Everyone, thanks for continuing to join us on this second annual Oncology Days. Happy to have the crew of Summit Therapeutics for the next fireside chat. We've got a lot of people to introduce, but starting from the left-hand side there, we've got Dave Gancarz, Chief Business and Strategy Officer. You've got the two co-CEOs, Maky Zanganeh and Bob Duggan, and then you've got the COO, CFO now as well, I believe, Manmeet Soni. And down at the bottom on a separate screen, you've got Allen Yang, CMO. Thank you all so much for joining us. Maybe we can kick it off to Bob, if you could just give us a brief introduction to Summit and how you came to discover and in-license your lead asset, ivonescimab. Yes, yeah. Thank you very much for hosting us, Brad. It's great to have your coverage, and we really appreciate it. Back in the summer of June 2022, the name and word Akeso came up out of about a group of 150 companies we were looking at, and the mantra was, we wanna locate a business that is a really drug production machine, not just in-license, then wants to out-license us. We found Akeso. We took a really deep dive into it, and we found, interestingly enough, that the founder of Akeso had been a part of the group that had worked with Imbruvica prior to us taking it on at Pharmacyclics. So she knew all about it, and then she also knew how Maky and the team had handled it and managed it, which gave us some, some natural affinity for the, for the two, two groups. So, we studied it for a good six months, and at the end of the day, we, we chose to put up $500,000, $500 million, with a B I should call it, as my friend calls it a brick, but it's $500 million and a $5 billion overall deal. And I give Maky and the team a lot of credit for negotiating that, that back-end, back-end piece. It's, it's, you-- as you see today, it's a very valuable, asset acquisition. We did it at a time... I'll just touch on the geopolitical issue. We did it at a time purposely. Many of us have a long track record in dealing with China. I brought robotics into China. Our other drug was partnered with Johnson & Johnson. We had many visits to China, and our view is, for humankind, the Chinese and the Americans need to get along, and they will. And I think Jamie Dimon and Kissinger, just prior to his death, did a visit over there and said, "Look, guys, this is what's gotta happen." And doing business deals like this helps that. So we exported money to China and imported a product. They thought that was great. We think it's great. It's gonna help a lot of Americans and others handle non-small cell lung cancer. So but I'll... It was a great, deep study. We have an excellent partnership with these people. We meet often, we talk often. We're here to do the very best we can with Akeso. I think the last comment, out of 90 companies from biotech that have gone public, three of them stand out of having met or exceeded expectations, and at the top of that list of three is Akeso. They are an exclusively successful business with highly qualified people, and they're really happy and proud to be their partner. I'll let Maky just give you a little address on how that deal was negotiated and why we're so pleased with it. Maky? Hi. Thank you, Bob. Actually, as Bob say, Akeso is a big biopharma company in China, over 2,300 employee, and they have a little bit market cap, around $5 billion. But they have over 30 compounds, and three of them is marketed, but six of them is a bispecific. And the ivonescimab is a PD-1/VEGF bispecific drug that we in-license in January 2023. At this moment of time, I can say that Akeso has 19 clinical trials ongoing right now in a multiple phase III, II, and I, and they enroll over 1,600 patients with ivonescimab in multiple therapeutic area. We decided to join one of the trials with them, the HARMONi in the EGFR post-TKI in non-small cell lung cancer, and second phase III that we started in the front line squamous, non-small cell lung cancer, two phase III, right as soon as we signed the deal, which Allen and Dave will go to deep down on these two trials. We didn't stop on that. For sure, we are going to evaluate this ivonescimab in our territory for other therapeutic area in the coming years, for sure. With that, if you have any other questions regarding Summit? Yeah. Yeah, I think the first question I'm sure you always get is: what is the difference here between the potential co-administration of PD-1 and VEGF antibodies, which has been tried in the past? Yeah, I'll take that, Brad. You know, so I think what people don't appreciate about ivonescimab being a bispecific... You said it, it targets PD-1 and VEGF, two validated targets in oncology, two very successful targets in oncology. But I think what people don't appreciate is that ivonescimab is unique as a bispecific, and I'm not aware of any other bispecifics that don't do this, is there's cooperativity between the binding sites. So the binding of VEGF to ivonescimab increases the binding of PD-1 by greater than 18-fold, and the binding of PD-1 to ivonescimab increases the binding of VEGF by 4-fold. And so that cooperativity in the affinity of binding leads to probably an accumulation of the molecule to where both ligands are present, which we believe to be the tumor microenvironment. What's also not underappreciated is that there are two binding sites for PD-1 and two binding sites for VEGF. And what's well described in the bevacizumab literature is that VEGF is a dimer and can cross-link two bevacizumab molecules, and it's been demonstrated with ivonescimab as well. You can have an ivonescimab bispecific bound to VEGF. The other half of VEGF is bound to another ivonescimab, and the other half of that ivonescimab is bound to VEGF. And so you have this daisy chaining of ivonescimab and VEGF. And once the VEGF is bound, that presents then high-affinity PD-1 binding sites. So you have multiple PD-1 binding sites, available to bind the lymphocytes. So you can think about the tightness of ivonescimab binding being much higher in the presence of both ligands, and then you have multiple binding hands for ivonescimab to lymphocytes and VEGF. And, you know, what you do is you enrich for binding of T lymphocytes that have high expression of PD-1, which are probably the most active in the tumor microenvironment. And finally, in terms of clinical activity, what happens when you enrich for the ivonescimab in the tumor microenvironment, you avoid it in being activated in the peripheral circulation. And that will prevent, you know, activation of lymphocytes in the peripheral circulation, as well as, you know, interaction with VEGF or the endothelium, which will probably improve the safety profile as well. 'Cause the safety issues you see with immune-related adverse, excuse me, IOs, as well as VEGF agents, are from off-target effects. So I think that's underappreciated. There's some also subtle things about the half-life being shorter, which also improves the AE profile, as well as the engineering of the Fc domain, which is Fc null, which has been demonstrated by Akeso to improve the immune-related adverse event profile, but I won't get too deep into those. Very helpful. Now, I guess when you were doing the diligence, what about the clinical data that Akeso had generated to date really helped reinforce and support that preclinical hypothesis that you outlined? I know investors sometimes are a little nervous to look at single-arm IO data and really place too much reliance on that. How did you think about that? Dave, do you wanna take that, or you want me to take it or? Yeah, no, I'm happy to, and then, Allen, please, please jump in. I think the—I mean, as I think we, we've walked through it in our corporate deck a few times, part of the, part of the impetus behind going, you know, from a clinical data perspective, backing up the preclinical hypothesis, really, stems from the phase II clinical trial that they ran, AK112-201, right? So that was a three, really four cohorts in that frontline squamous, frontline non-squamous, second-line EGFR mutant, and third, second line, post-immunotherapy in platinum doublet. So basically, you know, a traditional second-line, driver mutation negative. We're extremely encouraged by each of those, and that's really what led to ultimately us launching the two phase III clinical trials that we did in the second-line EGFR setting post osimertinib, and then ultimately in the frontline squamous setting in the fourth quarter of last year. So, you know, important to know, we were confident enough in the data, Brad, that, you know, we immediately launched two phase III clinical trials, not something that's typically what you see from an in-licensing perspective, and certainly, you know, in a non-big pharma perspective as well. But we really what we looked at also as we saw the data is, this was we needed to immediately show the differentiation between what, what this drug was, an ivonescimab, a bispecific with PD-1 and VEGF target, as, as Allen just described, from the PD-1 franchises that exist out there in the pembrolizumabs and the nivolumabs, et cetera, right? And so the frontline squamous setting is directly against pembrolizumab plus chemotherapy. And then the second-line EGFR mutant setting is a place where pembrolizumab, via the KEYNOTE-789, and then nivolumab, via the CheckMate 722 trials, were unsuccessful. So those two phase III trials were able to immediately differentiate ivonescimab versus anything that exists in the market today, but also from all the PD-1 franchises that exist. So we are not looking to be the eighth, ninth PD-1 on the market. This is a differentiated MOA, as Allen just described, and clinically, we're looking to prove that straight through. I would also say, in addition, if you look at the pipeline that Akeso has generated, it's not a this is we're starting in non-small cell lung cancer, but this is not a non-small cell lung cancer drug exclusively. There's 50+ indications which have been approved in PD-1, PD-L1, VEGF. Really, what we were able to see is, you know, the part of the value of this deal is now instead of having to launch basket studies and look at, you know, colorectal and head and neck and triple-negative breast cancer and earlier-line non-small cell lung cancer and hepatocellular carcinoma, et cetera, gynecological solid tumors, we can leverage the data that's being generated from our partners at Akeso. Each time we look at that data, you know, we obviously were encouraged enough to immediately run two phase III clinical trials, and then we were emboldened enough, even in the beginning of this year, to be able to say we plan to expand that clinical development plan for ivonescimab in 2024, early 2025. That's really generated also by the data we saw at the time of the diligence and continue to see maturing over the course of the past several months since we've consummated the deal. Yeah. And that's a great segue because this is a big year of clinical enrollment execution at Summit, and then also a big year of randomized data updates from your partner, Akeso. And could you walk through the design and cadence of one of those studies from Akeso, which is monotherapy ivonescimab versus Keytruda, which I'm sure has a lot of investor interest? ... Yeah, absolutely happy to do so. So, Akeso currently is engaged in four phase III clinical trials, right? Just to kind of lay a background, Brad, to what you just described, right? And so the, well, I think we'll talk about the second-line EGFR one in a moment, based on what you just said. But then, you know, they're engaged with our HARMONi-3 trial in frontline squamous. They're running their own sister study to that, exclusively in China, in frontline squamous. And then the other trial is frontline PD-L1 positive, non-small cell lung cancer, TPS, PD-L1 TPS score greater than one, so basically PD-L1 positive expressors. Monotherapy, ivonescimab versus pembrolizumab, straight up. So no contribution of components, no determining what the value of each of the individual agents are, monotherapy. Obviously, Keytruda has been very successful in this study that, you know, it's akin to the KEYNOTE-042 study, if you will, in that TPS positive. The important part, what you know, and we sometimes are asked: "Why didn't you, you know, look to join into that study?" I think the important piece there, one is they'd also completed or were nearing completion of enrollment in that study. But secondly and importantly, the standard of care a little bit different between China and the Western markets. The KEYNOTE-042 study, while approved, is not generally considered standard of care in the PD-L1 low population, so the TPS score 1-49. And so translating that into the U.S. and Europe was a little bit difficult. It monotherapy PD-1 is really considered standard of care in the PD-L1 high population, you know, TPS score greater than 50. So, Akeso designed a study, pembrolizumab versus ivonescimab, PD-L1 positive. They completed the enrollment for that, and what they've announced is basically that they have a planned statistical analysis, interim analysis, excuse me, a planned interim analysis in the second quarter of this year, so Q2 2024. And then, you know, the final analysis, which is, it's event-driven, right? PFS is their primary endpoint, and so they're event-driven for the analysis timing. Since we're close enough, they're able to disclose the interim analysis from a timing perspective, but the final analysis is likely at the end of the year, if you will. And so ultimately, they'll, their plan is to take a look at that interim analysis via, you know, an independent DMC and then, you know, have a decision made whether or not to... They've achieved their pre-specified planned analysis at that point, or continue on and see that at the end of the year. Yeah. And I know it's your partner's study, but how would you describe the statistical bar for the interim to be positive, and what was used to inform that hurdle? Sure. So I think from a so it is, it is our partner study. We're not sponsoring the study, so I do wanna make sure that that's, that's completely clear. But, so in terms of the second part of your question, what was used to inform that? I think the, you know, historical studies from a control perspective, KEYNOTE-024, KEYNOTE-042, are probably fair points to consider there. And then, there is a phase II monotherapy study that Akeso ran, AK112-202. So that's monotherapy in non-small cell lung cancer, and so that's a single-arm study that was ultimately... You know, then, the next step was to run this randomized phase III in this setting. Right. From a statistical bar perspective, you know, what's the hurdle in terms of achieving the interim analysis? So I'm not aware that Akeso has described that publicly, so it's not our place to necessarily describe that. What I would say is it's an interim analysis, one, so there's always a higher threshold than an interim analysis versus a final analysis. And it's a head-to-head against Keytruda, and I'm not aware of any drug that's ever gone head-to-head against Keytruda successfully in non-small cell lung cancer, right? So I think that, you know, inherently puts a bar on it that's relatively high. But I think those are probably the two points that I can lean on. But nonetheless, Akeso are confident enough to run the study and determine when the interim analysis points would be and the final analysis points would be. So we're anticipating hearing what's next. Yeah. And then what subgroups, patient subgroups could be important, within these results, be they interim, be they final, as you think about supportive data of your current plans and potential future plans? Yeah, Dave, you want me to take that one? Please. Yeah, so I assume you're alluding to the 303 study. So just to recap, Brad, what Dave said, I mean, I think we have a lot of information coming in to help us inform our development plans, right? So we have four phase IIIs that are running. Two of them are being conducted by Akeso, two of them are global studies. One of them, which is our fast-to-market study, is the HARMONi study. It's ivonescimab chemo versus chemo in the EGFR. So pretty low bar, you know, fast to market. The other three studies are against PD-1, so it's a very aggressive development plan, and two of them are head-to-head against Pembro. And you're talking about the 303 study, which I like because it's a very pure experiment. It's ivonescimab versus pembrolizumab, monotherapy in non-small cell lung cancer frontline, right? So these are patients who are PD-L1 positive. The subsets of the data that we're gonna look at to inform the rest of the development program is get an idea of, like, how does ivonescimab compare to pembro? So the base case is, like, we should be able to beat pembro for those patients that have low PD-L1 expression because we have that VEGF component. Mm-hmm. The interesting thing will be: how much can ivonescimab beat pembrolizumab in the high PD-1 expression? So how much better does the cooperativity make ivonescimab compared to pembrolizumab? That information can then be used to extrapolate our development programs, which are actually very bread and butter, kind of boring, which is basically taking Merck's development programs for all their Keynote studies, sort of figuring out what the benefit is of ivonescimab over pembrolizumab, and then asking, how big does the study need to be based on the original Keynote study for us to get an indication or design a phase III in that indication? That goes not only in non-small cell lung cancer, but can be extrapolated to other tumor types as well. Now, we're not only gonna be doing that. You know, as Dave alluded to, there's a lot of data that Akeso is generating, but I think that breakdown of the 303 study will help inform our development programs. And then, more specifically, and I think you're getting into it, they're enrolling high PD-1 expressers, low PD-1 expressers, squamous, as well as non-squamous. So we'll have a pretty good map of the activity of ivonescimab in non-small cell lung cancer from that data. Okay. And then, whether this is at the interim or final analysis, if it is positive, what should give investors confidence that a randomized benefit generated in a patient cohort that is all Chinese patients will be relevant for the potential success in informing a Western or global population dataset? You want me to take that, Dave? Sure. Go ahead. Yeah, go ahead. Yeah, so a couple things. So I think there's two parts to that, right? So is Chinese data different from Western data? And the answer is no. I mean, we're all humans, right? The standard of care medicine is similar but not identical between those two regions. And the one thing I'll say is, having worked now with Chinese companies, is that their data is actually very pristine, right? So what's different between Chinese data and Western data is in Chinese studies, the sponsor actually has study staff on site. And so that means that the transcription from the medical record and from the physician-patient interaction into the clinical database is perfect. You don't have some remote staff or CRO collecting that data. So the data quality is very high quality. The other thing I'll say is that these days, especially in lung cancer, they're all global studies. So any study that is a Western study will have a significant amount of patients from Asia. So, you know, it's really just a proportion. And, you know, what we've seen, and maybe Dave can expand on this, is that consistently, maybe the standard of care is different, maybe they're less aggressive in treating patients. They'll treat younger patients in Asia, in China because of cost issues, but the magnitude of benefit, the hazard ratio, seems to be consistent across Chinese studies as well as Western studies. Yeah, I think that's a great point, Alan. Excuse me. And in 2019, the FDA, actually, and JCO, published a meta-analysis that really spoke to that concept, looking at immunotherapies and the value, or the magnitude of the benefit of the immunotherapies, in patients of Asian descent versus non-Asian descent. Patients of Asian descent tend to have numerically longer prognoses for survival in general. So with chemotherapy, with immunotherapy, first line, second line. However, the magnitude of the benefit derived from by those patients of Asian descent versus non-Asian descent has been very consistent. And so whether it's irrespective of line of therapy, combination, monotherapy, and so that's that hazard ratio has been pretty reasonably consistent across all you know different cohorts and whatnot. Again, it was... I believe it was 2019 in JCO that meta-analysis was published. So there is that support as well, that if something that works in one population should translate globally, and that's obviously what we're doing here. Yeah. Brad, to, if I might just weigh in one second. You know, the team that has worked together now for going on 20, 20 years plus is very excited to make significant changes for the betterment. We're gonna work, you know, 60, 70 hours a week, sometimes more when Maky makes us. But we want to do something big and significant. Lung cancer is huge. Lung cancer is growing. Lung cancer is reasonably well underserved, not overserved. So that is, that's gonna win you many friends as you attempt to take that on, and we really have won some friends inside the FDA, given what we were doing at Pharmacyclics and with a patient-friendly therapy, one of the first to introduce that concept. The risks were there, but the returns were there also. So we look at this as a big opportunity. What will bring people to the market is the application vetted by the FDA and a clearance, and a label that says, "You know, this team did well." If you suffer from that disease, you're not gonna step aside, especially because of one key factor, the adverse event ratio here is really small. So with nothing to lose, a lot to gain, if you get an overall survival, a progression-free survival that stands out, the resistance will melt. And, yeah, I'm a believer too. Humans are humans, not 100%, but 99.9%. So, that's why we went after this. It's significant, it's big. The team that developed the product has a tremendous track record. We have a track record of development. We have credibility, we have access to money, we have access to people looking at what we're doing. And yeah, there's a lot of support here because it's not a rare disease. This is a disease that, you know, can come visit someone next to you, if you keep your eyes open long enough. So we're thrilled to be a part of it, and then we really thank, you know, your willingness to support and put a report out there prior to this data being released on an A for investors. They're always looking for something that could it really be big if I do win? And we think this is an outstanding opportunity to win big across the map of investors, of the people that are doing this, the patients and the caregiving society. So that's why we're in it. It's with a, we bring a lot of excitement to this. Yeah. Appreciate the comments. And, look, I think we wish we could have a lot more time to discuss this, but I think it would be helpful to squeeze in just an overview of the situation in second-line EGFR mutant, 'cause it's very unique. You know, you know, Akeso has essentially completed a study. It's filed in China with their regulatory body. Just walk through this dynamic and when we can expect updates on this. Sure, and Brad, just to be clear, I wanna make sure we're answering your question right. You're talking about the way in which the HARMONi trial was designed, considering the trial that was being run in China? Yeah. Yeah. So, at the time of the deal, effectively, the team at Akeso was nearing completion of the enrollment of this study. And so what we wanted to do was be able to take this study, which we thought was a very important population, and really apply this to a more global setting, including the territories that we had. So we had multiple discussions with the FDA in order to create a multi-regional study, so think Europe, North America, and China, and create that study based on, you know, the need that existed in second-line EGFR mutation. Again, as we spoke to earlier, a number of drugs have tried to go into the space and have not done as well and not performed as well, so it's an underserved population. And so, you know, with the agreement, the FDA, in some back-and-forth negotiations, we were able to, you know, design a study that leveraged those patients enrolled at Akeso who were second-line post a third-generation TKI, so ensuring that the standard of care was consistent across, and then adding a number of patients in North America, in Europe. And it, you know, roughly one-third, two-thirds split, two-thirds in China, one-third in North America and in Europe. And really, the purpose there being to show, you know, global consistency across the data. And then, you know, we felt it was an opportunity to quickly serve patients in our licensed territories as well, for patients who need this therapy and can benefit from it most. And so that in sum, you know, takes where we are now in the design of the study. We've announced that we plan to complete enrollment for the global setting in the second half of this year. And then finally, I think you made a point with respect to data readouts from this front. Because there's an overlap in the enrollment population, in China, while there is still some acceptability of front, first and second gen, tyrosine kinase inhibitors, it's still, you know, 80% plus patients receive a third-generation TKI akin to osimertinib or similar. And so what we expect is, and what Akeso has announced, is that the portion of the study that they were conducting in China, that was powered sufficiently from a PFS perspective, from a single region perspective, to submit. And so they have opted not to disclose the top-line data, and keep that confidential such that the enrollment across the multi-regional study is not biased by, you know, any pre-release results. But they have gone ahead and they've announced that they submitted that data to the Chinese regulatory authority, the CDE. And so they have also announced at Akeso that they expect a decision roughly in the second quarter of this year. So a little bit different in terms of the approval process. PDUFA dates, you know, that we have with the... In the U.S., with the FDA, they don't exist quite in the same way in China with the CDE, so it's a little bit less exact in terms of timing there. But they expect, based on, you know, their historical experience in China, to receive a response in the second quarter of this year. So, you know, and if they are approved in this setting, that would allow for a full label to be released, and so we would get a data readout effectively on the Chinese portion of the HARMONi-A trial, if you will, is what they call it, in China. And so I think, you know, we are blinded to that data. We do not know what that data looks like. We do not have access to that data. That data is truly kept separate from us, and we've firewalled that specifically to protect the integrity of the global study. What we do know is that it was filed in China, and it was filed shortly, you know, after enrollment. So we, you know, those are signs of good news, if you will, in terms of what that data likely is bearing. But we're gonna we'll find out, you know, when a decision is made by the CDE in order to protect the integrity of our global trial. Yeah. Great. Unfortunately, we're out of time, but team, thanks so much for sitting down on the fireside with me. And I look forward to all the updates throughout the rest of this year. Thanks so much. Appreciate the time, Brad. Thank you.