good evening.
Ladies and gentlemen, this concludes today's conference call. Thank you for your participation.