Summit Therapeutics Inc. ($SMMT)

Thank you for standing by. My name is Kate, and I will be your conference operator today. At this time, I would like to welcome everyone to the Summit Therapeutics ASCO 2026 Update Call. I would now like to turn the call over to Dave Gancarz, Chief Business and Strategy Officer. Please go ahead.

Good morning, and thank you for joining us. Team Summit is pleased to be hosting this call from Chicago, where the oncology community has gathered what has already been an exciting ASCO 2026 Congress. This meeting continues to showcase the rapid pace of innovation across cancer research and treatment, and we're energized to be a part of this important scientific and clinical discussion directing the next wave of medicines for patients with cancer. We issued 2 press releases over the weekend relating to encouraging Phase II data in metastatic colorectal cancer and of course, the historic results of the Phase III HARMONi-6 trial featuring ivonescimab presented as part of yesterday's plenary session at ASCO. The Phase II CRC is a global data set, including patients enrolled in the United States and China, and the HARMONi-6 study was conducted exclusively in China, sponsored by our partners at Akeso. All data in the HARMONi-6 was exclusively generated managed and analyzed by Akeso. The press releases are available on our website, www.smnctx.com. 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 Bob Duggan, our Chairman of the Board and Co-Chief Executive Officer; Dr. Mahkam Zanganeh; our President and Co-Chief Executive Officer; Manmeet Soni, our Chief Operating Officer and Chief Financial Officer; Dr. Bilal Kapiti, our Chief Medical Officer; Dr. Allen Yang, our Chief R&D Strategy Officer, and Dr. Howard Jack West, our VP of Global Medical Affairs. I am Dave Gancarz, our Chief Business and Strategy Officer. Before we get started with 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. Some in cautions that these forward-looking statements are subject to risks and uncertainties and that may cause to 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 slides being displayed on the webcast link. I'd encourage you to use the webcast link to see the slides being presented this morning that will accompany our comments. Following comments from our team, we will take it. And with that, I would like to hand it over to Dr. Jack West to walk through the beginning of the presentation.

Thank you, Dave. Yesterday, as you are aware, even snab Abitur, in a presentation as part of the plenary session of ASCO. The presentation titled ivonesumab plus chemotherapy versus tislelizumab for chemotherapy in previously untreated advanced squamous non-small cell lung cancer. Overall survival results of the Phase III HARMONi-6 trial was delivered by Dr. Chengdu, MVPC principal investigator of HARMONi-6, Director of the Lung Cancer Center at Shanghai Chest Hospital and tenured professor. Prior to discussing the results of the study, we will reinforce the study design and baseline characteristics that were discussed at ESMO last fall as well as published simultaneously in the first paper for the study in the Lancet. The study was highly significant in its primary endpoint of progression-free survival. And of course, the focus of the data release was the overall set data from this study. Revisiting the schema for the HARMONi-6 trial. This study evaluated ivanezumab in combination with platinum-based chemotherapy compared with tislelizumab, a PD-1 inhibitor in combination with platinum-based chemotherapy in patients with locally advanced or metastatic squamous non-small cell lung cancer, irrespective of PD-L1 expression. HARMONi-6 is a single region multicenter phase study conducted in China and sponsored by Kesa with all relevant data exclusively generated, managed and analyzed by ICASA. Key eligibility criteria are shown here. Patients were randomized 1:1 and stratified by stage of cancer and PD-L1 tumor expression at baseline. Patients received either ivonasumab at 20 milligrams per kilogram plus carboplatin paclitaxel or 2 telizumab plus carboplatin paclitaxel for up to 4 cycles, then received either ivanafinab or tillizumab as maintenance therapy for up to 24 months. The treatment was to be discontinued for intolerability, progressive disease or initiation of new antitumor therapy. This study's single primary endpoint was progression-free survival by independent radiologic review committee. The focus of today's progression will be overall survival. The trial included a total of 532 patients. Baseline characteristics show that this was a predominantly male population, nearly all with Stage 4 disease and it's important to underscore that these patients with advanced squamous non-small cell lung cancer included patients with characteristics that have traditionally been considered as potentially associated with bleeding on anti-angiogenic therapy. Specifically, approximately 2 serves had a central tumor 17% had encasement of major blood vessels in the chest, 9% had tumor cavitation and nearly 1 in 3 had a history of some offices. The breakdown of PD-L1 expression showed approximately 40% had a PD-L1 negative cancer with the remaining 60% of PD-L1 positive cancers show 40% in the low range of 1% to 49% and about 20% with high PD-L1 expression of 50% or greater. The median follow-up time of this current data cut is 21.4 months. As the planned interim analysis of the study, the trial was positive for overall survival with a hazard ratio of 0.66 and a corresponding p value of 0.001 and and representing at least a 4-month difference in median survival, though this remains early at this time. The curves separate early at approximately 6 months. after treatment begins and continue to staff with additional time. Landmark 2-year overall survival rates were 64.7% for those patients receiving bivenetimab compared to 48.6% for those receiving anti-PD-1 therapy with tislelizumab. This represents the first randomized Phase III study conducted in driver mutation negative frontline non-small cell lung cancer against another PD-1 therapy in combination with chemotherapy to achieve a statistically significant benefit in overall survival. When we look at various subgroups, it's important to highlight that the size of the subgroups is smaller by definition and not designed to show statistical significance on their own. The subgroup analyses for overall survival confirms the benefit of preplanned subsets as indicated by point estimates for each subgroup landing on the left side of the dividing line favoring vena Overall, showing that the study results were observed broadly and not driven by a specific subset or subsets of patients. These overall survival curves show benefit in patients with no, low and high PD-L1 expression, representing PD-L1 TPS score less than 1%, and on to 49% and 50% or more, respectively, at baseline. Patients with negative PD-L1 tumor expression had a hazard ratio of 0.64 and those with low PD-L1 tumor expression at a hazard ratio of 0.67 and those with high PD-L1 tumor expression at a hazard ratio of 0.64 -- in other words, ivimexmab with chemotherapy demonstrated benefit compared to tislelizumab with chemotherapy across the entire spectrum of tumor PD-L1 expression. Ivonescimab continued to demonstrate an acceptable and manageable safety profile in the HARMONi-6 study consistent with previous Phase III studies of ivanesumab plus chemotherapy. No additional safety signals were noted in the HARMONi-6 study. Treatment-related serious adverse events occurred in 41.4% of patients receiving ivansimab plus chemotherapy and 34.3% of patients for Citilrizumab plus chemotherapy. Treatment-related adverse events leading to discontinuation in the study occurred in 5.3% of patients receiving ivonescimab with chemotherapy compared to 4.5% for those receiving teplizumab of chemotherapy. The most common treatment-related adverse events in both arms were commonly associated with platinum doublet chemotherapy and included anemia, decreases in neutrophil counts and white blood subcons. Most of the possibly VEGF-related adverse events occurring in the ivanesumab plus chemotherapy arm were classified as grade 1 or 2. Grade 3 or higher hemorrhage events were observed in 2.6% of patients in the ivenesimab plus chemotherapy arm compared to 0.8% of patients in metinzumab plus chemotherapy arm of the study. In summary, ivonescimab provided a statistically significant and clinically meaningful overall survival benefit for patients with advanced squamous non-small cell lung cancer as first-line treatment in the HARMONi-6 with a hazard ratio of 0.66, which was consistent with all key subgroups including those with negative low or high PD-L1 tumor expression. Regardless of PD-L1 tumor expression, patients received consistent benefit ivonesimab's strong performance of all levels of PD-L1 expression is important as ivonescimab appears to provide clinically meaningful improvements to patients irrespective of PD-L1 expression. Ivonescimab was well tolerated with low rates of adverse events leading to discontinuation or debt, both comparable to the tislezumab plus chemotherapy arm. Prior to HARMONi-6, there were no known Phase III clinical trials in non-small cell lung cancer that have shown a statistically significant improvement in both PFS and now Ops, compared to PD-1 or L1 inhibitor therapy in combination with chemotherapy in a head-to-head comparison. Following the success of the CASO HARMONi-2 study in China, where the PFS benefit was observed in a monotherapy setting for patients whose squamous or non-squamous tumors were positive for PD-L1 expression. This is second time in which hibenestumab-based regimens have become the first known investigational therapy to demonstrate a statistically significant benefit compared to standard of care PD-1 or L1 inhibitor-based there. This underscores the specific value that ivonescimab in HARMONi-6 regimen could bring to patients in this setting with the opportunity to include the differentiated mechanism of action for physicians and patients to choose from. We believe that ivonescimab has the potential to become a new standard of care for advanced famous non-small cell lung cancer, and we look forward to the near-term readout for our global Phase III study, HARMONY II, evaluating ivoneximab in frontline non-small cell lung cancer, with today's positive HARMONi-6 overall survival update. We gained even more confidence in the potential for ivonescimab to make a meaningful difference in the lives of patients with lung cancer. On that note, we want to extend the heartfelt thank you to the patients and their families, the clinical site personnel and the Akeso team for contributing to and conducting the HARMONi-6 trial. Additionally, it is worth highlighting that the Lancet published a full permanence manuscript concurrent with yesterday's plenary session. And with that, I'd like to turn it back to Dave.

Thanks, Jack. I'd like to echo Jack's comments around our gratitude for the patients who enrolled on HARMONi-6, their family members, trial site personnel, investigators and pieces team. We are highly encouraged by the read-through of this study to HARMONi-3 and frontline all-comers non-small cell lung cancer as well as HARMONi-7 in non-small cell lung cancer with high PD-L1 expression. Anti-PD-1 therapy with or without chemotherapy, depending on PD-L1 status is the overwhelming standard of care in frontline lung cancer without driver mutations. Ivonescimab both as monotherapy and in combination with chemotherapy, now compared favorably in both settings in Phase III studies conducted in China. While additional HARMONi-3 data will be important to see in the coming quarters, the consistent statistically significant, clinically meaningful results in progression-free survival and overall survival in HARMONi-6 and the PFS and OS data generated to date from HARMONi-2 are very encouraging, and we look to our ongoing global frontline lung cancer studies and beyond. One additional point I'd like to ensure we go over. There were some commentary with respect to subgroup analysis -- to the subgroup analysis hazard ratios that were disclosed in the fourth slot for overall survival related to results by age groups presented yesterday. As you may recall from ESMO 2025, while patients under 65 and over 65, both showed a PFS benefit from ivonescimab plus chemotherapy as compared to disalizumab plus chemotherapy the effects were seen less and older patients. An analysis was performed by Akeso to review differences in baseline characteristics between those over 65 in the ivo arm versus the Tisle arm to understand this difference, in doing so, multiple imbalances were noted, including target lesion size and the presence of brain metastases. This was specifically addressed previously during the ESMO 2025 presentation. Correcting for these baseline differences explain the substantive portion of the difference in hazard ratios by age for PFS. And it is important to see that written on the slide on the screen right now. If you are on the webcast, the slides from ESMO 2025 note that when adjusting for these covariants, the adjusted PFS hazard ratio for those patients greater than 65 years old was 0.69. Note that for both PFS and OS, not even considering the imbalanced baseline characteristics, the older subgroup did not show any detriment. Once adjusted for these baseline differences, the hazard ratio for PFS was normalized the overall population. Therefore, the difference noted appears to be more -- most likely driven by the imbalance baseline characteristics. These differences were seen in PFS could be seen in the OS for slots as well and can happen in clinical trials. Each subgroup is not powered and is not necessarily balanced for baseline characteristics, and if prognostic factors are not balanced, a subgroup can be impacted as we described previously last October. Importantly, remember that HARMONi-6 is the fourth Phase III study conducted evaluating vines. In the first 3 studies, results for patients under and over 65 were very comparable. In the global HARMONY study, the longer-term follow-up of OS showed a numerically better hazard ratio for those patients over 65. So HARMONi-6 is the only study where we see this difference in this unpowered subgroup had imbalanced baseline characteristics. Let's move on and discuss the continued deep experience we have with ivonescimab. Ivonescimab has read out 4 Phase III clinical studies to date, all 4 of which had positive data, leading to 2 approvals in China thus far. At this time, a total of 15 Phase III clinical trials have either been announced, are currently ongoing or have read out in multiple tumor types. For clinical trials have been initiated since 2019 between Summit and Akeso, evaluating ivonescimab in a variety of solid tumors. When considering investigator-initiated in collaborative studies, A total of 155 clinical trials are now listed on clinicaltrials.gov. The enthusiasm demonstrated by investigators around the world generate data and seek positive signals for patients facing high unmet medical needs really speaks to the opportunity and optimism surrounding ivonescimab. Together with our partner, Akeso, we have enrolled over 4,000 patients in either Summit sponsored or Akeso sponsored clinical trials around the world. Commercially, in China, over 70,000 patients have received ivonescimab. Turning to our pipeline and our global Phase III HARMONY study. In April, we provided an update with respect to the squamous cohort of this study. We added to our protocol and interim analysis for PFS for the specific purpose of providing a potential opportunity for earlier regulatory discussions, specifically with the U.S. FDA. to achieve statistical significance at this early interim look due to the meaningfully higher bar compared to the upcoming planned final PFS analysis based on minimal also spent on the interim analysis. The interim PFS analysis was reviewed by an independent data monitoring community or an IDMC, and the committee recommended the study continue as planned. Importantly, no safety concerns were noted this study continues to be double blinded. In line with prior guidance, we expect the final progression-free survival and interim overall survival analysis for the squamous cohort in the second half of this year. For the non-squamous cohort, we expect the final progression-free survival analysis to occur in the first half of 2027. The study continues to be double blinded, and we do not have further information regarding the results of the study. We look forward to the results of the final PFS and interim OS in the second half of this year. With respect to the non-squamous cohort at HARMONi-3, we have completed screening for patient enrollment and expect to complete enrollment of the 1,000 patient cohort this month. We continue to enroll in HARMONi-7 and HARMONi GI 3, look forward to continuing our work with Cortex in head and neck cancer as well as Rev Med with novel RAS inhibitors kicking off the GSK collaboration, testing ivonescimab with ADCs and expanding the number of collaborations we have with other agents with novel mechanisms of action. With that, I'd like to turn it over to Allen to review the Phase II CRC data in combination with FOLFOX chemotherapy, the backbone chemotherapy or Phase III HARMONi GI 3 clinical study. Allen?

Thanks, Dave. At this year's absence fibenextomab data in colorectal cancer was also featured from the global Phase II study, AK-112-206, which evaluates 2 doses of ibibo is per kilogram and 10 milligrams per kilogram in combination with FOLFOX chemotherapy as first-line treatment in patients with microsatellite stable metastatic colorectal cancer. The study was conducted in China and the U.S. Akeso had previously disclosed encouraging Phase II study data with ivenestumab in combination with different chemotherapy regimens in microsatellite-stable CRC. The standard of care chemotherapy in first-line metastatic study is most often FOLFOX. And so we expanded the Phase II study to include 2 cohort of ivanesumab at different doses in combination with bulb. This was the basis for our Phase III study, HARMONi GI 3, as Dave alluded to. This also represents global data as a mix of patients were enrolled from the U.S. and China for these 2 arms. In this analysis, all patients experienced a reduction in tumor burden compared to their baseline assessment. The addition of ivenestumab to Folfox delivered deep and durable response rates and responses were consistent across the 2 dose levels. In the overall study population, ivanesmab plus FOLFOX chemotherapy achieved an adjusted response rate of 70.8% and a disease control rate of 100%. The treatment responses in the higher dose of ivonescimab plus Folfox arm were more durable than the lower dose of ivo plus Folfox. With the duration response landmark estimate at 9 months, of 79.1% and 41.5%, respectively. For patients in the higher dose ivonescimab arm, the landmark PFS rate at 9 months was 76.1%. While progression-free survival remains immature, the high proportion of patients progression-free at 9 months is encouraging. The study demonstrated an acceptable and manageable safety profile for the ivonetumab regimen and no new safety signals were served. This was consistent with previous studies of ivanefmab, including Phase II data in metastatic microsatellite stable CRC and demonstrate the potential for a favorable benefit risk profile for ivanesumab plus FOLFOX in this setting. In total, including both arms, 20.4% of patients experienced serious treatment-related adverse associated with either ivenesumab or chemotherapy. There were no ivonescimab related deaths and 1 ivonescimab related discontinuation, supporting the tolerability and ability to manage step-adverse specs. These support continued expansion of IVS clinical development in metastatic colorectal cancer. They also support the design of our global Phase III HARMONi GI 3 study in microsatellite stable metastatic colorectal cancer that is currently enrolling. We are pleased with these results at Aseko and are excited about the potential to help patients facing colorectal cancer. The disease has a particularly poor outcome in the metastatic disease setting with a 5-year survival rate between 13% and 18%, underscoring the urgent need for improved treatment options. Before concluding the call, I wanted to take the opportunity to remind everyone of our upcoming catalysts and recent accomplishments. As we've discussed on past calls, we will continue to provide further details on additional new global studies throughout the year as they are ready to share. To date, we have initiated a global Phase III studies in non-small cell lung cancer, colorectal cancer and head and neck cancer through our partnership with VorTeq. We look forward to continuing to grow our global pipeline and explore ivonescimab's potential to help more patients in new tumor site. For HARMONi-3 trial, for the HARMONi-3 trial evaluating ivonestumab with chemotherapy in frontline all-comers non-small cell lung cancer, we have completed enrollment in the squamous cohort. We are now completing enrollment for the non-slam cohort and expect to conclude enrollment this month. As I mentioned earlier, the final PFS in analysis for the squamous cohort are expected in the second half of the year for the nonsquamous cohort and the final PFS analysis is expected in the first half of 2027. Turning to our BLA filing. Based on our Phase III HARMONi study seeking approval for IV SMS plus chemotherapy in the EGFR-mutated non-small cell lung cancer study post TKI, the submission is currently under review with the U.S. FDA. The agency has provided a target PDUFA date of November 14 later this year. We continue to grow our commercial capabilities as we prepare for the anticipation of ibanesimb's potential first U.S. approval and potential launch later this year. Okay. I'd like to give it back to Dave Gancarz.

Thanks, Allen. On today's call, we've covered ivonescimab's accomplishments thus far in the clinic, but this is only the beginning of the vast potential market opportunity set for ivonescimab across solid suit. We have discussed this several times before with each successful data set, it becomes -- the reality becomes closer. Ivonescimab has the potential to be a platform blockbuster drug. Ivonescimab is well positioned to make a significant impact across the solid tumor treatment landscape. Between checkpoint inhibitors and anti-VEGF therapies with an estimated total addressable market to be in excess of $100 billion globally. Looking only at the checkpoint inhibitor market for non-small cell lung cancer, market estimates for immunotherapy are expected to exceed $20 billion per year by 2028. On the slide, you see on the screen now, many solid tumor settings where anti-PD-1 and anti-VEGF therapies are highlighted PD-1 and PD-L1 indications in green and anti-VEGF indications in purple. The ones highlighted is in yellow represent the indications where we are currently running Phase III trials for ivonescimab globally, lung and colorectal cancer silly. There are several additional opportunities for ivonescimab including, in addition, novel settings were neither have been effective, such as EGFR mutant on small cell lung cancer. Ivonescimab's differentiated profile as we saw with Harmony 6 achieving a statistically significant highly clinically meaningful PFS and OS benefit supports its platform potential across multiple indications, each of which could be blockbuster opportunities on their own. We have only just begun to see the potential of ivonescimab to help patients with solid tumors. These are exciting times at Summit, and we encourage you to stay tuned to our journey as we continue to expand the Ivinhema clinical development plan in new tumor settings. We'll now turn the call back to the operator to see if there are any questions that our team can help answer. If you can please open the line for questions.

[Operator Instructions] Your first question comes from the line of Tyler Van Buren with T.D. Cowen.

Congratulations on the tremendous and potentially practice-changing data presented this in -- just can you provide your latest thoughts on how you believe the PFS hazard ratio and now the impressive OS hazard ratio for HARMONi-6 will translate to the ongoing HARMONi-3 trial. And as the follow-up to that, -- what is -- specifically, what is your confidence that Ivo is performing similarly to HARMONY 6 in the ongoing HARMONY 3 trial, considering the fact that it passed on the recent interim PFS analysis.

Thanks, Tyler. I think with respect to the overall confidence on HARMONi-3 as we mentioned on the call, as well as we've mentioned a few times, historically, the purpose for that interim analysis was specifically -- as we look at the landscape overall competitively, there are multiple PD-1 VEGFs in class of which we are significantly in the lease. And so we looked at an opportunity to take the final PFS timing in the second half of this year. and with and look to accelerate the timing by which we could speak to the U.S. health authorities in effect the regulators and in that case, specifically the -- and so with the minimal ALP allocation, we looked to perform that interim analysis, as I mentioned on the call. And so we -- and as I said earlier, the IDMC looks recommended to continue and recommend no changes to the study. With that, we have no change in terms of our overall confidence because what we did in that process would not change the final PFS threshold in effect. It was extraordinarily minimal in terms of the costs on the final. So as we look now at the data from HARMONi-6, we see 2 things. We see a highly statistically significant PFS and a highly statistically significant OS. And so that's in the same setting. It gives us a lot of confidence as we look at the translation overall from 1 study to another in that same study that we have -- are very well positioned with respect to the second half of this year. I'd also remind, if you look back at the gold standard endpoint OS when we look at the HARMONi and the HARMONi-A studies, we had remarkably consistent median OS from the East and the West as well as highly consistent hazard ratios. So we've seen in the past consistency overall between data with ivonescimab in China as compared to globally. And then the final point I would make is, overall, again, we've had 4 Phase III readouts in total. All 4 have been positive. And so when we look at the trajectory of that data, it's all pointing in 1 direction at this point, and that's been positive. And so from that perspective, while no 1 has a clear crystal ball. It is very much -- as we look at the data, we see everything moving and aligning in the same direction from that perspective.

Dave, I'd like to add, Tyler, thanks for the question. Akeso has been a terrific partner. So the HARMONi-6 and HARMONi-3 trials are very similar. It's not almost identical. In addition, Akeso has helped us enroll patients from China for the HARMONi-3 study. So about 1/3 of those patients will be from overlapping sites and investigators with the 136 study. So the 1 thing I'd just like to point out is we take -- we took a calculated risk trying to bring this drug to patients earlier. But the enrollment for the swims cohort just recently completed. And therefore, that data we understood that risk, so if we took it. Obviously, we were not happy with the results, but we thought that was important for patients. But as the data matures, we expect our data to strengthen, although we haven't seen it.

Your next question comes from the line of Salveen Richter with Goldman Sachs.

Congratulations on the data here. Two for me. One is, how do you think the strong squamous results read through to the non-squamous port the study, and secondly, at the presentation, the presenter noted that the median OS was reached with the last patient event. Could you put that finding in context and expectations for OS on additional maturation?

Thanks, Salveen. Why don't we start with the first question that you asked there with respect. Can you repeat the first question? I just want to make sure I've got full context on the first question.

Sure. Just how to think about the read-through from the squamous result to the non-squamous portion of the study.

Very good. And so I think it's important, I'll give a little bit of history here, Salveen. I think this is good context overall. At the history of HARMONi-3 for example. We started in Swetnaand that was generally because when we entered into our transaction with Akeso, the Phase II data in squamous in combination with chemotherapy, was very strong and was maturing. And so we immediately -- and I think Bob has alluded to this a few times in the past, it was very important that we -- when we entered into the transaction with a cast we started very quickly in terms of establishing a presence with the PD-1 VEGF specific. And so the squamous data in Phase II was mature. It was highly encouraging, nd that footprinted an immediate opening of that study. As we then looked at the nonsquamous portion, it was just simply less mature at that point in time. And so with line in terms of traffic. -- fast forward now to the middle of 2024. You see the positive data from HARMONi-2 that showed monotherapy IVO performing well in both squamous and non-squamous histologies. At that same time in 2024, the Phase II non-squamous data in combination with chemotherapy was also maturing was highly encouraging. So I say all that because when we get to now HARMONi-6, and your question with respect to the read-through, that HARMONi-6 data was highly validating to the Phase II data that we've seen in AK112201, the Phase II study. And so we saw highly encouraging Phase II data in squamous, that then translated to the HARMONi-6 success that we've seen now. we have highly encouraging Phase II data in non-squamous as well. And so that data becomes a little bit more validated as well with the Phase III replicating the Phase II data. And when I say repiping, for example, the median was nearly identical between the Phase II and the Phase III. And so what we're seeing is the date we've relied on in terms of the encouraging opportunity in non-Swiss that Phase II data, has been -- that same study has been shown to replicate Phase II to Phase III. Obviously, it's frontline lung cancer as well, and so highly encouraging opportunities or present in the existing Phase III data in Tumi is highly encouraging. So there's no -- there's certainly nothing negative with respect to the non-squamous portion. I'll turn it over to Jack for the second half of that question with respect to...

Median...

With respect to the last patient who passed away leading to the median.

The highlight there is that at that part of the curve, it's a very small number of patients. And so a single patient death among 4 patients at that time led to a drop just below the median, but that's a very unstable finding is defining the lower limit of the confidence interval for that median, which means it can only improve from what that is, and that's exactly what Akeso, I believe, expect be the case as the data mature and there is a much large population to draw from, who gets out to and beyond the median point. So -- that is the lowest number that would ever be seen and we might anticipate based on the patterns that, that isn't truly a representative number and that it's going to end up with further follow-up as a stronger difference in terms of absolute number of months between the 2 arms.

And Salveen, this is Allen. I'd add to -- I understand the question about staying this translating over to non-squamous a greater unmet need in Western markets. I want to point out the HARMONi and HARMONi-A study. Those were nonsanctologies with the same chemo backbone, even though they are EGFR mutant non-mall cell lung cancer. And again, all the strong ivonescimab data in complete different tumor types of CRC TNBC. So the drug is active. So the jump from slams to nonamusystology is small compared to the breadth of this molecule.

That's right. And I think the other piece I would add on top of Jack Knight's explanation. When you look at the curve overall, what you are seeing is the curve separating 6 months, but then continuing to expand. And that's really what reflects the hazard ratio of 66% and that relative improvement in reducing the risk of death.

Yes. Obviously, the median is just 1 point in time, but that shape of the curve as everyone highlighted, including of the plenary session. it is widening as the patients continue over time and the curve moves to the right. So that median kind of underrepresents the benefit that was really seeing.

Yes. So when you look at the baseline tizaluzumab lost therapy, which performed either on par with or slightly above historical results with respect to the rationale 307 study, which is the pivotal study in which sizolizumab plus chemo was approved, that relative improvement of 34% relative improvement on top of that 22-month, 23-month benchmarks, you would certainly expect that to be a bit higher than the 4 months. just the math would tell you, it's closer to 7% to 8%. And so when you look at the median follow-up time of 21 months and change, what this really represents because those curves are widening further with more time, that has a ratio in respective confidence interval and thus the p-value becomes statistically significant showing that there's clearly the benefit already with more opportunity to continue to look at longer-term follow-ups, if you will. But this is the final -- this is the primary overall survival analysis. It is statistically significant and highly statistically significant at that. And I think that 34% relative risk reduction is the important part to look at.

Your next question comes from the line of Yigal Nochomovitz with Citi.

Congrats on the very, very strong result at ASCO. Thanks for also mentioning the covariant analysis that you did at ESMO with regard to the PFS. I'm just curious if you were to apply that same math and logic to OS, what the conclusions may be. And curious as to why the ASCO discussion didn't put forward that piece of analysis. And then also, could you just clarify as to why the interim was triggered at 204 versus land 225 events as defined in the protocol for the study.

Thanks, Yigal. And so I think the -- so we appreciate the comment with respect to the covariant analysis -- and so importantly, there was not a separate co-variate analysis run at this point with respect to overall survival. However, the baseline characteristics to be very clear, don't change over the course of the study, right? These are the baseline characteristics of the patients entering in. And so the baseline characteristics is the PFS analysis or remain, of course, consistent with those -- the overall survival analysis. And that's why we thought it was important today to remind everyone of this particular topic, which was discussed back in October where those imbalanced characteristics -- baseline characteristics within the greater than 65-year-old patients between IVO and tile is very relevant. So as you saw that translate from a PFS hazard ratio of about 0.88 down to about 0.69 when you took into account the fact that those in the ivo arm had higher rates of brain metastases had larger target lesions at baseline, right? Those baseline characteristics when adjusted normalize the difference between those under and over 65. I think it's also -- it is really important also to note that this is the fourth Phase III study conducted with -- the other 3 did not show any detriment when looking at those over 65 as compared to those under 65. And so this is where it's important to remember, these are nonpowered subgroups as well. And so you don't have necessarily balanced baseline characteristics amongst the subgroups, and you also aren't powering your study to reflect the results of those patients. So we see other studies for example, there are studies that have been run were highly statistically significant oral survival benefits for 2 is an example of this, where the results in first-line EGFR mutant non-small cell lung cancer osimertinib plus chemo versus osimertinib monotherapy, about 1/3 to 35% of those patients were enrolled in Asia, ex China, but that specific subgroup that region showed a hazard ratio of 1.00, representing 1/3 of the patients or more enrolled in that study. However, I think anybody would argue that osimertinib plus chemotherapy works in China, but not in the rest of Asia from that perspective? And then also works in the U.S. and Europe. So I say all that just to provide example an example of a place where when you look specifically at a drug group and then you try to extract too much from that, it's very difficult to do because you don't balance for everything else that goes into a very well-designed plus clinical study. And so as we think about that, there was no detriment to patients over 65, either from a PFS or an OS perspective. And I think that's really important to point out.

I'll take the next question, and then you can add -- so we answer the question. The other question was about why they did the OS analysis slightly earlier versus 220. It's not uncommon. It's a goal, and it's often hard to predict how many patients you'll have at the time of the analysis because there's a cleaning and sort of preparation of the data and the locking of the database. So as long as you're within well within 10%, that's not unusual. I can't comment that question is probably exactly on, but it's often as part of a regulatory discussion, there may be a query from a regulatory agency. That's the reason I see that they would slightly vary from their targets.

Your next question comes from the line of Brad Canino with Guggenheim Partners.

And congrats to you, your team and your partner on those data. Now the 0.66 hazard ratio and the at least 4-month benefit, can you contextualize these results within the past fine squamous lung trials that have changed practice -- and then you always get a lot of questions on the translation of that benefit to HARMONi-3, but do you need to translate that magnitude? Or is there some margin where even a lower result could be significant enough to still change practice?

Yes. This is Jack. I will feel that I spend a lot of my time talking with my colleagues who are click oncologists. And I would say that A huge amount of the excitement about HARMONi-2, I know I'm going back in time, was just that as impressive and as integral as pembrolizumab has been a sense that it was an impenetrable plateau that we might never exceed in our careers and just seeing the capacity to do better than that is remarkable and all of the potential opportunities to exceed that with pembro or potentially other checkpoint inhibitors. Squamous, in particular, is a setting that has been -- has had a dearth of developments over time. as compared to non-squamous, where there's new driver mutations and targeted therapies that chip away, but squamous has really been left without many new opportunities. And that would make any development especially welcome. Seeing a PFS benefit is not negligible and in many settings of oncology that is eagerly accepted as enough to adopt a new therapy. I think that in lung cancer, non-small cell, at least particularly, we often impose a higher bar of overall survival. That said, if it is a hazard ratio below about 0.75 or 0.8, that is enough for nearly every oncologist I speak with to consider that to be very clinically relevant, clinically meaningful and worth adopting as a new treatment. I would also say that when I've spoken with and seen results of survey questions from colleagues about, well, if you see a PFS benefit but the overall survival may or may not be statistically significant but trending in the right direction. You get a play, a mix of different opinions about whether that is clearly enough. But about half of my colleagues really feel that PFS benefit and even a modest trend of improvement in overall survival is perfectly welcome first to their patients. and secondly, themselves because this is not a comparison against placebo or chemotherapy alone. This is the first time we're seeing an improvement against such a high bar, and it's not accompanied by a counterbalancing major liability and toxicity. So people are saying, if this is compared to pembro or teplizumab and you clearly exceed on PFS and it's in the right direction for OS and not accompanied by a problematic increase in toxicity. Why would my patient not want to pursue that option. So yes, there's going to be a range in what clinicians required to adopt something, I would say the results we saw yesterday would be on the very far end of that range and really not controversial, but with a lot of room to see less than that and still be enough to motivate patients and most oncologists or many oncologists to readily adopt an improvement in some, even if not every parameter across the board.

Your next question comes from the line of Mohit Bansal with Wells Fargo.

My congratulations as well. So I would love to talk a little bit about the median follow-up at the point of interim in Harmony versus many 6. To what you can comment on that? And was there a difference between the median follow-up in HARMONi-3 interim versus 6 interim that could explain why you did not hit the increment at that time point.

Yes. This is Dave. I'll jump in and then I'll ask Bilal to provide any additional color. So what I would say overall is enrollment patterns are a little bit different as we know in any study in China versus any study globally, the enrollment patterns are a little bit longer. So what you will see in general, when you look at enrollment in a global study is a little bit more back-ended enrollment, one in to longer period of making very general comments with respect to enrollment in a global study as compared to China where you tend to ramp up very quickly. And enroll the duration of the study over a shorter period of time. And so while Moki, we're not going to give particular color in terms of here's median follow-ups in very specific related to HARMONi-3 as it would be incredibly unusual to provide that commentary on an interim look. But what I would say is there are patterns that you can look at across global studies in general across studies conducted in a single region and particularly in China, in general, where the distribution of events, the follow-up time will be a little bit different just naturally just based on the traditional patterns that you see for enrollment. And then I'll ask Bilal, if there's anything else you'd like to add.

Agree with Dave. I think more important rather than the median is the pattern of enrollment. And so sometimes it's a little hard to translate 1 to the other for the last interim for HARMONi-3, we took a calculated risk because we want to get this drug to earlier to the patients. And I think we're really fine out. We are very confident with how this is going to arsenal.

Your next question comes from the line of Cory Kasimov with Evercore ISI.

This is Josh on for Cory Kasimov. Given there's presidents of China-only trials, allowing for approval in the EU such as rationale wondering if there's any plan to use the HARMONi-6 data set to look for plain BU? And if not, how can these results help with the HARMONi-3 applications.

Thanks for the question, Josh. I think I'll make a couple of points here. So obviously, so when we entered into the great partnership with Akeso. One of the things that we were pretty clear on with respect to the U.S. individually, was that we never had an intent to take a single region study conducted outside of the U.S. and look to bring that specifically and specifically in China and then look to bring that to the FDA for approval. I think the FDA had made plenty of comments prior to that, that, that was not what they were looking for. We then, of course, open the HARMONi-3 study. And with respect to HARMONi-3, that will be a very study for which we would take approval, especially in the United States. but there's complementary considerations. There's another state randomized Phase III in the same setting, particularly in the squamous cohort of harm. And so from a package perspective, Harmony if could be included to strengthen that overall package. And so the other piece is when we look at, to your point, Josh, questions and other geographic locations. Those are things that we can continue to consider. And so obviously, we're running HARMONi-3 in Europe as well. So that's part of the calculus that needs to go into this. And part of this is also is we have -- if you take the totality of events, we completed enrollment in the first quarter of this year for the squamous cohort and then also this data is -- it was a late breaker at ASCO. So it's pretty fresh in terms of what we have here. And so part of that, as we look at next steps, we'll consider multiple options. But it's important that we have the global HARMONi-3 data reading out in the second half of this year. And so we can look at combining packages in certain ways, but this is also unlike the rational 307, there wasn't necessarily a study being run in those regions at the same time, which is where we were always -- we've stuck very consistently about our strong strategic and operational desires to bring ivenesumab around the world. And so with that, we can look at whether it makes sense to combine those packages based on what things look like when we get through the second half of this year as well, which makes that a much more straightforward question to answer.

Thank you. Your next question comes from the line of Ren Benjamin with Citizens.

And let me add my congratulations as well. I guess the question I have, kind of given all that you know now for the HARMONi-6 study and the required kind of amount of follow-up which occurred for the interim OS to hit statistical significance. Can you maybe talk us through your thoughts as to why maybe you would delay the reporting of the interim OS for ARM? How do you maybe optimize so that you have the right amount of follow-up and the right amount of events that might occur so that both PFS and OS are potentially hitting in the second half of this year? And maybe as a follow-up, I think you mentioned the OS significance boundary was like 0.049 for the RMV study. Do we -- is it fair to apply kind of the stat since you numbers specified the stat plan SP1 That we see in Army 6 to ARM E3 and why you would choose a one-sided test over a 2-sided test.

You added a couple of questions in there. I think...

I'm sorry, Dave.

Good. So I think One of the points with respect to the one-sided test versus the 2 side of tests, I mean, I think that's probably a little bit I think there's a little bit of noise in 1 of the media coverage to our Hill. I don't think that's a particularly relevant aspects here. The idea of both HARMONi-3 and HRV is looking to show statistical superiority over PD-1 plus chemotherapy. And so that is -- we're not looking at the other way around. And so the different -- there's really no functional difference between the 2 -- it's just a different way to describe the results of the same test. With respect to the stat plan for HARMONi-3. I appreciate the question. But I think as I mentioned a couple of times and as we talked about, is proteins comment across nearly all interim analyses. We don't plan to provide individual details on the individual statistical plan for the study. And that includes both the previous interim PFS look as well as the upcoming interim OS look. I think the third piece, I think, which is important is your question with respect to the bar in the interim OS at the end of this year, less the bar in terms of what the thresholds are, but the ability to compare with the follow-up time in HARMONi-6 or other studies and looking at the timing of HARMONi-3. So HARMONi-3 as we've talked about, this is an interim OS analysis, but it's also the final PFS analysis. And so those are effectively tied together. So we'll look at the final PFS analysis based on our prespecified number of events, and that's about looked at the end of those events look like they'll come in the second half of this year. And that's the end of the testing for -- in tria final PFS analysis, you also, at that same time, have a look at interim OS or you have a look at OS on an interim basis. So I would say we should set no expectations that the idea is an interim OS look at the second half of this year is a make-or-break look. But I think it will be very informative in terms of what that looks like from overall survival. And that will also take place at a median follow-up time that's less than what the HARMONi-6 follow-up time was. And so HARMONi-6, I believe, completed enrollment in January of 2025. This analysis had a data cutoff that was presented yesterday at the end of February 2026. And so you've got last patient in plus about 13 months there. We talked about the fact that we completed enrollment in the first quarter of this year. And then we're saying that this final PFS and interim OS will take place in the second half this year. So while you don't know necessarily when in the second half, it's obviously going to be less than 13 months of median follow-up time. So we think that's very informative in terms of what directionally where OS looks, but I certainly wouldn't go into this with the expectations that we said OS as an endpoint is make or break in the second half of this year. We have a look just like most trials do at OS at the time of the final which is prespecified and that's what we're looking at the second half of this year. And so within that interim OS gives us directional inference in terms of where we go from what that data looks like to describe the OS at this point.

Your next question comes from the line of David Dai with UBS.

I also want to congratulate from the data. So mentioned, Dave, was that there was imbalance between the 65 years of age and 65 million based on lesion size in BMA. So how do you think this might impact the selection for HARMONi-3 trial? And do you expect to exclude some patients with these kind of covariants for HARMONi-3 trial?

Yes. I have say question, David. So the -- and I appreciate what you're asking, Importantly, HARMONi-3 remains completely blinded. So if we step back, what you aren't able to defined within subgroups when -- before you -- as you look at the data, is what different core variables will be unbalanced within the arm. So I think it's a little bit of a speculative question of will different subgroups, which are not stratified in the trial will be contain imbalance baseline characteristics. Again, I would say -- so there's no way to know that before you go into the trial. But I would also say that's where looking at subgroups can be helpful. And I think as Jeff mentioned in his comments, -- but they're not powered for individual results, right? And so what you're looking for is do you see a subgroup of hazard ratio over 1 and particularly directionally well over 1 that gives you pause to say clinically is there's something here that may be more informative maybe than what we had thought hypothetically going into a study. I want to be very clear, all subgroups has a ratio of less than 1. All subgroups received benefit from ivonescimab plus chemotherapy in comparison tizalizumab insemitherapy. All subgroups trended were to the left of the line on the forest plots, right? So there were no subgroups that were detrimental when received had a detriment from bands as compared to PD-1. That's a really important context here. And so even with the imbalance, of these variables. We did not see a detriment to any of these patients, right? It was a smaller improvement but an improvement, nonetheless, right? And I think that's the difference here that I want to make sure we don't sight of. This isn't an example where we're looking at a subgroup with a 1.3 hazard ratio and saying, hey, you really need to take a step back and understand if there's something there. And so there's no way to not a priority going into the study the Western patients versus the eastern patients or the PD-L1 high versus the PD-L1 low will ultimately have more brain metastases versus less or whatnot because that's not really what's planned for -- but I think that's where the -- that's where we'll see that data that comes through. But it is very important that all subgroups were less than 1. And therefore, none of these imbalances actually led to detriment.

Yes, Dave...

Yes, just SP1 I was just going to add 1 thing to reassure you. There are questions which we believe could impact the outcome -- and so things like brain metastases as well as PD-L1 expression level are stratified for in the HARMAN study.

Yes. Just to add on it, Jack. And if you look at the 95% conference interval, I think they are overlapping between the 2 age groups, there's further that I mean this could be fairly random.

Your next question comes from the line of Dara Azar with Stifel.

Congrats on the data. Could you please characterize the growing separation of the OS curves. Do you attribute this to ivonesimab or the histology more -- and how strong is the case to see a similar phenomenon in non-squamous, non-small cell considering HARMONi-2 OX hazard translation from PFS was a little bit different in that mix histology study.

I -- this is Jack. I think that the most noticeable thing again, when you see the separation becomes clearer as the chemotherapy has been completed. Chemotherapy is kind of a normalizing effect and then you -- once you're at the point where you're directly testing the ivonescimab against the other here immunotherapy intolizumab, the longer you go, the more that differential becomes apparent. I think that with non-squamous non-small cell lung cancer, it's different because there's going to be ongoing maintenance pemetrexed. And so that may still have some kind of normalizing or effect that will change it from a paradigm where there's a prolonged period of just anetumab as monotherapy in the maintenance setting against pembrolizumab. So it will be a little different, but you still see the separation occur. And I I'm optimistic that, that's what we will see, especially as if patients are fortunate enough to be doing well without progression -- in some cases, patients will have pemetrexed discontinued due to cumulative myelosuppression issues, renal issue and even though Pevatrexid is generally considered a very well-tolerated therapy. It has cumulative toxicities if patients are on it for enough of a period that it really becomes longitudinal. So there will still be patients who are just on ongoing essentially monotherapy of in HARMONi-3 ivonescimab against pembrolizumab. But the separation, I think, will be there, but it will be a little different question in the non-squamous population, both because of the underlying differences in biology and because there is not a maintenance chemo component in squamous.

And again, I think the only thing I would add to is really the -- again, you go back to the highly encouraging Phase II data generated in the space, where we saw very -- and some of this was disclosed as recently as LCC 2024. And obviously, that's highly encouraging data as well that helps provide additional comfort on that front as well in terms of the applicability of ivanefmathlus chemotherapy in the nonsquamous cohort.

I'd now like to turn the call over to Dave Gancarz for closing remarks.

I want to take the time to thank everybody for attending today's call. obviously, the historic results of HARMONi-6 is we've gone over multiple times, is a day for celebration. The rest of your day. And for those of you here in Chicago, we hope you have a wonderful rest of your ASCO.

Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.