Summit Therapeutics Inc. (SMMT) Earnings Call Transcript & Summary

All right. Good afternoon everyone. Tyler Van Buren here, senior biotech analyst at TD Cowen. Thank you very much for joining us here at TD Cowen's 46th Annual Healthcare Conference. For our next session, it's a privilege to have a fireside chat with Summit Therapeutics, and it's my pleasure to introduce Dave Gancarz, the Chief Business and Strategy Officer; and Allen Yang, the Head of R&D Strategy. Dave and Allen, it's a privilege to have you guys here. Thank you very much for joining me.

Thank you, Tyler. Really appreciate the invite.

So maybe we'll start, we've got a lot of questions, but maybe we'll start with just 1 high-level question, to set a foundation. Again, I'm sure most are aware at this point, but maybe you could just briefly recap the Akeso partnership for ivonescimab, how Summit's role has evolved over time as the program has progressed into late-stage development and global studies and now regulatory review.

Sure. No, I appreciate the question, Tyler. So we entered into the deal with Akesobio, who are our partners based in China for ivonescimab, a PD-1 VEGF bispecific antibody. That deal was signed in December of 2022. And then after traditional customary review that it went effective in January 2023. Akeso at that point was running 2 Phase III studies in non-small cell lung cancer, one post-TKI, EGFR-mutant non-small cell lung cancer and then one in frontline PD-L1 positive non-small cell lung cancer. So effectively HARMONi-A and HARMONi-2. As we entered into the transaction with Akeso, our immediate intent was to also move into late-stage development immediately. So we expanded HARMONi-A into a global study and that became HARMONi as well as looking to start immediately into frontline non-small cell lung cancer, and that was the chemo combination squamous cohort of HARMONi-3. And so we -- part of the benefit in working with such great partners at Akeso, a significant amount of data had been generated at the time and also very quickly, and then they've continued to invest heavily in ivonescimab given the plethora of products that they have in progress and now approved at different stages in China. And so we work very closely with Akeso on an ongoing and regular basis. And now as we've introduced our third and now fourth Phase III clinical study globally. So HARMONi in post TKI EGFR mutant lung cancer, HARMONi-3, which was then expanded into 2 cohorts, squamous and non-squamous chemo combination frontline non-small cell lung cancer, HARMONi-7 in PD-L1 high non-small cell lung cancer. That's the monotherapy setting. And then finally, recently last quarter, we introduced the first-line microsatellite stable colorectal cancer study as well. And so that's IVO in combination with chemotherapy compared to standard of care bevacizumab plus chemotherapy. And so we've announced that we intend to continue to expand that clinical development pipeline, as you alluded to, Tyler. So we also announced last week on our earnings call, the Illuminate study, which will be a cooperative group study based -- a multiregional study in Europe and China, and we'll consider expanding that into the United States as well, and that's in frontline PD-L1 positive head and neck squamous cell carcinoma. And so that's the first study that we've announced in 2026, and we've mentioned that we continue -- we plan to continue to announce additional studies as those are ready to launch as well so.

Great. And we'll get into each of those studies and indications in just a moment. But I wanted to spend a little bit on the molecule's design and the clinical implications given the data that you all and Akeso have reported a lot of PD-1 VEGFs out there now following in your footsteps. As we spoke about the other day, following earnings, it's very possible that ivonescimab may have kind of just hit the goldilocks level in terms of its design. And as you think about cooperative binding and daisy chaining. So just maybe elaborate on the molecule and how that's been in your opinion, supported by the data that you've seen so far?

Yes. Thanks for the question. So I think it's now a validated class of agents, the PD-1 VEGF, right? So there's now multiple Phase III studies that show a benefit of PD-1 VEGF bispecifics over PD-1. So I think the class is derisked. The one thing I'd like to communicate is that ivonescimab is unique. And unlike the history of PD-1s, which was the first generation of checkpoint inhibitors where the PD-1 seem to have similar data and almost interchangeable. There was a question of PD-1 versus PD-L1. With the bispecifics, because of this cooperativity the format will matter, okay? So ivonescimab is designed around VEGFA binding sites and PD-1 binding sites. Some of the other molecules will try to bind PD-L1 and not PD-1. Some of the other molecules won't have the daisy chaining ability, right? So we know that there's what we call intramolecular cooperativity, the binding of PD-1 increases the binding of VEGF in vitro and VEGF increases the binding of PD-1, but then there's this also unique feature of daisy chaining with some of those molecules don't daisy chain and I think that will impact the efficacy. And we're beginning to see differences arise. The last part I'd say about the format being important is where the binding is. So some molecules have an X shape where there's a VEGF and then the PD-1. And then there are some that have the VEGF PDL-1, but then there are some that have like a super wide structure where they have a PD-1 and a VEGF. And we think that will be important as well. And they may daisy chain a little bit differently. And I think the daisy chaining is important in terms of increasing the cooperativity for binding a PD-1, but we now know that it has to do with sort of how it interacts with the PD-1 on the surface of cells, and that may cause sort of down regulation and degradation of the receptor. We believe that's going to be important in the future as well. Now given that complexity, it's not just a molecule blocking the receptor, right, it seems to be that there's some dynamic structures to this, and that will be important. And the format will matter. And I think there's enough differences in the different company's formats that will make clinical impacts as well.

Great. So let's start with second-line lung cancer or the EGFR mutant second-line setting, obviously, positive studies with HARMONi-A and then HARMONi, the global study that you all ran. So the FDA accepted the BLA. We have a PDUFA date now. So can you walk through the interactions that you have with the FDA as part of that filing, the acceptance and how things have progressed to the extent that you can share those details with us.

Yes. So similar to what we mentioned last week on the earnings call. So we have continued to have very fruitful conversations with the agency. We don't get into kind of the meeting-by-meeting discussions at this point. But the review time line was provided, and that includes the PDUFA date of November of 2026. And so we continue to look forward to the continuation of the review by the agency. And so we have the utmost respect for the FDA as I think we've been very clear on. And so with that, we don't necessarily go back and forth in terms of discussing meeting by meeting publicly, but what it does is it informs the continuation. Obviously, the acceptance was announced also recently and then there's a traditional cycle that comes with that mid-cycle review meetings, late cycle review so on and so forth after the application orientation meeting earlier on in the cycle. So there's that normal process set up, and we look forward to continuing to work with the agency through that process.

Great. So I'm convinced you guys should get approval. Based upon the product that's out there and its safety profile and your data, but maybe for the audience, you can elaborate about the HARMONi data, response, PFS, OS and what -- where your conviction lies following the data that you guys should get approval?

Yes, it's a great question, Tyler. So if we step back, right, there have been 4 Phase III clinical studies that have read out at this point with ivonescimab, 3 of which were in China in single region, randomized Phase IIIs and then the global HARMONi study, a multiregional Phase III. 4 Phase III clinical studies that have read out, 4 Phase III clinical studies that have read out with positive data. So that's a pretty good batting average with which to start. When we dive specifically into HARMONi. So we had a statistically significant progression-free survival benefit. And obviously, our -- as we continue to review the overall survival benefit was not statistically significant at the time of the primary analysis with additional follow-up of Western patients and part of that dealt with the delay in enrollment in the West. It was a Phase III study that had never been tested in the West. And so that delayed enrollment about 4 months or so in terms of physicians getting comfortable with the data, getting comfortable with the bispecific molecule, risk of metastases to the brain and the ability to control that bleeding so on and so forth. And so once we kind of accounted for that long-term follow-up, we had the nominal p-value of 0.03, which implies the benefit for overall survival as well. And that threshold below the magical clinical meaningful 0.80 was seen in both the primary analysis and the long-term follow-up. When we look at what's in the field right now, right, there's 1 fully approved regimen that's the amivantamab plus chemotherapy regimen. So that was approved on a progression-free survival benefit, a trend but not statistically significant overall survival benefit. So very much akin in terms of efficacy data. And then when we look at the safety profile, there's been some well-established tolerability concerns with respect to amivantamab. We believe that the data that's been shown in the HARMONi study as well as HARMONi-A, HARMONi-2, HARMONi-6, have shown a very manageable safety profile. And we think when we look at the totality of the evidence, that's meaningful with respect to the need out there in terms of options for patients and physicians to choose from. We also -- overall response rate was numerically higher in the ivonescimab-arm duration of response did not have overlapping confidence intervals in terms of ivonescimab versus the chemo-only arm. And so as we look at the data, we see very clear risk benefit profiles that favor ivonescimab as compared to standard of care chemotherapy in the study as well as what we see and then just in the marketplace, what's available for patients and the need for additional options, we think the study showed that this regimen has a nice place there. And I think that's been generally consistent with the feedback we've gotten from KOLs in that space as well with respect to the desire for optionality and that this regimen has shown what they're looking for in terms of that optionality.

What about the enrollment in U.S. versus ex U.S. and that split as well as the consistency of the data between the Western and the Eastern populations. Do you believe that based on everything you know that the FDA is kind of comfortable with that enrollment split and that the data are constant enough for approval?

I mean, with respect to the enrollment split so we saw about 38% in the West, about 62% in the East. That's reasonably consistent in terms of many of the EGFR mutant trial. So EGFR mutation positive lung cancer is -- has a bit of a higher prevalence in patients of Asian descent as opposed to many western patients. And so we typically do see a higher enrollment in Asia in EGFR mutant non-small cell lung cancer in general. So that 50% to 65% is a reasonable range in terms of what's seen from an enrollment percentage there. So I don't think there's been a lot of question with respect to enrollment splits by any stretch. I mean, I think when you bring up consistency, we talk about gold standard of overall survival in terms of what that looks like. it's really difficult to make an argument that the data is not consistent. It's actually more consistent than is often seen in randomized Phase IIIs in general, from a regional breakdown, especially when those individual regions are not powered, median overall survival in the West, 17 months for the ivonescimab plus chemo arm compared to 14 months for the placebo median overall survival in the East, 16.8 months versus 14 months incredibly consistent from a numerical median perspective, hazard ratios in Kaplan-Meier curves, I think if you overlay them when you look at earlier maturity versus including later maturity with Western patients, remarkably consistent. And I think we've shown that in a couple of presentations as well. So I think the consistency has been established pretty solidly. And so now it's really making that case with respect to the benefit risk profile for the application.

Yes. And just adding to what Dave said, the number of patients, right, that as you said, the EGFR-positive non-small cell lung cancer is more prevalent in Asia. But those numbers of 150 patients from the West were pretty sort of negotiated with the agency. So we think that we've met that obligation. There was never that number designed to show independent sort of statistical significance in a region, but just to show consistency of the results globally.

Okay. That's very helpful. What's your latest perspective on the market opportunity in this setting for Summit in the Western population?

Sure. I think we've spoken earlier. When you look at the vast amount of settings by which we believe ivonescimab has the opportunity. So when you look across, not only non-small cell lung cancer, but when you go beyond lung cancer into those tumors that are PD-1 sensitive or checkpoint inhibitor sensitive, those that are VEGF-sensitive as well as places like EGFR mutant non-small cell lung cancer, which doesn't have an approval in either a checkpoint inhibitor or anti-VEGF therapy. That total available market, this is about 3% of that. And so from that perspective, it's a small portion of the overall opportunity for ivonescimab. However, it's an opportunity to lay the groundwork, right? And so it's a thoracic oncology indication. So you're able to build experience with thoracic oncologists. We look to our next readout that's in frontline non-small cell lung cancer in the squamous histology cohort. And so the opportunity to really work with thoracic oncologists have that availability of the drug to be able to use and administer in patients and understand is always helpful in terms of setting the ground for the next step. Obviously, there's commercial underpinnings as well that come with that interactions with payers, health systems and so on and so forth as well.

Yes. As a clinician, it is a rare population, but it is the same physicians that treat the EGFR positive in the frontline. But as Dave said, it's an opportunity to enter the market early but the HARMONi-3 readout is going to be critical for us.

That's great. So we'll go ahead and move to the front line then. Was there in the audience at the plenary session at ESMO when you guys gave that presentation, again, remarkably consistent, beautiful PFS separation across the subgroups, as you guys have shown in prior trials. And you mentioned on the recent earnings call that you're now doing a PFS interim analysis in Q2 with HARMONi-3 in squamous population. So as you split it around ESMO. So maybe you could talk about what changed there? And what is giving you confidence to take that earlier interim analysis in Q2 based upon the historical data and HARMONi-6,etcetera.

No, it's a great question. So when we look at the historical readouts that have taken place to date so there's been 2 randomized Phase III studies that have gone head-to-head against the PD-1. So HARMONi-2 IVO monotherapy, pembro monotherapy, and then that's in the PD-L1 positive frontline lung cancer. And then HARMONI-6 that you're alluding to, Tyler read out last fall at ESMO. IVO plus chemo versus PD-1 plus chemo frontline squamous, right? And so HARMONi-6 is pretty much a direct read-through in terms of HARMONi-3. There isn't much better of a read-through in terms of a Phase III study than a randomized Phase III done with effectively incredibly similar combinations in an incredibly similar setting, right? And so -- when we look at HARMONi-2 and HARMONi-6, both were highly statistically significant in PFS, both achieved that at an interim PFS look, right? And so one, when we look at the opportunity to accelerate the timing. It's one following the data that's been generated by our partners at Akeso. So we said we'll continuously learn from the data generation from our partners. We've now seen 2 randomized Phase IIIs hit the interim PFS. And so that begs the question in terms of almost why not as opposed to why here. But secondly, and very importantly, what it also does is it accelerates the conversation with the health authorities, right? You can have discussions with the health authorities, but it's a different conversation when you go in with this is a statistically significant positive primary endpoint in a Phase III study. That's a different conversation, right? And so with an interim PFS, that analysis to be conducted in the second quarter, as we said, that accelerates the opportunity to potentially have a conversation with the health authorities based on potentially positive readout in that scenario.

Great. And as we think about that interim analysis, is it fair to say that the duration of follow-up and the number of events is going to be designed to be very similar to what you saw with the positive in terms of HARMONi-6 and HARMONi-2 potentially a little bit?

Yes, I don't know that we've commented specifically in terms of expectations on like median follow-ups or whatnot. We started enrolling the squamous cohort of HARMONi-3 a little bit earlier than the nonsquamous when we -- as I mentioned in the opening there. But nonetheless, I think we're confident with respect to what we've seen in HARMONi-2 and HARMONi-6 and then what that should read through based on the similarities of the study.

Okay. Yes. If I could 30 seconds just tie it together. You asked like what is the partnership with Akeso. They've been a great partner. They provided a lot of data. They continue to provide great Phase II data, Phase III data. But if you look at what we've done with HARMONi-3, I mean, that study was designed before any of these studies read out. But then the Akeso HARMONi-2 study readout. This is when we have the confidence to throw in the nonsquamous cohort there, right? Because we saw in HARMONi-2, there didn't -- the efficacy benefit existed in both histologies, right? And now the HARMONi-6 data has read out very strongly in combination with chemo, and that's a very similar population to the HARMONi-3. So I think that informs that decision, and as Dave alluded to, the goal is to bring this to patients earlier, right, as fast as possible, right? And as Dave said, you can have that discussion. PFS and OS are dual primary endpoints. When you have one of those endpoints hit, it becomes a positive study, and you can have that pre-BLA meeting. Prior to having that data in hand, you can't have a BLA meeting, right?

And for HARMONi-3 and squamous, which is reading out first. What do you think is the bar for PFS and OS in order to file and receive approval? And remind us when OS is coming.

Sure. So the last question is easier. So interim OS consistent with the previous disclosure and what we said about the final PFS analysis in the second half of 2026, right? In terms of bars, I think as opposed to -- I never want to speculate in terms of the agency and what specific directions and part of that is it's a total package consideration, safety data becomes very important and then the end points reading out in each is important. When we talk to KOLs and physicians, what they've said pretty consistently in terms of what they're looking for about 0.75 for PFS, about 0.8 for OS. Those -- when you have dozens and dozens and ultimately, hundreds of conversations with KOLs as well as significant high treating physicians. They tend to coalesce around those 2 points. And obviously, the study takes that into consideration in terms of this design as well.

Would you say that, that KOL feedback on PFS and OS in terms of expectations is pretty consistent with the non-squamous population and maybe you could remind the audience when we're going to get that data as well.

So for clinicians, yes, I mean, I think that seems reasonable. I mean if you go back in history, like the 25% improvement in PFS and 20% improvements is this dates back to prior to these targeted therapies and immunotherapies back in the old days when you had chemotherapy, what's the bar that wouldn't change your practice? That seemed to be a reasonable bar. I mean what we're seeing with ivonescimab has been better than that. So we're hoping that we can beat that minimum, but it's more of a what you say, and it seems to go across products. It's not specific to IVO. And then the other question was?

The timing of the PFS OS for non-squamous.

Yes. So we've said the plan is to complete enrollment in the second half of 2026 and that would lead to a planned PFS analysis in the first half of 2027. We've been a little bit less specific in terms of overall survival, not because there's not one plan. We're just still it's still in the first quarter of '26 and so as we look at the first half of '27, we have the plan, but we want to make sure we get to the number of events before we give any formal guidance with respect to that timing. But in general, final PFS would be in the first half of '27.

Yes. So the enrollment started after the squamous, and it's been very brisk, but it is a larger sample size. So it's hard to give specifics, but it seems to be enrolling very well.

All right. That's good to hear. So I guess just -- so HARMONi-2 ivonescimab is obviously already proved on the basis of that in China. So Akeso doesn't necessarily have to update that OS data, HARMONi-6.

But you're going to ask anyway.

Yes. Well, no expectations for HARMONi-2, but what about HARMONi-6, right? Akeso might update that. And again, it's not in your hands, but is the -- is it fair to say that we might get HARMONi-6 and we're probably not getting HARMONi-2 or.

So I'll remind you that this is Akeso study, and they haven't issued formal guidance with respect to either study in terms of an OS update. What I would say is the protocol has been published with respect to HARMONi-6 and that's a larger sample size as well. And that's an important distinction between HARMONi-2 and HARMONi-6. The HARMONi-6 study is a bit of a larger sample size so you can kind of infer from looking at the protocol, there's likely a '26 event somewhere in there. HARMONi-2 because that was -- as I mentioned in the beginning that study was in flight when we did the deal. So right, that's specifically designed single region, exclusively in China, PFS, not really thinking about global implications. That study reads out positively and everybody goes, great, but we're changing the goalpost after the study. We want to talk about OS like yourself. And so what that -- it's a fair question, but I think if we look back in terms of history, what that goalpost did effectively move after. So in fairness to our partners at Akeso, they really haven't provided guidance, and we won't leapfrog above them. HARMONi-6, that was kind of upsized in order to take into account some of these conversations.

Okay. Fair enough. We have 4.5 minutes to talk about all the other indications. Frontline lung cancer is huge. I think everyone knows that. So let's move to colorectal. Why did you guys choose that as the first expansion indication beyond lung? How is that program progressing? And when could we get data?

So we -- it is funny. I was about to say we just began enrollment in that study. So I appreciate that when will we get data. So we're not quite there yet in terms of guiding on that point. But look, I think a couple of important points, right? So microsatellite stable colorectal cancer, not a PD-1 indication, right? That's a historical VEGF indication. We had very encouraging Phase II data there. We tested that, as we mentioned, in multiple -- with multiple chemotherapies. We provided the FOLFOXIRI data in conjunction with our partners at Akeso and ESMO 2024, continue to enroll that both in China and the U.S., with additional cohorts for different chemotherapies settled on the FOLFOX6 regimen based on discussions with KOLs review of the data, that's matured a bit. We're highly encouraged that led to the go-forward there. It's also a cornerstone opportunity. That's a significant number of patients, that's an unmet need. There hasn't been a lot of progress in the last 20 years in terms of MSS CRC, a couple of EGFR inhibitors, right, but not the broader market for all patients there. And so that's a significant opportunity for patients with a need, and it's another cornerstone opportunity for ivonescimab.

So Tyler, maybe I can let your appetite for when we will look at data. So a couple of things. So remember, we are very excited about this CRC because it indicates that ivonescimab is unique, right? At the simplest way you can think of it is the VEGF component is competing on bevacizumab. But we think that there may be something unique about ivonescimab and sort of cracking that immunotherapy going into these colder tumors. So as Dave mentioned, there was FOLFOXIRI data published by Akeso in ESMO 2024, which was the excitement clinically that led to the GI-3 study. We decided to move forward with FOLFOX and during that, we did a global Phase II to expand Akeso's ongoing Phase II. So now there will be global data for Phase II, looking at the FOLFOX regimen with ivonescimab and that data, you might see sooner. Can we say like maybe this year?

Yes, probably this year.

And that will be very important data because Pfizer has released their FOLFOX combination data as well at the end of last year at SITC. So that will be a sort of a data point that can be compared. You should never compare single-arm studies to against each other, but everyone does.

Thanks for that, Allen. You guys -- so you earlier, Dave, you mentioned GORTEC, yes, ILLUMINE trial head and neck. So basically, same questions for head and neck. Why do head and neck, how is that program going to progress when we see data?

So that will -- we said early Q2 with respect to FPI there. And so look, there's a -- head and neck is another setting where you would biologically makes a lot of sense for ivonescimab. It probably wasn't one of our top 3 or 4 settings in terms of where to go next, however, we were approached by the GORTEC Cooperative Group. And anytime you're approached by an external party who has significant interest in running a study of unmet need with the compound. That becomes really important to take that seriously. And so that led to some pretty quick movement with respect to moving forward with the study. That's a multiregional study. And again, we'll take a look at bringing that into the United States as well. We'll consider that over the course of the next few quarters. And what that really does is it continues to broaden the scope. In addition, as I said, if it's not one of our top 3 or 4 places where we intended to go, that means there are additional settings that we are looking at those -- looking at sponsored indications as well in those settings that we plan to continue to move forward later this year.

So what are your top 3 or 4 settings in terms of where to go next?

I love the question. We have them. But I think as an anecdote to that when we announced colorectal cancer in October of 2025 that we had planned to go first-line colorectal in Phase III by November of 2025. There were 2 other competitors, shall I say, who were going to go into colorectal cancer in the frontline setting. And so we're going to wait until we're basically ready to go forward with those indications as opposed to providing too much groundwork. We're in the background laying the foundations for those settings right now. And part of that is we're ready -- we'll announce that when we're basically ready to start enrolling.

Fair enough. We'll do my best to exercise some patience here. But in closing, since we're up on time, like to ask you both what aspect of the Summit story do you believe is most underappreciated by investors?

Yes. I think I alluded to this before. I mean everyone is asking us about HARMONi-3 and what indication we're going to next I think people think of this as operational execution, who can throw the more studies out there the fastest. But again, I think the format of the molecules is very underappreciated. I think ivonescimab is at that goldilocks or sweet spot in terms of design, binding affinity, daisy chaining that will make it competitively much more advantageous to use across some of these other formats. The other formats may work but they still have to prove themselves, right? So there's a lot of things to look at.

And I think on that point, not all PD-1 VEGFs are interchangeable. And we have now shown data in 4 Phase III clinical studies, 4 Phase III positive clinical studies. That's -- if you're going to make an adjustment, there's a lot more floor -- room to the floor than there is to improve upon that one. And two, there aren't a lot of compounds that have started with that track record that people are not excited about going forward and ultimately get proved out.

Wonderful. With that, Dave, Allen, thank you very much.

Thanks. Really appreciate it.