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

All right. Good afternoon. Thanks, everybody, for joining Jefferies Healthcare Conference in London. My name is Clara Dong. I'm one of the biotech analysts here at Jefferies. So sitting next to me, we have Chief Business and Strategy Officer, Dave Gancarz; and Manmeet Soni, Chief Operating Officer and Chief Financial Officer of Summit Therapeutics. Welcome.

Thank you for having us.

Thanks.

So Summit is definitely a very well recognized name in the industry. But just to set the stage for our discussion and for our audience here, can you share a little -- a brief overview of the company, what's your mission, what's the current development of your bispecific ivonescimab and your just broader strategic vision?

Sure, happy to. So Summit Therapeutics is a mission-driven organization. Our mission is simply put to make a significant difference for patients who are suffering from cancer. And so our co-CEOs, Bob Duggan and Maky Zanganeh have a storied history with their experience in not only biotechnology, but the health care sector as a whole. And in our current state, we are focused as I mentioned, on cancer and the way in which we are seeking to execute on that mission is through the development of ivonescimab, our PD-1 VEGF bispecific antibody. So ivonescimab is a specifically engineered bispecific antibody, and its intent is really to improve upon the previously established efficacy and safety standards of those 2 targets. And so that intent is what we look to carry out our mission on. Very importantly, there are -- this is not a concept anymore at this point. And so there are over 3,000 patients who have been dosed in a clinical setting with ivonescimab. And when you expand that into and incorporate the commercial setting in China where the drug is approved, that number expands to over 40,000 patients who have received ivonescimab. Currently, there are 14 Phase III clinical trials. There are 4 global studies that Summit is sponsoring in addition to 10 additional trials that are being sponsored by our partners, Akeso in China. So you can see the vast breadth and depth of the program from that point. And so with that, that becomes our mission -- the execution path for our mission.

Great. And you did have a lot of data events this year, and we will definitely touch on all of that. But maybe before we talk about the efficacy of ivonescimab in broad indications and I also -- I just want to take a step back and talk about the safety profile of ivonescimab, as you mentioned, a lot of patients have been treated. And how is the patient experience, especially on the safety so far compared to single-agent anti-VEGF and PD-1?

No, thank you for that question, Clara. And I think it's a really important point because as we speak about -- I talked about the molecule was designed by our partners at Akeso to improve upon both the safety and the efficacy standards that were established in those 2 targets and specifically with respect to safety. Nothing illustrates the tolerability of ivonescimab better than the recently disclosed HARMONi-6 data by our partners at Akeso. So this is a single region Phase III study conducted in China, that met its primary endpoint in progression-free survival. And importantly, is in a space where anti-VEGF monoclonal antibodies really haven't been able to be developed. If we go all the way back to 2004 in the JCO paper that spoke to the difficulties of bevacizumab in the history of hemorrhage and significant hemorrhage, fatal hemorrhage events that took place for squamous non-small cell lung cancer patients. What we've been able to show with -- through our partners at Akeso is the tolerability of ivonescimab in squamous patients. And so that was very important. That was also demonstrated as a part of the HARMONi-2 study as well in the monotherapy setting that included both non-squamous and squamous patients. And then we take that forward in the HARMONi study, the global study that Summit sponsored, we saw very consistent results with the safety profile that was demonstrated in the HARMONi-A study in China, in the same setting in that second-line EGFR mutant population. And so we saw consistency of that data between the East and the West. And then we saw 2 particular Phase III trials, whereby historically, anti-VEGF has not been tolerated. And this is a place where we think there's a clear distinguishment when we talk about, hey, is it the VEGF contributing more? Is it the PD-1 contributing more? This is really where we speak to the novel mechanism of ivonescimab, that's really different than the 2 administered individually.

Yes. And I would add, right? This is distinguished, right, because we had engineered, right, our partner, Akeso, had engineered it so smartly, right, so that because of the cooperative binding, we see this impact, right? And another thing to note is the half-life right? Half-life for ivo is approximately 7 days -- 7 to 8 days, which is much less the other comparable drugs and whether it's VEGF or PD-1 alone. And that cooperative binding and the half-life makes it right, much -- having much better efficacy and reducing toxicity. So that helps us a lot.

And then since you already mentioned the ESMO data HARMONi-6, so maybe we start talking about that first. So you reported hazard ratio of PFS 0.6. So maybe just help us contextualize that number? What does that really mean to patients? And then squamous non-small cell lung cancer, I think historically, it has been really difficult to treat but just anti-VEGF single agent because of the hemorrhage risk you just mentioned. So like data from HARMONi-6 change people's perception on that?

I think the best way to change perception is through data and through a randomized clinical trial, right? And so when we step back contextualizing the results as a whole, 0.60 hazard ratio effectively is intended to represent a 40% improvement over existing standard of care. And so when we started this journey, the first trials that read out were HARMONi-A, which was in the second-line EGFR ivo plus chemo versus chemo alone. And that was a place where the PD-1 antibodies had historically been unsuccessful, both from a PFS and an OS perspective. And so the next question became good. You were successful in a place where PD-1s weren't, how about going head-to-head? HARMONi-2 monotherapy, ivo versus pembro and head-to-head against the PD-1. That was successful. And the next question became, but the standard of care is largely dominated by chemo combinations, and some of these questions might have been asked by a lady to my left. And the -- well, can you carry that forward? That's really what will be the dominant standard of care in frontline lung cancer is and can you show a result there? And so this 0.60 hazard ratio in HARMONi-6 answers the third question of frontline the overwhelming standard of care across many solid tumors is immunotherapy plus chemotherapy. And so this was really the groundbreaking piece of rising tides raise all ships was the concern, and this was a clear difference the curve separate and continue to separate really through the median follow-up time for HARMONi-6. And so we see a median PFS difference of 11.1 versus 6.8 months. So there's about a 4-month difference there in terms of just the median difference, and then the hazard ratio represents about a 40% difference in the single region study that was conducted by our partners at Akeso. And so that then reads into the global study that we're conducting with HARMONi-3, which looks at both squamous and non-squamous patients, and that will be the most direct answer to your question, Clara, with respect to changing care. But the feedback has been extremely positive from physicians, both KOLs and in the community with respect to the data at this point.

Yes. So Clara, one thing to add, right? If you remember, 18 months ago, right, there were -- in early 2024, right? There were a lot of questions whether this China data will translate into Western patients? Whether the PFS will translate to OS and the early OS will be sustained? And now we have answered all those 3 questions through these 4 positive 3 trials, right? And that's how -- it's a combination of the data and the safety, as we -- as Dave mentioned earlier, right, that we have now the safety pool of that. Over 3,000 patients, we don't upgrade it on a monthly basis, but it is much higher now, and it's increasing as we are enrolling. And we already mentioned, right, HARMONi-3 study, which is the squamous study is now over 80% enrolled, right? So those tells you right that the safety efficacy is all there, and it's a combination of the data sets altogether.

Great. And then you just mentioned HARMONi-3 trial, the global trial. So I mean recently, you also shared an update of the patient number for the trial and then you say you will conduct separate analysis for squamous and non-squamous population. So maybe just walk us through the rationale here?

Yes. So I think on HARMONi-3, right, we wanted to make sure that we have enough probability of success on both arms, right? Squamous and non-squamous, they are 2 distinct populations. And you know there is different even the treatment right over there, durations over there. And non-squamous is twice as big as squamous and it's growing. So it was very important for us to make sure we have enough that we even wanted that in the future when we read out the data that 1 data set is more stronger than others, so now we have powered them individually in the same protocol, and that will allow us to have the squamous results much sooner. As I said earlier, a few minutes ago, that squamous study, even with 600 patients, we are saying it's over 80% enrolled, right? So the data set we said we expect to complete the enrollment in the first half of 2026. I can say that we are enrolling pretty good on that metric. And non-squamous is expected to complete enrollment by second half of 2026. So you will see the data sets for squamous, right, the results should come out in the second half of '26. And in first half of '27, you will see non-squamous. So we are accelerating the time line because the enrollment is going so strong on both sides and making sure the probability has increased.

And then how should we think about the time line for pivotal readout? And are you going to conduct both PFS and OS analysis?

That's correct.

Yes, that's right. So for the squamous population, we've been clear that we plan to -- the data that Manmeet just spoke to in terms of second half of 2026. The intent there is that, that would be a primary PFS readout, and then there would be an interim look at overall survival at that point in time.

Great. And then also, very recently, at CITIC, your partner, Akeso also reported an updated data for HARMONi-A with an updated hazard ratio for overall survival at 0.74. So maybe just tell us a little bit more about the data, like what's the key takeaway from that updated data, especially in the context of long-term overall survival benefit?

Yes, great question. And so part of what Manmeet just spoke to in terms of when we look at PFS translating into OS, and then there's also been a notion where anti-VEGF has been combined 2 monoclonal antibodies or a monoclonal antibody and a TKI. But there's been a lot of combinations of PD-1 and VEGF. And there's been good data with respect to progression-free survival, but does that always translate into overall survival. Anti-VEGF tends to compound adverse events over time. And so the longer you administer anti-VEGF, the more the toxicities tend to arise has been the notion, and that ultimately leads either discontinuation of therapy, which is harmful in terms of achieving your OS standard, or frankly, those adverse events can become life threatening at times. And so what this showed was that, that notion that the anti-VEGF portion of the antibodies is going to be a PFS driver and not an OS driver. It basically kind of broke that notion. It was direct evidence against the idea that this compound is going to be mainly PFS without OS. The first study that was conducted that was a randomized Phase III is a randomized Phase III that showed an overall survival benefit over standard of care. And so what we didn't see were discontinuation rates that were high. What we didn't see were compounding toxicities. What we saw was a tolerable regimen that over time showed an overall survival benefit that was statistically significant. And that's the single region study conducted in China. But it's the first Phase III study that was run with ivonescimab, and it's very important that, that now has a statistically significant overall survival benefit as well.

And then as you mentioned in the beginning, the novel mechanism, so do you think the sustained overall survival benefit actually offers any new insights into the contribution of PD-1 and VEGF components? And we are seeing what appears to be a long tail effect with ivo and a point that many physicians we've spoken with have frequently discussed and agreed upon. So do you agree with that as well?

Yes. I mean I think the IO tail or that long tail is generally associated with immunotherapy, right? And so the HARMONi-A data as well as -- and I would say the HARMONi-A overall survival curve and the HARMONi overall survival curves were generally a consistent shape, the hazard ratios were generally consistent as well. The long-term follow-up analysis was 0.78 with HARMONi and 0.74 on HARMONi-A. And so you can see that very consistent results, consistent shape of the curves. And so with that, you see what appears to be the IO tail there. And that further speaks to 2 things. One, PD-1 monoclonal antibodies themselves weren't successful in showing PFS or OS benefits. This showed both the PFS and an OS benefit. It appears to have that IO tail. And there's been a lot of discussion with respect to anti-angiogenic therapy for EGFR mutant patients. And so the contribution of targets is clear. I think the one thing I would go further, though, is I often want to break apart from the idea of how much was PD-1, and how much was VEGF. I think what Manmeet spoke about in terms of this is a novel mechanism, this is different. It is through its cooperative binding capabilities, a new approach to treating cancer. And I think that's something that was demonstrated. Even when we look historically at PD-1 plus VEGF in monoclonal antibodies in EGFR mutant, we have not seen an overall survival benefit.

I think another thing to note is the sustained OS benefit, right, and HARMONi-A has already demonstrated, right? When we did earlier maturity, data cuts, right, at 50% maturity, right, it was around 0.79, 0.80, it was ranging at different times. Now it's 0.74 when it has matured. Same thing we have demonstrated on the Western patients data and HARMONi, right? Even after waiting like with the September data cut, which we did, it was coming into a significant number. So it is showing that as you sustain, right, because you have to wait for the maturity of the data, and that has been pretty encouraging.

And then before we move to HARMONi trial. I also want to ask, this is a second-line EGFR mutation. So do you think this long-term overall survival benefit have any readthrough to frontline trial as well?

Yes. I mean it's certainly a fair question. I would say it's difficult to make that assertion without the data. That's why we're running the studies. What I would point to, though, is the consistency of the results of the Phase II and III data. And we saw that again, even with HARMONi-6, the Phase II data showed 11.1 months of median PFS. The Phase III data showed 11.1 months of median PFS, right? So we saw that consistency in translating through. I think when we look at the frontline data, some of that -- there was a longer-term follow-up in some of the Phase II data that we saw there. This was presented at ELCC in 2024 with about 22 months of median follow-up time. And we're seeing that tail that you talked about, it's a single-arm study. It's a Phase II, but you see that tail. You're seeing the consistent results when Akeso ran the Phase III study. And so I think when you take the totality of all of this data, that's really what encourages most -- again, 4 Phase IIIs have read out, 4 positive Phase IIIs, different settings within lung cancer and now the 10 Phase III trials that Akeso is running that are now well beyond just non-small cell lung cancer. We have that trial this now up in microsatellite stable colorectal cancer. And so when we look at all of the -- it's really the totality as opposed to kind of saying this one piece is this directly read through. It's really the totality of the evidence across all of the studies.

And then for HARMONi trial in second-line EGFR mutated non-small cell lung cancer. Maybe tell us what's the significance of this trial and what are the key takeaway from the data and especially in the context of BLA submission as well?

Yes. So I mean, I think this is the first global study, right? And so this was a place where people were looking at the comparability of what we've seen in the readouts from China and how that translates in. I think when we look at the gold standard of overall survival, we saw extraordinarily consistent results, both looking at hazard ratios and medians. And so when we look at medians, basically 16.8 to 14 months, 17 months to 14 months when we compare the East and the West. When we look at hazard ratios at the same follow-up time. So Manmeet spoke about is we continue to follow the drug. And again, contrary to what people have assumed that you'll continue to get worse, we saw an improvement in overall survival with longer follow-up time. And so when we look at now consistent follow-up time, as we know, HARMONi was enrolled sequentially. And so the follow-up times between the East and the West were different. But when we look at that, about 50% data maturity, if you will, number of events over total patients enrolled. We saw in China, about 0.8 to 0.82 at that point in time, we see in the West 0.84. So remarkably consistent results at the same follow-up time, which is incredibly important when we look to -- as we continue to expand our development plan, looking at the results that are coming from our partners at Akeso, looking around at the standards of care. This becomes really important to show that. So I mean that's -- first and foremost, an incredibly important data point. And then secondly, this is an area of high unmet medical need, right? There's one fully approved regimen in the space in post-TKI EGFR mutant patients. And so this is a place where we believe ivonescimab plus chemotherapy has a significant place to make a difference for patients. And hence, that's the reason for when we see the results moving forward with an application. There is no regimen in this space that is demonstrated an overall survival benefit that's been approved by the FDA. And so that's an important point as we think about the risk-benefit profile, which we -- in our review of the data is there in this space.

And I guess based on your interactions with the FDA, like how should we think about the balance of importance of primary overall survival analysis as well as long-term follow-up data because, obviously, the changes in long-term data will likely be driven by ex-China patients?

Yes. I think I understand where you're going with that question. The -- so as we said, announced, we intended to submit our BLA in this quarter. And part of that was really taking into account all of those factors, right? The consistency of the data, the East to West, the long-term follow-up analysis that was performed. Understanding, to your point, the FDA had asked for a statistically significant overall survival benefit. And so when we take all of those factors together, that's really where we come to the conclusion that we believe that this is meaningful in this space for patients, and it's in the best interest of patients to move forward, and this is our perspective.

And we've also noted, right, none of the approved therapies have seen any OS, which got recently got approval, right? So yes, we understand the bar is high, but I think if you look the combination of all the data, including HARMONi, which has shown OS significant, HARMONi-A, right, there. So all those things will be combined. And now we have much more data sets, which will be coming in the next 6 to 9 months.

Great. And also, you recently opened new trial in colorectal cancer. So maybe talk about your -- the opportunity there and your development path.

Absolutely. So we've been clear from the beginning of this year that there's a significant opportunity in non-small cell lung cancer for ivonescimab, but this is not a lung cancer drug. It happened to be the place where we started. And that's evidenced as well by the pipeline demonstrated by our partners at Akeso with so many trials outside of lung cancer. But obviously, ESMO 2024, there was data that was provided with FOLFOXIRI chemotherapy backbone that was highly encouraging. And we continued to run that Phase II study with multiple chemotherapy backbones. We also enrolled patients in the United States in that setting. And so when we looked at the totality, we were able to compare several data points, different chemotherapy backbones, different follow-up times. We had multiple endpoints that we're able to assess both safety and efficacy. And so that gave us the confidence with which to move forward in this space. And it was -- another example of a place where PD-1s have not been historically as active. There has been a VEGF component. But we think that the novel mechanism that exists here is explaining that increase that we're seeing in the efficacy profile in -- to Manmeet's point, with the half-life maintaining that tolerable safety regimen profile as well in the regimen.

And can you also talk about your collaboration with Revolution Medicine about the RAS(ON) inhibitors combination?

Absolutely. We're extremely excited about this, and we're looking to begin dosing patients early next year. And so what that really does is the next step becomes -- as we move forward as an industry at oncology, novel, novel combinations are exceptionally important. And this is really the first step for ivonescimab in that -- from that perspective. And so in walking through the tolerability of ivonescimab, that gives us confidence with which to combine with several different targets. So the multi-RAS and the targeted KRAS inhibitors from Rev Med are extremely exciting and are something that we watch closely, and it became very much a clear pathway by which we could look to combine and do what's best for patients. That is step one for us also in terms of potential combinations. We've been very clear that we believe we have a strategic advantage by not looking to combine with those molecules in our pipeline, but to follow the data to collaborate in a clinical trial collaboration setting with multiple other targets that exist. We can follow the data, and then we can find where the data points to -- I think we've talked about this historically, but we don't believe there's a single platform of ADCs that will become the standard of care across all solid tumors. And we've seen this with chemotherapy as well, there's not a single chemotherapy backbone that is the standard of care for all solid tumors. And so it's very important for us to -- instead of looking to synergize within our own pipeline, really to follow the data to do what's best for patients.

Great. And lastly, what are the key milestones in the next 6 to 12 months that investors should watch for?

A lot of them, right? I already mentioned about, obviously, BLA filing this quarter, right, which we plan to submit for HARMONi or EGFR second-line, completing enrollment for squamous arm for HARMONi-3 in first half of 2026, completing enrollment for non-squamous arm in the second half of 2026, and then finally, pivotal data for squamous arm in the second half of 2026. So those are a lot of milestones in near term, and that's why -- that was the reason, right, we make sure our balance sheet is strong enough, right, to carry on for the next 12 to 18 months. And now we are -- we can say we had $0.75 billion in the bank, right, after doing this latest $500 million financing.

And that allows us to look to expand the lead that we currently have in this space.

Yes. And our success has been, right, the mantra for our success has been right, focused retention and massive action. And by putting focus, we think we can achieve much faster than what anybody can do. And that is pretty much visible that we have already a lead in lung for over 2 years, right, based on other people who are following in lung and similar in CRC, right, other companies are going to start their Phase II, III, we are starting Phase III. So that will be a distinguished -- you are ahead in the game.

Great. Very much looking forward to all those milestones. And thank you so much, Dave and Manmeet for this session. Thank you for all the audience here joining us. Enjoy the rest of the day.

Thank you. Thank you for having us.

Thank you for your time, Clara.