Thank you for standing by. My name is Tina, and I will be your conference operator today. At this time, I would like to welcome everyone to the Summit Therapeutics Update Call. All lines have been placed on mute to prevent any background noise. During the speaker's remarks, there will be a question -and -answer session. To ask a question, simply press star, followed by the number one on your telephone keypad. To withdraw your question, press star one again. It is now my pleasure to turn today's call over to Dave Gancarz, Chief Business and Strategy Officer. Dave, please go ahead.
Good morning, and thank you for joining us. We issued a press release yesterday morning relating to the Phase III HARMONi data, featuring Ivonescimab, presented as a part of the Presidential Symposium at the International Association for the Study of Lung Cancer's 2025 World Conference on Lung Cancer, otherwise known as World Lung or WCLC 2025. The press release is available on our website, www.smmtpx.com. Our 8-K was filed today and is available on our website and via the SEC's website. Today's call is being simultaneously webcast, and an archived replay will also be made available later today on our website. Joining me on the call today is Robert W. Duggan, our Chairman of the Board and Co-Chief Executive Officer; Dr. Maky Zanganeh, our Co-Chief Executive Officer and President; Manmeet Soni, our Chief Operating Officer and Chief Financial Officer; Dr. Urte Gayko, our Chief Regulatory Quality and Safety Officer; Dr. Allen Yang, our Chief Medical Officer; and Dr. Jack West, our VP of Clinical Development. Before we get started with the rest of the call, I would like to note that some statements made by our management team and some responses to questions that we make today may be considered forward-looking statements based on our current expectations. Summit cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Please refer to our SEC filings for information about these risks and uncertainties. Summit undertakes no obligation to update these forward-looking statements except as required by law. One item of note, this presentation is being webcast with slides, so we'll be referring to the slides being displayed in the webcast link. I'd encourage you to use the webcast link to see the slides being presented this morning or otherwise to take a look at the slides that are on our website. Following comments from our team, we will take questions. Before I hand it over to Jack to walk through the details of the presentation, I'd like to give a little bit of an overview based on the presentation yesterday and the details in our press release. HARMONi is a multi-regional study evaluating Ivonescimab plus chemotherapy against standard-of-care chemotherapy alone. This study represented a continuation into a multi-regional study into a multi-regional setting of the original single-region HARMONi A study that was performed by our partners at Akeso . in China. We licensed Ivonescimab effective January 2023 and immediately went to the U.S. FDA in order to discuss bringing the open study from a single region to a multi-regional setting. Once aligned, we began enrolling in mid-2023 and completed enrollment in the beginning of October 2024. This resulted in sequential enrollment of patients, first in China and then in the western regions of North America and Europe. As a result, at the time of our pre-specified primary analyses of both primary endpoints, PFS and OS, the majority of events were driven by China. Let's discuss the timing of the analyses performed. The primary PFS analysis was performed in July 2024, as per the protocol at the pre-specified number of events. Due to the sequential nature of the enrollment, as I mentioned, these events were reached prior to completing enrollment, and hence there were fewer patients in that analysis than the 438 patients noted in the schema, mostly coming from Asia. As a result, we performed a total PFS analysis when we performed the primary overall survival analysis in April 2025. This allowed for the inclusion of all Western patients and more maturity of these patients, roughly nine months of median follow-up time, to evaluate the global view or multi-regional view of progression-free survival in the multi-regional study. However, for the primary OS analysis taking place in April 2025, which we noted in our press release, the pre-specified number of events was reached, as per our protocol, but the follow-up time for Western patients, again, that was approximately nine months, was not mature as it was far short of the median survival in either arm. We therefore noted at that time in our May press release that we would continue to follow Western patients for additional time on study. We locked the database in September 2025 when there was longer follow-up and 76 events in Western patients. The number of OS events in Western patients at this point in time was in alignment with the estimation of events for Western patients expected to be included in the primary analysis per our protocol. We included in yesterday's presentation at WCLC 2025 the updated OS analysis that we just completed that included longer-term follow-up of Western patients. When we licensed Ivonescimab in the beginning of 2023, we sought to bring Ivonescimab to patients, one, as quickly as possible, and two, in particular with respect to the setting, those patients with EGFR-mutant non-small cell lung cancer who progressed after targeted therapy, where there are very limited options and many drugs have failed to show a benefit here. We sought to bring an opportunity for those patients to have an additional therapy option. As I mentioned, and as we've discussed over the past two and a half years, the setup of this study was a bit unique in continuing a single-region study into a multi-regional study. Therefore, the follow-up postdoc analyses are uniquely critical to evaluating the study with sufficient timeline study for Western patients. As Jack walks through the details of the presentation, we felt it would be appropriate to provide this background and understanding prior to Jack taking you through the results. With that, I'll hand it over to Jack to walk through the presentation.
Thank you, Dave. Yesterday, as you're aware, Ivonescimab data was featured in a presentation at WCLC 2025 as part of the Presidential Symposium for the second straight year. The presentation titled Ivonescimab versus placebo plus chemo, Phase III in patients with EGFR-positive non-small cell lung cancer progressed with 3rd Generation EGFR-TKI treatment, HARMONi, was given by Dr. Jonathan Goldman, M.D., Professor of Medicine at UCLA in the Hematology Oncology Division at the UCLA Director of Clinical Trial in Thoracic Oncology and also Associate Director of Early Drug Development and Chair of the University of California Lung Cancer Consortium. Revisiting the schema for the HARMONi trial, HARMONi evaluated Ivonescimab in combination with platinum-doublet chemotherapy compared to placebo plus platinum-doublet chemotherapy in patients with epidermal growth factor receptor or EGFR-mutated locally advanced or metastatic non-small cell lung cancer, non-squamous non-small cell lung cancer, who has progressed after treatment with a 3rd Generation EGFR-tyrosine kinase inhibitor or TKI. This was a global Phase III clinical trial conducted and sponsored by Summit , for which top-line results were announced in May of this year. Key eligibility criteria are shown here. Patients were randomized one-to-one and stratified by geographic region and presence of brain metastases at baseline. Patients received either Ivonescimab at 20 mg/kg plus pemetrexed carboplatin or placebo plus pemetrexed carboplatin, then received Ivonescimab or placebo in combination with pemetrexed for up to 24 months. Treatment was to be discontinued for intolerability, progressive disease, or initiation of new anti-tumor therapy. The study had dual primary endpoints of overall survival and progression-free survival by independent radiologic review committee. Secondary endpoints included response rate, duration of response, and safety. The dual primary endpoint is important. As you know, the study was a positive study based on achieving its PFS primary endpoint. The baseline characteristics showed balanced arms for age, gender, region, race, smoking status, and the presence or absence of liver and brain metastases. Patients in the study received a prior 3rd Generation TKI either in the front line or after an early generation agent. Approximately 60% had a deletion 19 mutation, 35% had L858R, and about 5% had a non-canonical mutation. Brain metastases were present at baseline in 25% of the patients on HARMONi. The trial included a total of 438 patients, including 165 from North America or Europe, representing 38% of patients in the study. In several EGFR-mutation-positive global Phase III lung cancer studies, over half of the patients who were randomized come from Asian territories. This enrollment breakdown is in line with other multi-regional studies of this tumor type. The progression-free survival curves show the trial met the primary endpoint with a hazard ratio of 0.52, with a corresponding p-value of less than 0.0001. Median progression-free survival was 6.8 months for the Ivonescimab with chemotherapy arm compared to 4.4 months for those patients receiving chemotherapy alone, a difference of 2.4 months favoring the Ivonescimab arm. At 6 and 12 months, almost 20% more patients taking Ivonescimab in combination with chemotherapy were progression-free. When we look at various subgroups, it's important to highlight that the size of the subgroups, they're smaller, and by definition, it's not designed to be statistically significant on their own. The subgroup analyses can be very informative nonetheless. The subgroup analyses for progression-free survival confirm benefit in all pre-planned subsets, as indicated by plots for each subgroup landing on the left side of the dividing line favoring Ivonescimab. There is really not a situation where one subgroup is an outlier or the study results were driven by a specific subset or subset of patients. Ivonescimab's benefit was demonstrated across all clinical and molecular subgroups that were evaluated. The progression-free survival curves showed benefit in both patients with and without brain metastases at baseline. Patients with no brain metastases at baseline had a hazard ratio of 0.59, which is very good and clinically relevant. Of particular importance in the EGFR-mutant lung cancer setting is the results in those patients with brain metastases with a hazard ratio of 0.34. Ivonescimab showed strong clinical performance against brain metastases. In this setting, it does cornerstone importance, particularly post-TKI, because Ivonescimab appears to overcome the poor prognostic implications of brain metastases. As Dave noted earlier, we performed a total PFS to include all Western patients. This analysis showed the consistency of patients in the Western region versus those in Asia. These curves show the consistency of data with additional time for Western patients from the primary progression-free survival analysis in the solid line to a later analysis at the time of the predetermined overall survival readout in the dotted line. The highlighting, overlapping curves and the consistent hazard ratio between the primary analysis and the total PFS analysis demonstrate that the multi-regional benefit holds with more mature data. The hazard ratios were consistent and favorable and highly clinically meaningful in both Asian and Western patients. Recall from the baseline characteristics that the study is approximately 62% Asian patients, which is in line with historical multi-regional studies conducted in patients with EGFR-mutant lung cancer and is representative of a multi-regional study from a breakdown perspective. We specifically overlaid the curves to allow for visual to show the primary analysis conducted with a pre-specified number of PFS events occurred per the protocol, primarily driven by events in Asia, and the total PFS when all Western patients were involved. The median follow-up time for Western patients was over nine months. You can see highly concordant curves here showing you visually that the data are highly consistent when including all Western patients. The hazard ratios are highly consistent overall from the two time periods, 0.52 - 0.57. The regional differences, both of the regions, are within 0.10 or 10 basis points of the global hazard ratio. These are consistent with highly overlapping confidence intervals. We wouldn't and don't expect the exact same numbers for hazard ratios for subgroups if there are smaller subsets of the total population. The overall survival curves separate with a difference at the median of 16.8 months versus 14.0 months, with a hazard ratio of 0.79 and a p-value of 0.0570. This was a strong result in this patient population. To date, there are no drugs approved in this setting that have demonstrated a statistically significant overall survival benefit. Our data show a hazard ratio of less than 0.80 and clear separation of the curves. Note that the curves begin to separate at approximately nine months of follow-up. You can see Western patients' median follow-up time just over nine months. Based on the follow-up time of these patients, as we stated in May at our top-line press release, we noted that we would continue to follow Western patients for additional time on trial as we felt that that was clinically relevant to the results of this study. Because Asian patients had been followed for over 30 months and exhausted complete follow-up at the time of the primary OS analysis, we used the Asian patients' data from the April 2025 data cut and then updated the follow-up of the Western patients. We locked the database in September 2025 when the median follow-up for Western patients was approximately 13.7 months and did approximately 4.5 months of additional follow-up for Western patients. There were a total of 76 OS events in the Western patients, which is in alignment with the original expected number of events in the primary analysis for Western patients when we began the study. Hence, we included in yesterday's presentation the updated OS analysis that included longer follow-up of Western patients. The long-term hazard ratio was consistent with the primary analysis at 0.78, with a nominal p-value of 0.0332. Median OS for this analysis remained the same in both arms from the primary analysis. Median OS in Western patients receiving Ivonescimab was 17.0 months compared to 14.0 months for those receiving placebo with chemotherapy. Median OS in North American patients specifically had not yet been reached in the Ivonescimab arm compared to 14.0 months in the placebo arm. Median overall survival in this longer-term analysis is highly consistent here with the two regions, Asian and Western patients, both showing highly consistent results in both the Ivonescimab arm and showing identical results in the control arm. As we noted in our press release yesterday, the statistical analysis plan for the study required a p-value of 0.0448 or less in order to achieve statistical significance at the time of the primary analysis of overall survival. These results show the impact Ivonescimab had versus standard of care in this setting. With the curves maintaining their shape and their separation at approximately nine months, the additional median follow-up time of Western patients demonstrates the consistency in the data between Asian and Western patients. Of course, the nearly identical median in the median overall survival also drives the regional consistency point home and punctuates the level of the value that Ivonescimab can bring to patients globally after its success thus far in China. This demonstrates both the consistency in the results across regions and the strong performance of Ivonescimab in this setting, a setting where no drug has shown an overall survival benefit. Important in this setting as well is the safety and tolerability, where Ivonescimab can play an important role as an option for physicians and patients facing this disease and the need for treatment. The overall survival forest plot shows consistency across the trial subgroups. In particular, as it is important to acknowledge that results in North America are of increased focus in today's environment, it's encouraging to note a hazard ratio of 0.70 amongst North American patients. There was no patient that had a detrimental impact on survival and received stability over time in the primary analysis. Both objective response rate and disease control rate were improved for Ivonescimab by an absolute difference of 11%. The median duration of response was improved from 4.2 to 7.6 months. I'd like to pause here to reemphasize what we have just seen. The primary analysis for PFS, which was strongly positive in July 2024, was backed up by the consistent results with Western patients having more maturity in a total PFS analysis that was performed. The overlapping Kaplan-Meier curve, the curve we saw a moment ago, where we overlaid the primary PFS analysis and the total PFS analysis, showed a higher level of consistency between the data with mature global PFS data in CVIS. The primary overall survival analysis was performed in April 2025 with a follow-up time for Western patients that was less than the median survival. Given the clinical relevance for following these patients, we did a recent analysis that lets us evaluate the results in the Western patients when there were the number of Western events expected in the protocol in the primary analysis. These results were highly concordant in hazard ratios and medians in overall survival, including Western versus Asian patients, demonstrating the consistency of the data. When we looked at HARMONi -3 and HARMONi -7, when we look at HARMONi -3 and HARMONi -7 in the front-line driver mutation-negative non-small cell lung cancer setting, the importance of overall survival is only further highlighted. The regional consistency seen in HARMONi is very encouraging in that way. Treatment-related adverse events showed small increases in the Ivonescimab group. Any grade events were increased from 93% to 95% and grade ≥3 events from 42% to 50%. Treatment-related adverse events leading to discontinuation of Ivonescimab or placebo occurred in 7.3% versus 5% respectively. Based on the dual targeting of Ivonescimab, we analyzed adverse events that were thought to be immune-related or VEGF-related. These were increased from 6% to 9.6% for grade ≥3 potentially immune-related events and from 3.2% to 7.3% for potentially VEGF-related events and will be detailed in the next slide. On the right, events are split up by a specific term. The most common events were lab abnormalities, nausea, and decreased appetite, consistent with the chemotherapy background. As such, there was little difference between the arms. Focusing further on immune and VEGF-related events, we see that most events were low-grade. The most common immune-related events were thyroid abnormalities, and other events were at low rates and similar whether the patient received immunotherapy or not. Among the VEGF-related events, proteinuria, hypertension, and hemorrhage each were seen in 10% - 14% of patients but were generally low-grade, and the grade ≥ 3 rate of hemorrhage was under 1%. Venous and arterial thrombotic events were similar in the two groups. I do want to pause here for a moment and speak to the highly validating and strong safety profile seen in the Asian patients that was also validated globally with the results of the study, where we saw generally consistent results. This again differentiates Ivonescimab from the results seen in prior studies of PD-1 plus VEGF monoclonal antibodies being administered together and the difference in VEGF-associated toxicities from a previous study with antiangiogenic therapy. In summary, Ivonescimab provided a significant and clinically meaningful progression-free survival benefit in patients with EGFR-mutated non-small cell lung cancer after progression on a 3rd Generation EGFR-TKI with a hazard ratio of 0.52, which was consistent across predefined subgroups, including those with brain metastases and consistent with the total PFS analysis that included all patients, including all Western patients. Overall survival showed a favorable trend with a hazard ratio of 0.79. Response rate and duration of response were also increased. Ivonescimab was well tolerated with less than 1% grade ≥3 bleeding events and low rates of adverse events leading to discontinuation or death. Most adverse event incidences were similar between the two arms. One additional point that I would make with respect to this particular setting and that Dave acknowledged earlier is that there are very limited treatment options available for these patients. With such limited options available, the patients with EGFR-mutation-positive non-small cell who progress after a 3rd Generation TKI, if only a single approved regimen in the U.S. of amivantamab plus chemotherapy, that regimen was approved based on a PFS benefit, reasonably similar to what we've seen here in a cross-trial comparison, admittedly, and with a favorable trend in overall survival without showing a statistically significant benefit. I'd also note that there may be meaningful tolerability differences between these regimens based on data, not only in this specific setting, but data presented as a whole, considering both compounds, Ivonescimab and amivantamab. This underscores the specific value that Ivonescimab and the HARMONi regimen could bring to patients in this setting with the opportunity to include a differentiated mechanism of action for physicians and patients to choose from. Importantly, we want to thank the patients and their families, the site personnel, and the Summit and Akeso team for the many roles they collectively played in carrying out the HARMONi trial. With that, I'd like to turn it back to Dave.
Thanks, Jack. Finally, there's one additional point that I would like to emphasize if you look at the read-through of this study from our other ongoing Phase III studies in front-line non-small cell lung cancer. Just about everyone would agree that EGFR-mutated non-small cell lung cancer post-targeted therapy is biologically quite different than front-line non-small cell lung cancer that is driver mutation negative. A way to show that via existing treatment options is that PD-1 therapy is the overwhelming standard of care, with or without chemotherapy, depending on PD-L1 status in the front-line driver mutation negative lung cancer setting. Those same PD-1 therapies did not show a PFS or an OS benefit in multiple multi-regional studies in the post-TKI EGFR-mutant setting. Ivonescimab clearly outperformed the results of the PD-1 monoclonal antibodies in previous studies. From a market opportunity perspective, there are fewer patients suffering from EGFR-mutated lung cancer. In this HARMONi setting, it represents much less than 5% of the potential market opportunity for Ivonescimab long term. When we look at these much larger front-line settings, overall survival will be important. The highly consistent results in overall survival in the HARMONi study, taking a look at the North American results based on today's environment and seeking consistency there specifically, are notable. Seeing regionally consistent results and seeing consistent hazard ratios and medians is very encouraging when we look at the HARMONi -3 and HARMONi -7 and beyond, where overall survival will be highly important. These results presented yesterday are highly encouraging in showing the regional consistent performance of Ivonescimab and Ivonescimab's ability to break into a setting where historically immunotherapy has struggled. Anti-VEGF therapy has not yielded much in terms of overall survival here in previous studies and continues to validate the opportunity presented by Ivonescimab to make a significant difference across a vast number of patients facing solid tumor diagnoses. Thank you, team. With that, we will now see if there are any questions that our team can help answer. Tina, if you could please open the line for questions.
As a reminder to ask a question, press star one on your telephone keypad. We do ask that you please limit your questions to one. Our first question comes from the line of [Miguel Natamovich] with Citigroup. Please go ahead.
Yeah. Hi. Thank you for taking the question. Could you comment, please, on the path forward with respect to our regulatory interaction on HARMONi? Presumably, you're going to have a meeting with the FDA to discuss these results. Are you going to do that with the current OS cut, or will you wait to do potentially another cut? Could you comment at all on what FDA has said with respect to the level of evidence that they want to see on the U.S. patients, in addition to the overall statistical significance on OS to support a U.S. approval? Thank you.
Thanks, Miguel. This is Dave. We believe the data is very encouraging, and it's viable. We previously disclosed that the FDA is looking for statistically significant overall survival benefit in this study. What I would say is the data cutoff for this analysis that we presented yesterday is September 2025, and so obviously, given today's date, it is only days old at this point. We're highly encouraged by this data, but we do need to plan the appropriate next steps in terms of ensuring that we provide Ivonescimab with the best opportunity to reach patients as quickly as possible. We plan to finalize that strategy in the coming days and weeks.
Okay, thanks. Then the other question I had.
Our next question comes from the line of Salveen Richard with Goldman Sachs. Please go ahead.
Good morning. Thanks for taking my question. Any hypothesis here as to what is driving the differences in PFS between the regions when you look at China versus ex-China?
I'll make the comment, and then I'll look at things I got for some data. With the total PFS analysis, you can see that the curves are highly concordant when you overlay those on top of the primary PFS analysis. That's a visually striking way to show that they're highly consistent when you include the Western patients. The hazard ratios are highly consistent overall between the two time periods in total, the 0.52 - 0.57. The regional differences are highly consistent with highly overlapping confidence intervals as being included in the slides. We wouldn't expect, and we don't expect the exact same numbers of hazard ratios for subgroups. In particular, when you have small subsets of patients or smaller subgroups, you'll have some variability in the exact numbers. As Jack mentioned, on the discussion from a PFS perspective, both in the longer-term follow-up, both the Asian patients as well as the Western patients were within 0.1 of the median for the study as a whole. Those are statistically highly consistent results. Of course, for overall survival, you see overwhelming clear consistency within the median, high consistency across the board in total. The median overall survival is nearly identical, Western region to the Asian groups. They were exactly the same in the control arm. Every, you know, non-these are mutually dependent patients. They each showed a control arm of 14 months at the median for overall survival and between 16.7 and 17 months of overall survival in the Ivonescimab arm. Highly consistent across the board.
I would just add that in my earlier comments, we emphasize not to overread too much in a subgroup analysis in terms of you can't evaluate each one separately if hypothesis generating. I think we should be reassured that when we look at the subsets based on geography for both PFS and overall survival, those results address the question in a reassuring way that, say, this is not a China-specific benefit, that it's overall looking very strong, particularly in the North American population that is, right at this moment, a particular priority. Even if we don't want to say, "Oh, this is better," there's certainly no suggestion that it's worse. I think it's very reassuring that the impressive observations that we've seen with this, out of China, not just here, but in other studies, are not remotely suggestive of this being a benefit that stops at the border of China.
Our next question comes from the line of Tyler Van Buren with TD Cowen. Please go ahead.
Hi. This is Greg on for Tyler from Cowen. Congrats on this data, and thanks for taking my question. I'd be interested to hear what feedback are you hearing from physicians at the conference following this dataset?
Yeah. This is Jack West. I have had very little time to sleep in between all the conversations I've had with my colleagues from the U.S., from all over the world, even some in Asia. I would say that it has been interesting. As people are well aware, there have been kind of mixed messages and responses to the results in what's been written about so far, largely in the financial setting. My colleagues have been congratulatory, have felt that the characterization of the results as negative for OS is something that maybe you should have an asterisk next to it or with caveats that this had many practical challenges with it. We have already acknowledged the sequential nature and, what we would now, with hindsight, call inopportune timing of the final OS analysis. When you actually look at what was achieved, a hazard ratio of 0.79, a p-value where it was, this is not a hazard ratio of 0.89 and a p-value of 0.62. We would not want to have the risk of this being potentially a false negative almost. To my colleagues who are treating patients, going back to their clinics this week and seeing patients with EGFR-mutation-positive disease, they say that they would be very eager to use the HARMONi regimen. They would prefer it over the alternative. Even some of the people who have been more critical of the trial still acknowledge that this would very likely be their preferred choice over what's currently available. When you look just in absolute terms at what was achieved in efficacy, the safety profile, and the remarkably favorable, I would say, tolerability, particularly in the context of what else we have, this is something that I believe patients and physicians would eagerly welcome us to have available. They have also said they consider these results overall to be very favorable and don't discount the potential utility of Ivonescimab in the first-line trials that are ongoing.
Our next question is from the line of Brad Canino with Guggenheim. Please go ahead.
Hello, and great to hear the updates from you all. One of the top investor questions I get is, will the HARMONi -2 interim OS of 0.777 hold up over time? I noticed that this analysis included 15 extra months of follow-up for the Asian subset since the last time Akeso cut the HARMONi -A OS data, which I think was December 2023. Is there anything to learn about the ability for PD-1 VEGF to maintain OS from this analysis? Thank you.
Thanks, Brad. I think that's a good question. A little bit on the specific point here, and then I think we can infer further from that. If we look at HARMONi A, which was the study sponsored by Akeso , that was highly overlapping but not the exact same patient population. About 86% of the patients from that study are included here, and those who received 3rd Generation EGFR-TKI are the ones that are included here. We saw the overall survival analyses that the Chinese Health Authority, the NMPA, had requested during the approval process for Ivonescimab in China back in 2023 and 2024. With 30% data maturity, we saw a hazard ratio of 0.72. At 52% data maturity, and when I say data maturity, I'm talking total events divided by the number of total patients in the study, just to be clear, we saw at 52% data maturity a hazard ratio of 0.80. A little bit of commentary had taken place with respect to, you know, therefore, as sometimes had been seen in historical studies associated with anti-VEGF therapy, a degradation of OS was a concern. We had maintained from the beginning that the 30% data maturity was a very early cut. That's not exclusive to Ivonescimab, being clear. That's much more of a general comment. When you get to 52% data maturity, you have a stabilization that takes place if anything else. Now what we're seeing in the, you know, you see within our forest plot in the Asian cohort, not exactly the same patients, it's highly overlapping, but not exactly the same patients, who show a hazard ratio now for overall survival of 0.76. What we're seeing here is not a degradation of overall survival, but actually, you know, comparable, consistent. It's a tick towards favorability. I'm not going to make a larger, broader statement on that. That is a piece of evidence now that we have a long-term follow-up on a randomized Phase III setting with Ivonescimab that shows no degradation in overall survival. The other piece I would say is that that's really addressing the VEGF component. If you look at this study and on the slides that were presented yesterday as well as are available on our website, you look at the longer-term follow-up of Western patients, and you look at the overall survival Kaplan-Meier curves. What we see from our perspective, in our opinion, is an IO tail. That tail seems to be clear and present throughout. That represents what we see in other immunotherapies. What we are seeing as a result of taking a look at this data is both the PD-1 and the VEGF components of Ivonescimab coming into play, as well as a differentiated efficacy profile from what had been seen historically with anti-VEGF treatments. We see, again, a tick favorable. I'm not making a larger conclusion there, but a tick favorable in terms of the hazard ratio associated with patients in Asia. While undisclosed, our colleagues at Akeso have also announced that the HARMONi A study showed significance in OS. That's their announcement, and they haven't given any further data, so I won't speak any further to that. That also backs up that same point with respect to the utility of Ivonescimab and what it has, the potential to do, and what it can be in that setting.
Our next question comes from the line of Asthika Goonewardene with Truist Securities.
Hey, guys. Thanks for taking my questions and the additional part of the call today. I've got a two-part question here. The discussion of Long Long took a break, so give you my meaning. Some from KOLs called it a little harsh. Jack, I was wondering if you could tell us what is your biggest disagreement with Ram's comments? The OS curves do not, the PEVRA event do not really separate until maybe about nine months in. This certainly underlines the importance of data maturity and suggests that maybe in the ex-China component, the data can continue to improve with further follow-up in time. Any hypothesis as to why you're seeing that early overlap?
Okay. I didn't quite hear the second part, but let me get into this and we can see. I'll preface this by saying that Dr. Ramalingam and I go back 25 years as respected colleagues and friends. We are not any, no, I'm just kidding. We are still friends. I would say that to me, the biggest issue is that he really minimized, I would say, the foreseeable, understandable issue of the overall survival cut, the relative immaturity of the OS data, and our ability to, you know, we had called that we would, that what would loom large is how do things look as we get more data from longer follow-up of the Western cohorts? I knew this was going to be a problem. I would say that the issue is just potentially throwing out the baby with the bathwater. None of us is claiming that this is statistically significant. It will not be. That is the way it went. As I said, I think we are always, as clinicians, looking for truth within the reality that the trials don't always provide clear answers. I think that this one was fraught with challenges in how it was developed and how the data ended up getting analyzed. We don't want to dismiss truly beneficial therapies inappropriately. My concern is that, and I also would say this is based on conversations with many other colleagues in the last, you know, 28, 30 hours, I think a lot of us come into it with biases about whether we believe that it's all going to be anti-angiogenesis anyway. If that's your view, it's very hard to overcome that bias. I believe that was the case here. I would also say that the reality is that Dr. Ramalingam is not coming in with experience with Ivonescimab directly or with bias specifics. Some of the conversations I've had just in the last few hours are with people who have actually used Ivonescimab, who are extremely committed to it, who have participated in this trial or others, and are strong believers because first, they've put patients on trials and said, "You cannot tell the difference in who's randomized to placebo or Ivo, and that's something you really like in a drug." They've seen what they've come to conclude are really good results as well. There's nothing like that clinical experience. That's my view. I would say that no one would ever say that Dr. Ramalingam is not knowledgeable or unfair necessarily, but I think that his view was about as far in the negative range of the confidence intervals of fairness as you could get within the admittedly ambiguous setting of the trial. This couldn't be said to be a slam dunk, so it's subject to interpretation. I think it was a quite uncharitable one, and more important than what I think because of where I'm sitting. Colleagues have unsolicited come to me saying that they're talking with each other. Without having a horse in the race, they really feel that that was not a really balanced and appropriate interpretation of admittedly still somewhat ambiguous data.
Our next question comes from the line of Corey Kasimov with Evercore.
Hey, good morning, guys. Thanks for taking my question. I recognize this isn't the subject of today's update, but is there anything you can share with regard to your latest strategic thinking with Ivo in terms of both interest in a potential partnership as well as plans to move Ivo into Phase III trials and additional tumor types like your partner's been doing? Thank you.
Hey, Corey. This is Manmeet. I think that I'm giving an update. First of all, yes, I would say we have full intention and plans to initiate a few more Phase III outside lung and also explore more in lung in the coming months, and you will hear that in the coming months from us. Unrelated to strategic activities, you know, we have always said we are always looking to expand the portfolio as soon as possible and as appropriate. We have also mentioned earlier, we are open to partnerships, right, to do and collaborate, which is, which should be and would be beneficial for both partners, for Ivonescimab, for all the patients to ensure that the drugs can be accessible and can accelerate development. I would say, I can say over here right now, we are always open to do all those strategic developments.
Yeah. Let me just reiterate, Corey, the comments that Manmeet made with respect to, you know, continuing the development of Ivonescimab as well. As we said in the beginning of this year, fully intend to continue and more to come on that point. We look forward to that later on as well.
Corey, I can only add one more thing, right? Every month, we are seeing more and more positive news on Ivonescimab. You just heard, right, a couple of weeks ago from our partner, Akeso , who announced the first OS for HARMONi A, right, which was an EGFR, right, that was in China population, and they will provide more updates in the coming months. I have to say in the conferences, you already know, right, HARMONi -6 a couple of months ago had what's up earlier, and that data will be announced in the upcoming conference to be seen. As our partner also mentioned, I will have, you know, HARMONi- 2 updated OS, which we call it the 0.77, which was a very earlier cut. The more mature OS data would be coming in the next, I would say, six months or before, which our partner has said. All those catalysts are upcoming and near-term catalysts, which just open up the value of Ivonescimab and would allow us to expand, you know, our portfolio pretty significantly.
Okay.
Our next question comes from the line of Mohit Bansal with Wells Fargo.
Great. Thank you very much for this update. I would like to go back to the discussion topic from the presentation yesterday. I fully appreciate the maturity of the OS cuts and all that. He made a comment that, you know, it does seem like the Western patient population does dilute the impact or effect of Ivonescimab overall. Even from ORR point of view, it does seem like lower response rates. How do you respond to that? I'm still going back to the fact that a lot of the investment thesis is dependent on Chinese data being translatable to the Western patient population. Why do you think this is not, this should not be a read for your broader lung cancer development program? Thank you.
I don't have the response rate. My understanding is the response rate in Western patients actually at least shows a difference that is stronger between the Ivonescimab and placebo arms than was seen in Asia, even if the absolute numbers are different. The relative difference, the delta between them, is actually greater. I don't think we would differ in the general conclusion that the Western patients diluted the effect of the Asian patients, but that's a time-dependent issue. It's just that, yes, if you have immature short follow-up in Western patients added to the much, much more mature data out of China, you dampen the effect short term. That doesn't mean that long term, that's going to be the case. That's why I would say it was a very inopportune time to do that final cut. If the timing based on the number of events in the West would have been corrected for the actual delay in time it took to get the trial up and running in the West, and it was done now, we would be talking about it differently. That's also something that some of my colleagues have said. When we talk about this as a negative trial, you're talking about the outcomes of a few patients. If it had broken the other way, this would be hailed as a triumph in every way. I think it's really worth bearing in mind that this is a very time-dependent effect. It was just very unfortunate that that's when the official final primary, the primary OS, was done. Yes, it did end up diluting that effect at that time, but we have seen and expect that we are prone to see in the future that any follow-up, if subsequent work is done, will demonstrate at least a stable, if not growing, improvement in OS as time goes by.
Yeah. The only thing I would add to that, Mohit, in Jack's first comment that he made with respect to response rates, it's not necessarily a direct one-to-one to take the HARMONi A overall response rates. Keep in mind the 14% of patients who did not come on to this study also didn't receive a 3rd Generation TKI. It's not necessarily that those numbers are identical. I think that's a conclusion a step too far in terms of speaking of the dilution of response here.
Because, yeah, that's not the exact same population that actually entered into HARMONi.
That's right.
Our next question comes from the line of Eric Schmidt with Cantor Fitzgerald.
Thank you so much for taking my question. I'm just curious as to if you have an explanation for why the EU patients fared a little bit more poorly in this study, and what the PFS hazard ratio is in North American patients. Thank you.
Your question was, what about what happened with the European patients and why they may have fared less well?
Got it. Yeah. This is also by Colo, right? From the analysis point of view, we have a subset of subgroups that we are pre-specified in looking into. For this particular study, the study was stratified by region, combining both Europe and North America together. The most important point is to look at that as the Western patients in terms of what it tells us and the results we see there for both PFS and OS at the time. When we look specifically into Europe, it's a little bit what Jack also has talked about. Europe has two things to be against it. One is it's actually the smallest subgroup within the region. Europe is smaller than the North America region. On top of that, it started to enroll last, because the study was only started enrollment in the U.S. specifically, Canada right away, and only then a few months later in Europe. I don't have any concerns about the Europeans. I know in this particular study, we talked so much about subgroups and time to take each subgroup of itself. I think what we can say is there's no subgroup here that has shown any detriment in terms of that we looked in and we specified. There's often not one subgroup that overwhelmingly drives the benefit. That's really the purpose of looking at subgroups. You can't take every individual number and go into a clinical study that has variance on voice visit and think that every number that comes off exactly perfect would be exactly in alignment with each other, identical, etc. That's what I can add to that question.
Yeah. What I would say is I'll look at a different study that, you know, we don't have a horse in the race with it. We're not in the same setting. Yesterday, the overall survival results were announced for osimertinib plus chemotherapy versus osimertinib in the FLAURA2 study in first-line EGFR-mutated non-small cell lung cancer. It was a statistically significant benefit that was announced, and it should be treated as such in a win for patients. Underneath that, in their disclosure of forest plots in regional differences, one of their defined regional subgroups had an overall survival hazard ratio of 1.00, right? That is not something that people are talking about. I agree with that. They shouldn't be because, as everything that Urte just said, looking that far into individual subgroups starts to make a bit of noise. I think that's an important context. Some of the analyses looking at the very small differences in certain points here are a bit more granular than statistics are intended to take into play.
Yeah. Subgroups are subgroups. The other thing is that I think clinicians and the broader world have been looking to see, does Ivonescimab and some of these other agents that have looked promising in China, do they work outside of China? If you see that there's a good result in a Western population, it is biologically implausible that you would see an effect that is very good in North America, but not a very similar biology in Europe. I think that is very hard to tease apart, how you could have China and North America look singularly similar, but different from the European population.
Our next question comes from the line of Kelsey Goodwin with Piper Sandler.
Oh, hey, good morning. Thanks for taking my question. In terms of locking the Asian population for OS, but then continuing to follow the North American and the European, was this agreed upon with the FDA at any point? Is there any precedent for this? Thank you.
What I can say is, if you did not go into detail with this additional longer-term follow-up with the FDA, we discussed that it would be valuable to look at it because the maturity of the Western patients itself is informative. The maturity of the Asian patients has completely been reached and exhausted at the time of the primary OS follow-up. It is way beyond the median for both of the arms. It is very hard over a long period of time to actually follow patients until everybody dies. I don't actually think any clinical study has accomplished that. This is an appropriate way of analyzing that. We can discuss that. We know with FDA certifications and views of it, but this is an appropriate way. We admitted from the very beginning that our intention is to follow up long-term the Western patients after the primary analysis for OS.
Again, I think that was clear in our press release in May as well.
Our next question is from Daina Graybosch with Leerink Partners.
Hi. Thank you for the question. Let's say that you don't receive FDA approval ultimately based on the data. In that scenario, will you do another trial in this setting? If yes, how might you design that trial?
Hey, Jen. Thanks for the question. This is Dave. I think I probably go back to my earlier comments from a moment ago with respect to the fact that the data cutoff for this study, ultimately being in September, has not given us a lot of opportunity in terms of planning the exact next steps with respect to agency interaction, how we'll take this forward, what the next points become. I'm not sure we're at a point of going any further than that at this point.
Our next question comes from the line of Clara Dong with Jefferies.
Hi. Good morning. Thanks for taking our question. For the HARMONi study, is there any additional analysis you plan to provide to us, especially overall survival data from the Western populations at a later data cut down the road, or will it kind of depend on your regulatory interactions later on? Also, for the forthcoming data readout from HARMONi -6 for the combo of VEGF chemo in frontline squamous non-small cell, would you be able to share the scope of data we should expect to see there, and what do you believe is a bar for success? Thank you.
Thanks, Clara. I think on the first question, yes to your implied answer, which was that would I think that would have to do with further interactions. I think on the second point, HARMONi -6, I just want to be careful in the sense that that is the study that is sponsored by and conducted by our partners at Akeso . Very excited for that data to be shared. However, in terms of bar for success, I think these are predefined statistical analyses. The comparator arm, obviously, is extraordinarily high as a bar with PD-1 plus chemotherapy. Importantly, from a timing perspective, this was a success on an interim PFS analysis, right? Hopefully, those bars are high across the board, high comparator, high-quality comparator, patient population that previously wasn't able to be treated with anti-angiogenic therapy. That's an important component here with the PD-1 VEGF bispecific of Ivonescimab.
You're talking about treating 266 or so patients with advanced squamous lung cancer with a myelosuppressive doublet combined with Ivonescimab and being able to complete that, not stop the trial. I believe no new safety signals will be the data. Along with the efficacy, the safety will be very reassuring and important to the clinical community.
We're very excited for next steps on that data. Given that is a study sponsored and conducted by Akeso , I'll leave it at that.
Our next question comes from the line of Reni Benjamin with Citizens.
Hey, good morning, guys. Thanks for taking the questions and congrats on the data. Maybe just, you know, based on these data, can you talk a little bit about how these slight differences might impact your statistical plan going forward with your Phase III trials? Could we expect any sort of changes, maybe in the number of patients being enrolled, just to make sure that statistical significance is held? Are you doing any other sort of additional evaluations to look at what these patients might be getting post-progression? Does that vary based on geography? Thanks.
Let me start with the second one, and then you can go back to the first one. We have looked at the NextGen therapy for the HARMONi study. Obviously, because of progressive disease, it was much further in the control arm compared to the IV arm. There is only much more treatment in the control arm in terms of the % of patients getting it, but they are getting it. In the control arm, there was 50% or more that have already started to get second-line treatment. What we have seen in second-line treatment is very much what we would expect. The majority of treatments were with additional chemotherapy. There was a meaningful cohort, approximately 20% of those patients that also get further EGFR-targeted therapy. Normal distribution suggests that there is also, you know, normal follow-ups with all the patients that can still get NextGen therapies.
Very good. I mean, I think on the first question, I'd reiterate some of the earlier comments with the idea that, again, with the September 2025 data cutoff, I think it's important to take a little bit of time to take a look at it, given that it's a bit days old at this point.
Our final question comes from the line of David Dai with UBS.
Oh, great. Thanks for taking my questions. Just regarding the nominal p-value based on the ad hoc analysis, I'm curious, you know, what kind of statistical analysis have you done to derive that nominal p-value? At the same time, just wondering, how do you think the FDA will view this nominal p-value given that it's less than 0.05 now? Is there a potential for them to view this as a variable and, you know, potentially get approval based on it?
Let me take the first one. For the first one, I am not the biostatistician. I'm just going to comment my ability to understand it. The general methodology in terms of assessing the p-values based on the Kaplan-Meier methodology is the same or similar between the primary analysis and this analysis. We have been very direct, and Jeff made several comments in this regard that we know, and of course, we would have loved to, but we know that we did not reach significance. We are not explaining that. The tool of assessing a p-value tells you still how much variability or lack of variability or uncertainty is in a given data set that you look at. We are not claiming significance here. It is more about the descriptive that there is not a lot of variability and tightness of the data at this long-term ORS analysis.
The directionality of it.
The directionality of it and being stable, right? Stable for us is good. That's what we are looking for in bringing in all these bigger follow-ups of our lifetime patients. What was the, sorry, what was the other?
You were going to say something about the FDA. The FDA.
That's right. With respect to the FDA, we have a high amount of respect and appreciation for our work with the FDA, including our appreciation of their working with us from the beginning of this process. As we said during this call, when we licensed Ivonescimab in January 2023, one of the first things we did was go to the FDA with respect to looking for a way to expand a single-region study that was open at the time into a multi-regional study. We have an immense amount of respect and appreciation for the work that the FDA does, as well as their collaboration efforts as a whole. I think to comment on how we think they will think about something just doesn't feel appropriate to us. We'll leave that to you. Our view is we are encouraged, as you said, by this data. I'm not going to comment with respect to how we think the FDA will feel it. It's very important that we walk through more details if that were to be the case.
Dave, this is Rob Duggan. Can I expand on your comments? I have a couple of things to point out. At the time the trial was launched, we were very, very appreciative that the FDA leaned in and allowed us to include China data and to do this, to pull this trial off. That was something that people did not expect. In retrospect, they obviously made the correct decision. At that time, I believe all of us underestimated the level of conservatism and caution amongst North American physicians with regard not only to bias specifics here that this was going to be novel, but also with regard to China data. This was a first. It took quite a bit of time to gather momentum to get off the tarmac, so to speak, and into the air. That's why the estimated time for completion of the trial then came in a bit shorter than had we been able to evaluate that properly, it would have. That's the only reason why.
There's a lot of paper.
The only reason why we have extended and allowed the maturity of the data to be equalized, so to speak, is so that one could get a fair analysis as to the response. You can clearly see it from the statistics. It was a very good idea that we did. The last comment here, I know Egall was cut off on his second question. Many of you appropriately were able to ask a second. Egall, if your second question is still of interest to you and of us or hasn't been answered, feel free to jump in.
With no further questions, I will now turn the call back over to Dave Gancarz for closing remarks.
Thanks very much. We're just checking to see if Egall was still there. No, in summary, I think we appreciate Bob's additional comments and appreciate the team's participation here. We're very happy as we currently stand with respect to this updated data analysis presentation from yesterday. I want to take this time now to thank each of you for attending today's call and your interest. A reminder that an archived version of the webcast will be available later today on our website. With that, thank you very much and enjoy the rest of your day.
Thank you for joining us today. This does conclude today's presentation. You may now disconnect.