Prepared remarks
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 Q3 2025 Earnings and ESMO Data Update Call. I would now like to turn the call over to Dave Gancarz. Please go ahead.
Good day, and thank you for joining us. We issued a press release on Friday morning regarding the expansion of our Phase III clinical development programs, unveiling the global Phase III study in first-line colorectal cancer. Yesterday, we issued a press release relating to the Phase III HARMONi-6 data featuring ivonescimab presented as a part of the Presidential Symposium at the European Society for Medical Oncology's 2025 Congress, otherwise known as ESMO 2025. The HARMONi-6 study was conducted in China, sponsored by our partners at Akeso. All relevant data was exclusively generated, managed and analyzed by Akeso. And finally, this morning, we announced our intention to submit a BLA this quarter for ivonescimab based on the results of the HARMONi study as well as expand our Phase III study plan with additional color to be provided in the first quarter. Additionally, on today's call, we will provide an update on our third quarter financial results and operational progress. Press releases are available on our website, www.smmttx.com. Our Form 8-K and Form 10-Q were also filed today and are available on our website and via the SEC's website. Today's call is being simultaneously webcast, and an archived replay will 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. 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 Head of R&D Strategy; Dr. Jack West, our VP of Clinical Development; and Dr. Fong Clow, our Chief Biometrics Officer. 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 information on these slides being displayed in the webcast link. I'd encourage you to use the webcast link to see these slides being presented this morning that will accompany our comments, and these slides are also available on our website. Following comments from our team, we will take questions. With that, I would like to hand it over to Jack to walk through the beginning of the presentation.
Thank you, Dave. Yesterday, as you're aware, ivonescimab data was featured in the presentation at ESMO 2025 as part of the Presidential Symposium. The presentation titled Phase III study of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small cell lung cancer, HARMONi-6 was given by Dr. Shun Lu, MD, PhD, Chief of Shanghai Lung Cancer Center at Shanghai Chest Hospital, Professor of Medicine at Shanghai Jiaotong University, and associate editor for the Journal of Thoracic Oncology. Revisiting the schema for the HARMONi-6 trial, this study evaluated ivonescimab 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, multi-center Phase III study conducted in China sponsored by Akeso, with all relevant data exclusively generated, managed and analyzed by Akeso. Key eligibility criteria are shown here. Patients were randomized 1:1 stratified by stage of cancer and PD-L1 tumor expression at baseline. Patients received either ivonescimab at 20 milligrams per kilogram plus carboplatin paclitaxel or tislelizumab-plus carboplatin paclitaxel for up to 4 cycles and then received either ivonescimab or tislelizumab as maintenance therapy for up to 24 months. Treatment was to be discontinued for intolerability, progressive disease or initiation of new antitumor therapy. The study's single primary endpoint was progression-free survival by independent Radiologic Review Committee. Secondary endpoints included response rate, duration of response, safety and overall survival. The trial included a total of 532 patients. Baseline characteristics show that this was a predominantly male population nearly all with Stage IV disease, and it's important to underscore that these patients with advanced squamous non-small cell lung cancer, included those with characteristics that we have traditionally considered as potentially associated with bleeding on anti-angiogenic therapies. Specifically, approximately 2/3 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 hemoptysis. The breakdown of PD-L1 expression showed approximately 40% had a PD-L1 negative cancer with the remaining 60% of PD-L1 positive cancers showing 40% in the low range of 1% to 49% and about 20% with high PD-L1 expression of 50% or greater. The figure for progression-free survival by independent Radiologic Review Committee analysis shows the trial was positive for the primary endpoint with the hazard ratio of 0.60 and a corresponding p value of less than 0.0001. Median progression-free survival was 11.14 months for the ivonescimab plus chemotherapy arm compared to 6.90 months for those patients receiving tislelizumab plus chemotherapy, a difference of 4.24 months favoring the ivonescimab plus chemotherapy arm. PFS by investigator assessment showed a consistent hazard ratio of 0.64. When we look at various subgroups, it's important to highlight that the size of the subgroups are smaller by definition and not designed to show statistical significance on their own, but they can be informative. The subgroup analysis for progression-free survival confirms benefit in all preplanned subgroups as indicated by point estimates for each subgroup landing on the left side of the dividing line favoring ivonescimab, overall showing that the study results were observed broad and not driven by a specific subset or subsets of patients. These progression-free survival curves show the benefit in patients with negative, low and high PD-L1 expression, representing PD-L1 TPS scores less than 1%, 1% to 49% and 50% or more respectively at baseline. Patients with negative PD-L1 tumor expression had a hazard ratio of 0.55. Those with low tumor PD-L1 expression had a hazard ratio of 0.63 and those with high tumor PD-L1 expression had a hazard ratio of 0.71. In other words, ivonescimab demonstrated benefit relative to tislelizumab across the entire spectrum of tumor PD-L1 expression. Objective response rate irrespective of PD-L1 expression was improved for ivonescimab by an absolute difference of 9.4%. In patients with PD-L1 expression less than 1% and those with PD-L1 expression of 1% or greater, objective response rates were improved for ivonescimab by an absolute difference of 8.5% and 9.9%, respectively. The median duration of response was also improved from 8.4 months for tislelizumab plus chemotherapy to 11.2 months for ivonescimab plus chemotherapy. Treatment-related adverse events showed only a small increase in the ivonescimab group. Any grade events were 99.2% versus 98.5% and serious treatment-related adverse events were 32.3% versus 30.2% in the ivonescimab and tislelizumab arms, respectively. Treatment-related adverse events leading to discontinuation of ivonescimab plus chemotherapy or tislelizumab plus chemotherapy occurred in 3.4% versus 4.2%, respectively. Based on the dual targeting of ivonescimab against PD-1 and VEGF, we analyzed adverse events that were thought to be immune-related or possibly VEGF-related. For the ivonescimab plus chemotherapy arm, compared to the tislelizumab plus chemotherapy arm, Grade 3+ potentially immune-related events were 10.2% versus 9% and potentially VEGF-related events increased from 2.3% to 7.5%. These events will be characterized further in the next slide. On the right, events are split out by the specific terms for adverse events. The most common events for ivonescimab treatment in combination with chemotherapy were common chemotherapy-related adverse events, including alopecia, anemia and various laboratory abnormalities, including neutrophil, white blood cell and platelet count decreases. As such, these rates were similar and manageable between the 2 arms. Focusing further on immune and VEGF-related events, we see that most events were low grade with approximately 9% to 10% of immune-related adverse events reaching Grade 3 or higher in either arm. Of interest, Grade 3 or higher immune-related AEs, serious immune-related AEs and immune-related AEs leading to discontinuation of ivonescimab or tislelizumab were all numerically lower in the ivonescimab. Among the possibly VEGF-related events, proteinuria was seen in 27.1%, hemorrhage in 21.4% and hypertension in 10.2% of patients, the vast majority being generally low grade with the rate of Grade 3 hemorrhage under 2%. Venous and arterial thrombotic events were 0 in the control arm compared to 1% for each in the ivonescimab. I want to pause here for a moment and speak to the validating and convincing safety profile seen yet again with ivonescimab in the results of this study now in combination with myelosuppressive platinum doublet chemotherapy in a population of patients with advanced squamous non-small cell lung cancer that was a real-world experience that included patients with central, potentially cavitary tumors, encasing vessels in some cases and a history of hemoptysis in a significant fraction. This clearly differentiates ivonescimab from what is feasible with a combination of routinely used PD-1 or PD-L1 directed immune checkpoint inhibitor plus VEGF monoclonal antibody therapies administered together. In summary, ivonescimab provided a significant and clinically meaningful progression-free survival benefit for advanced squamous non-small cell lung cancer as first-line treatment of patients in HARMONi-6 with a hazard ratio of 0.60 that was consistent across all key subgroups, including those with negative, low or high tumor PD-L1 expression, and those with liver or brain metastases. Hazard ratios in patients with negative low and high tumor PD-L1 expression were 0.55, 0.63 and 0.71, respectively. Ivonescimab's strong performance across all levels of tumor PD-L1 expression is important as ivonescimab appears to provide clinically meaningful improvements to patients regardless of the degree of PD-L1 expression. Response rate and duration of response were also increased. Ivonescimab was well tolerated with less than 2% Grade 3 or higher bleeding events and low rates of adverse events leading to discontinuation or death, both comparable to the tislelizumab plus chemotherapy arm. The incidences of any grade treatment-related adverse events were similar between the 2 arms. 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 compared to PD-1 or PDL1 inhibitor therapy in combination with chemotherapy in a head-to-head setting. Following the success of Akeso's HARMONi-2 study in China, where the PFS benefit was observed in a monotherapy setting for patients who had squamous or non-squamous tumors that were positive for PD-L1 expression, this is now the second time in which we see ivonescimab-based regimens becoming the first known investigational therapy to demonstrate a statistically significant benefit compared to standard of care PD-1 or L1 inhibitor-based regimen. This underscores the specific value that ivonescimab and the HARMONi-6 regimen could bring to patients in this setting. With the opportunity to include a differentiated mechanism of action for physicians and patients to choose, ivonescimab has the potential to become a new standard of care for advanced squamous non-small cell lung cancer. And we look forward to HARMONi-3, a global Phase III study reading out in the coming months and years. Importantly, we want to thank the patients and their families, the clinical site personnel and the Akeso team for carrying out the HARMONi-6 trial. And now I'd like to turn it over to Maky.
Thanks, Jack. I would like to echo Jack's comments around our gratitude for the patients who enrolled in HARMONi-6, family members, trial site personnel, investigators and, of course, the Akeso team. We are slightly encouraged by the readout of this study to our other ongoing Phase III study in frontline non-small cell lung cancer, HARMONi-3, HARMONi-7, PD-1 therapy with or without chemotherapy depending on the PD-L1 status is the more overwhelming standard of care in frontline driver mutation-negative lung cancer. Ivonescimab both as monotherapy and in combination with chemotherapy compares favorably to the result of the PD-1 monoclonal antibody previous studies. While additional overall survival data will be important to see in the future, consistent, clinically meaningful, statistically significant results in progression-free survival in HARMONi-6 and progression-free survival and interim overall survival data of HARMONi-2 announced previously are very encouraging when we look to global studies HARMONi-3, HARMONi-7 and beyond. Yesterday's HARMONi-6 results presented at ESMO and subsequently published in the Lancet are highly encouraging in showing the consistent performance of ivonescimab and its ability to break into a setting where existing anti-VEGF therapy is not an option due to historically observed tolerability concerns from early phase clinical trials. HARMONi-6 continues to validate the opportunity presented by ivonescimab to make a significant difference across a vast number of patients facing solid tumor diagnosis. I would also like to highlight several important updates to our Phase III clinical development program that we have announced over the past few days. As we announced Friday, our clinical development plan has expanded beyond lung with the addition of our global Phase III HARMONi-GI3 trial, a brand new study evaluating ivonescimab as first-line therapy in unresectable colorectal cancer, including studies sponsored by our partner, Akeso. This brings a number of planned or ongoing Phase III clinical trials to 14 in total, evaluating ivonescimab in multiple solid tumors, including lung, colorectal, breast, head and neck, biliary tract and pancreatic cancer. This is the fourth global Phase III study and the first global Phase III study to be conducted with ivonescimab beyond lung cancer. I will review the HARMONi-GI3 study design and what drove our conviction to initiate this study shortly, but I wanted to take a moment to remind everyone of the impressive development efforts behind the growing collective pipeline of ivonescimab. Turning to our ongoing Phase III trials, I will provide a regulatory update on HARMONi and as well as updates relating to a HARMONi-3 protocol amendment, including expectations for data readouts. I would like to take a moment to express our gratitude in working thus far with the FDA regarding our clinical development of ivonescimab. With 4 Phase III clinical studies, we have had a number of interactions with the agency and their feedback and advice are invaluable. When we plan to move forward with the HARMONi study upon signing the collaboration agreement to acquire the rights to ivonescimab, we have had multiple interactions with the agency regarding how to proceed. The collaboration demonstrated our ability to move forward with a clinical study based on early phase clinical trial data that had been generated in China prior to our acquisition of all rights given the strong potential of ivonescimab and opportunity to make a meaningful difference to patients in a setting that has very limited therapy options in something that really reflects the agency's commitment to patients facing difficult diagnoses with limited options. We are incredibly proud to work with the agency and appreciate the endless hours that members of the agency spent with the best interest of patients always in mind. Based on the result of the HARMONi study, today we announced that we will submit a biologics license application, or BLA, with the FDA in order to seek approval for ivonescimab plus chemotherapy for this proposed indication in the United States. We intend to submit the BLA during the fourth quarter of 2025. As previously disclosed, the FDA noted that a statistically significant overall survival benefit is necessary to support marketing authorization in this setting. After careful consideration of the safety and efficacy profile of the current FDA-approved options to patients in this setting, the positive regional consistent results of this Phase III multi-regional study as well as discussions with key opinion leaders and physicians, who have administered ivonescimab to patients, we believe that the safety and efficacy data generated in the HARMONi study demonstrate that patients suffering from EGFR-mutant non-small cell lung cancer in this setting can benefit from the ivonescimab regimen. This is a monumental moment in the development of ivonescimab, and we are excited for the opportunity to work with the U.S. FDA in order to discuss our application. Yesterday, we also announced updates to our global Phase III HARMONi-3 study, which is intended to evaluate ivonescimab combined with chemotherapy compared to Pembro and anti-PD-1 antibody combined with chemotherapy in patients with first-line metastatic squamous and non-squamous non-small cell lung cancer. This study is currently enrolling patients globally and is conducted with registrational intent for the United States and other regions within Summit licensed territories. The primary endpoints for this study are progression-free survival and overall survival. Summit has amended the protocol for the HARMONi-3 study in order to separate the statistical analysis of data of the primary endpoint by histology. Therefore, there will be a separate analysis to evaluate ivonescimab plus chemotherapy compared to Pembro plus chemo in patients with squamous non-small cell lung cancer and in patients with non-squamous non-small cell lung cancer. As a result of having 2 separate intention to treat analyses within the HARMONi-3 study, the analysis for squamous tumors and non-squamous tumors may be conducted at separate times as each analysis will be conducted upon reaching pre-specified numbers of events in each cohort. Ultimately, it will allow us to read out data earlier for squamous non-small cell lung cancer and ultimately potentially move forward more quickly in frontline lung cancer for patients seeking improved options over the existing standards of care. Currently, we expect to complete enrollment in the squamous cohort of HARMONi-3 in the first half of 2026 and expect to reach the prespecified number of events for the progression-free survival dual primary endpoint analysis for the squamous cohort in the second half of 2026. An interim analysis for overall survival may be conducted at a similar time. Turning to non-squamous. At present time, Summit expects to complete enrollment in the non-squamous cohort of HARMONi-3 in the second half of 2026 and expect to reach the prespecified number of events for the progression-free survival endpoint analysis for this non-squamous cohort in the first half of 2027. An interim analysis for overall survival is planned to be conducted based upon reaching a prespecified number of events. In order to sufficiently power each of the dual primary endpoints in both cohorts of the study, Summit plans to enroll approximately 600 patients with squamous non-small cell lung cancer and approximately 1,000 patients with non-squamous non-small cell lung cancer for a total of approximately 1,600 patients enrolled in HARMONi-3, which is reflected in this updated HARMONi-3 study design slide. While we are increasing the sample size, we are over 80% enrolled in the squamous cohort. And as I mentioned, we believe we will complete enrollment in the first half of next year, and the non-squamous cohort is enrolling fast and with complete enrollment shortly thereafter, currently projected to be the second half of next year. This ultimately will allow us to have this analysis fully powered by cohort in order to allow for us to have a clear regulatory path forward for frontline lung cancer around the world. As mentioned earlier, our Phase III clinical development program has expanded beyond the lung with the intention of HARMONi-GI3, a global Phase III trial evaluating ivonescimab plus chemo compared to beva plus chemo as first-line therapy in patients with unresectable metastatic colorectal cancer. Here, we see the study for HARMONi-GI3, which has a primary endpoint of progression-free survival. Clinical trial sites in the United States are planned to begin activating by the end of this year, and we currently expect to enroll a total of 600 patients in HARMONi-GI3. Each year, 48,000 patients are estimated to be diagnosed with or have recurrent metastatic microsatellite stable metastatic colorectal cancer, also known as mismatch repair proficient colorectal cancer or pMMR CRC. There have been limited options approved in the United States in the last 20 years for those first-line patients whose tumors are not positive for certain biomarkers or other activating mutations. Microsatellite stable metastatic colorectal cancer is a setting where monoclonal PD-1 inhibitors, such as pembro and nivo have failed to show a clinically meaningful benefit. Anti-VEGF therapy like bevacizumab plus chemotherapy is the standard of care for many patients with first-line metastatic microsatellite stable metastatic colorectal cancer. Based on extensive feedback from KOLs and treating physicians in this space, we have opted to evaluate ivonescimab with FOLFOX in this study. I will take a moment to walk through the data we have previously shared in first-line CRC as a brief reminder as to the potential of ivonescimab in this setting. While the data is with FOLFOXIRI, a more intense chemotherapy regimen, we also noted in our release that we enrolled patients in both the U.S. and China with FOLFOX as well to test ivonescimab with multiple chemotherapy options. FOLFOX in combination with a monoclonal antibody such as beva represents a preferred treatment regimen for physicians treating MSS CRC patients in the United States and other Western territories. Last year, at the 2024 Annual Congress of the European Society of Medical Oncology or ESMO 2024, Akeso presented encouraging AK112-206 Phase II data of ivonescimab in combination with FOLFOXIRI chemotherapy in patients with microsatellite stable metastatic colorectal cancer. Here, we see the figure for the Akeso AK112-206 study. In this Phase II study, ivonescimab, in combination with chemotherapy demonstrated an overall response rate of 81.8% and a DCR of 100% in 22 patients. This cohort of AK112-206 was conducted in China sponsored by Akeso with all relevant data exclusively generated, managed and analyzed by Akeso. In the ivonescimab-plus FOLFOXIRI chemotherapy arm, there were no treatment-emergent adverse events that led to the permanent discontinuation of ivonescimab as of the data cut-off from the ESMO 2024 presentation. Subsequently, as I said, this Phase II study was expanded to include additional patients from the U.S. and China to study ivonescimab in combination with FOLFOX chemotherapy. The data from the initial patient cohort presented at ESMO 2024 have continued to mature in addition to the global Phase II data generated in combination with FOLFOX in the United States and China, which supports the design of Summit Phase III HARMONi-GI3 study. In addition to the announcement of HARMONi-GI3, a new global Phase III study in first-line unresectable metastatic colorectal cancer, Summit today announces its intention to expand its ivonescimab clinical development program with an additional set of Phase III clinical studies. We intend to provide additional color with respect to these Phase III studies in the first quarter of 2026. With that, I will now turn the call over to Manmeet to provide an operational and financial update for the quarter.
Thank you, Maky, and good morning, everyone. Today, in addition to providing you an update on our cash position and operating expenses, I will also provide color on our clinical operations. Let me start with an update on the clinical operations product. The HARMONi-3 study is enrolling ahead of our goals. And as Maky mentioned, we have enrolled over 80% of the newly planned 600 squamous patients cohort, and now expect to complete enrollment for the squamous cohort of HARMONi-3 during the first quarter of 2026. To remind you, the non-squamous cohort in HARMONi-3 was initiated during the first quarter of 2025, and that too is enrolling ahead of the plan. And now we expect to complete enrollment for 1,000 patients during the second half of 2026. Our HARMONi-7 study was initiated during the first quarter of 2025 and we have activated over 50% of the selected sites globally. And for our newly announced Phase III, the HARMONi-GI3 study, we have already started planning and sites are planned to begin activating in the United States prior to the end of the year 2025. On the financial front, let me start with our cash position. We ended the third quarter of 2025 with a cash position of approximately $238.6 million. Turning to operating expenses. I'll provide details on both GAAP and non-GAAP numbers. You can refer to our press release issued this morning for a reconciliation of GAAP to non-GAAP financial measures. As a reminder, our non-GAAP expenses exclude stock-based compensation expenses. Our total GAAP operating expenses for the third quarter of 2025 was $234.2 million, compared to $568.4 million for the second quarter of 2025. The decrease in GAAP operating expenses was primarily due to the higher stock-based compensation expense of approximately $348.2 million as a result of the modification of unvested stock options recorded during the previous quarter. Overall, our non-GAAP operating expenses during the third quarter of 2025 were $103.4 million, compared to $89.6 million for the previous quarter. The increase in non-GAAP operating expenses was primarily related to an increase in R&D expenses related to HARMONi-3 and HARMONi-7 trials. And with that, I will hand it back over to Dave.
Thank you, team. We'll now see if there are any questions that our team can help answer. Kate, if you could please open the line for questions.
Questions and answers
Your first question comes from the line of Yigal Nochomovitz with Citi.
So the first one I had is, when could we expect to see the first OS cut from HARMONi-6? Would it be before the second half 2026 PFS readout for HARMONi-3 and squamous? And then the other question is given HARMONi-6 was powered 86.3% for a hazard ratio of 0.7 but you hit on a lower hazard ratio of 0.6. I'm curious what that may imply about OS powering for the study given that was powered at 80% for a hazard ratio of 0.73, the implication potentially that you may have more OS power than originally designed?
Thanks, Yigal. This is Dave. So one thing that I want to make sure is clear, as we mentioned, this is a study that was designed and conducted by our partner, Akeso. And so one thing that we don't do is get in front of Akeso with respect to disclosing additional details beyond what they have currently disclosed. And so I think if we look overall, obviously, the protocol is included within publication. And I want to congratulate again our partner, Akeso, for both the presentation and the Lancet publication that became available yesterday. But in terms of differentiating details between the planned and adjusted power and whatnot, I leave that to our partners at Akeso. But I think one thing that you can see from, in general, the plan for testing is that there's likely something that can be reviewed in 2026. But it's important to remember that from a time to event perspective and a prespecified number of events in an analysis, we hope patients do well, and we hope patients continue to exceed expectations into knowing exactly the order of events becomes a little bit difficult. But this is events driven. So at some point next year is probably a fair estimate, but more specific to that is a little bit beyond where we would like to disclose at this point and defer to our partners there.
And then just the other follow-up. Obviously, Maky, you talked a lot about new studies, CRC, and then you mentioned an additional set of Phase IIIs where you might get more details in 1Q '26. So all of that points to questions around funding. I'm just curious if you could speak at least to some extent as to what options are being evaluated to extend the runway, what the priorities are in terms of how you may raise additional capital?
Maky prefers that I handle the questions. Yes, we have an ATM available with approximately $350 million. I've already received some interest in additional capital, and I'm keen on it. I invested more capital a few weeks ago, so we will proceed straightforwardly on that. I appreciate the opportunity, and I believe others do as well. You'll see how this unfolds. I won't speculate on the amount just yet, but I am familiar with all the figures and our future plans. We have clear evidence that this product demands significant investment. It has the potential to enter a market where the leading player generates around $34 million in revenue in the next three years, with $17 million to $18 million in free cash flow. This represents a considerable opportunity, and we do not want to overlook it. We also believe that the key to achieving this is for our team to have control to start, stop, and adjust several factors that lead to our ultimate success, and we are satisfied with our current position. I hope this addresses your financial concerns.
Thank you. And I’ll hand it back.
Congratulations on the unprecedented HARMONi-6 results. I guess I want to ask about the BLA submission. Given the confirmation of the ivonescimab BLA by year-end based upon the HARMONi data, can you provide any color as to how your interactions with the FDA have gone? And how the present approvals with amivantamab or Dato might support approval of ivonescimab?
Thanks for the question. So yes, we announced today that we are planning to file in the fourth quarter of this year. We are actively finalizing and putting the match together. We have continued interaction with the FDA. And obviously, after we have made the submission, we are looking forward to getting specific feedback and giving some color earlier next year after the submission. We have indeed reviewed the most recent approvals, as you mentioned, and we are fully aware that neither of those other approvals included a significant OS benefit. We have also disclosed previously, but I'm just repeating that the FDA has told us that they are looking to inspecting OS in our setting. But we do think that the totality of our data from a combination of efficacy and safety is a strong package and should be moved forward to becoming available for these patients. So therefore, we are moving forward with the submission as we have announced.
That's great. And just as a quick follow-up, did you discuss the latest overall survival data that surpassed the statistical threshold at World Lung with the FDA?
Yes, we are not going to go into the details of exact discussions with the FDA, but I can confirm that we are in close contact with them and will be sharing information whenever appropriate with them.
Great to see the data at ESMO and a large crowd yesterday. Maybe another follow-up on the BLA. I understand the logic of trying to get this drug to patients as quick as possible, given the data that you have, but from a business perspective, can you help me understand the strategic thinking of now wanting to submit the HARMONi study and undertaking that review issue of how to deal with the OS as the first time the FDA will review a BLA package for ivonescimab especially when you have HARMONi-3 potentially coming as soon as the second half of '26 for PFS and OS. I guess my thinking was that might be a better package to submit first and then have HARMONi come as a supplement or something like that. So just how you're thinking about that would be helpful to hear.
Sure. So we have had certainly many discussions just to confirm internally and there are many open scenarios. But in principle, our thinking is that each indication will have its own submission. This particular package is ready now. We have mature data. We have shown consistency in the data with our long-term follow-up between the rest of patients and the Asian patients. And we think this is the right opportunity, and we are going forward. That doesn't mean in the future we will continue going to look at this as we might do other packages in the future. And depending on exactly what comment or feedback we ultimately also get from FDA, we will make those adjustments to support it in the future.
And then separately, just quickly on the colorectal Phase III. You mentioned there's some undisclosed in-house data. Can you talk qualitatively about what that is, the extent of it and what thesis were explored? And then when we expect to see those data presented to further support the Phase III?
Sure, Brad. This is Dave. One of the things Maky mentioned was that we had previously shared data with our partners at Akeso in 2024 at ESMO, which validated findings for not only colorectal cancer but also head and neck and triple-negative breast cancer. Following that, both Akeso and an expansion of the Phase II study included patients in the U.S. We reviewed multiple chemotherapy regimens with ivonescimab, along with a novel combination using ivonescimab in this context. This process has provided exposure to the drug and allowed us to compare historical outcomes with different chemotherapy regimens to confirm the consistency of our findings. Ultimately, we decided to proceed with the FOLFOX regimen based on current standards of care and the strong preference from both patients and physicians. A considerable amount of data has been generated across various regimens, which gives us a high level of confidence. Additionally, our partners at Akeso are conducting a Phase III study in this area, which further reinforces our confidence regarding ivonescimab’s potential.
Regarding HARMONi-6, the PD-L1 status was noteworthy, and we observed that PD-L1 negative outperformed PD-L1 positive. Could you help us understand what is happening there and the translational work you plan to conduct to assist oncologists in determining the best approach?
In relation to HARMONi-6 and PD-L1 expression, I don't view the negatives as necessarily outperforming the others; rather, the differential effect appears to be slightly greater in patients with PD-L1 negative status, which isn't surprising to me. As a clinician who speaks with colleagues, we've long acknowledged that while other FDA-approved regimens offer some minor benefits from adding a checkpoint inhibitor, those benefits are quite limited. Patients within this group generally have poor outcomes even with our current standard of care, indicating significant room for improvement. This might suggest that VEGF components are particularly relevant in this context. It's also crucial to point out that these findings are based on subsets. We will have more details to evaluate, particularly in relation to consistent trends between HARMONi-6 and HARMONi-3. Notably, in patients with high PD-L1, that group comprised about half the size of the other groups. Therefore, I wouldn't want to overly emphasize any particular subset analysis. They all indicate the same trend or overall conclusion of superiority with ivonescimab, albeit to varying degrees.
Brad, I'd like to revisit your question about EGFR. We were very pleased that the FDA approved the trial. There were several key issues we needed to address during that trial, one being the translatability of data from China to the U.S. We made significant progress on that front. This remains a dynamic topic. Another issue was related to bleeders in EGFR, which we have resolved. Additionally, we dealt with the serious concern of brain metastases, which personally affects my family, and we also addressed the bispecific aspect. This progress would not have been possible without the FDA's approval to proceed. Moving forward, our trials will always include patients from China, likely in a 1/3 to 2/3 ratio, and we are pleased about that. On the record, ivonescimab performed exceptionally well, with a progression-free survival hazard ratio of 0.52, outperforming any other drug in that market. The p-value was significant. It's crucial to note that when receiving feedback from the FDA, it is a complex process that we navigated successfully. We needed a minimum of 150 patients outside of China, and we managed to exceed that number by reaching 175. However, we initially underestimated how challenging it would be to get doctors to take on this trial, which caused a slow start due to inertia. As this information becomes more accessible, we believe it will be seen as a successful human patient trial, and we appreciate the FDA allowing us to proceed. This gives context to our intention to submit. We are a patient-focused company and believe that patients have benefited and can continue to benefit, with the final decision resting with the FDA. The FDA is one of the most respected agencies worldwide, and we fully support that. I hope this provides some insight into our investments and future plans. If things go well and we get the treatment into patients' hands, everyone stands to gain. If not, we are committed to making necessary adjustments.
Curious, was there something in the HARMONi-6 data that prompted the protocol amendments to HARMONi-3 beyond this kind of the staggered enrollment run rate? And what impact will these changes have on the powering of the HARMONi-3 subset?
Cory, this is Dave. So thanks for your question. So I mean, I think there are multiple reasons in terms of updating the design of HARMONi-3. So one, it accelerates our frontline lung cancer opportunity as a whole. Since we began enrolling the squamous cohort first, we believe that we'll be able to complete enrollment in the first half of next year, and this will allow for a data readout in the second half. Because we're rapidly enrolling the squamous cohort as well, we can complete that enrollment in the second half of next year. But two, it reduces regulatory risks by separating the 2 histologies to individual intention to treat analyses, we do not risk the overall population being statistically significant, but one subgroup looking a little better than the other mainly through sample variability, and this could lead to risks regarding approval for one histology and the other. Additionally, we've seen advisory committees from the FDA earlier this year that there's increased importance on the results of U.S. patients, which becomes a subset of the 2 histologies. Without the change, U.S. patients are effectively a subset of a subset at that point. Now we have individually powered squamous and separately powered non-squamous histologies for both primary endpoints of PFS and OS. And so they're independently powered at the histology level now, and so 2 ITTs. Separately powering the individual histologies is effectively a cleaner assessment of the data. It allows us to keep pace in non-squamous as well because given the PD-1 plus chemotherapy performs a little bit more favorably in non-squamous patients, I.e., typically, it has a longer overall survival than squamous patients. The progress in additional targeted therapies that we see in non-squamous mutation variability some historical results in non-squamous trials. We really want to ensure that there's a little statistical variability like an overperforming control arm or something like that, that can raise issues. Again, we increased the sample size. We're rapidly enrolling the cohort, so the analysis is driven by a readout of events, it's an event-driven analysis. Increasing the sample size for non-squamous really had very little impact on the timing of the readout there. We don't see a change in probability of success in either of the opportunities. We view them both as being cleaner. Specifically to your question, Cory, with respect to what we saw with HARMONi-6 yesterday, what that does is allow for a direct read-through now to an ITT population in the HARMONi-3 study. It's now just in a global setting instead of a single region in China. So there's a direct read-through here. We've seen historical comparability in terms of the data generated in Asia versus the rest of the world. We're very excited with the ability to have that direct read-through in accelerating that squamous opportunity by breaking out into 2 separate ITTs.
Congratulations on all the progress. A common question we receive from experts is regarding the comparison of a VEGF PD-1 to a PD-1, or a previous PD-1 VEGF combination. It's evident that the VEGF component outperforms the earlier tested VEGF component, but it's unclear if the PD-1 component is superior. Can you clarify your position on this? If it turns out to be the case, wouldn't that pose a challenge for overall survival benefit, as it appears PD-1s are primarily responsible for utilizing the long tail in those trials? I believe this is the main concern at the moment. Could you provide some insights into the confidence level regarding overall survival here?
Yes, this is Jack West. I think it's challenging to assign too much value to one side of a molecule over another. We haven't typically done that with other molecules targeting met and EGFR. It's important not to overlook or undervalue one side just because it's focused on the met aspect. The key point is to evaluate the data from the ongoing readings. If the efficacy is confirmed and tolerability is good, we should consider all the data and determine whether it justifies a shift from current standards. I don't believe we should have a different set of criteria assuming that this operates through a VEGF or immunotherapy mechanism. Inferences are often subjective, different clinicians may draw different conclusions based on their own beliefs. Overall, the main consideration should be the efficacy and tolerability, weighed against existing options. If our treatment appears superior, we have numerous therapies with benefits that may not last for many years, which still hold value. There are various types of efficacy benefits that clinicians and patients recognize differently. I think we should concentrate more on actual clinical outcomes rather than assumptions about which side of a molecule holds more significance in any given context.
Yes. William, I'll add. This is Allen Yang. I'll add that we've always been under the hypothesis, and I think the data are showing that the 2 put together are cooperating and better than the sum of the parts. Akeso smartly designed this molecule such that the PD-1 and VEGF work together. The HARMONi-6 data reading out positive doesn't indicate that it's just the VEGF. And it's not just an indication. But again, I think VEGF is important in a lot of different diseases, and this puts them together in a smart way. If you look back to the HARMONi-2 data, remember, there was an improvement, not only in the low PD-L1 expressing patients but also the high PD-L1 expression. This is the sweet spot for PD-1. So the VEGF clearly makes it better. I think John Heymach also alluded to in the discussion of that, that not only were they cooperating, but the VEGF may play a role in immunotherapy as well, and there's growing data to support that as well. So the answer to your question is, we think, again, both sides are important and how they're engineered and put together indicates that the MOA is important. I also want to add that the safety that we've seen across 4 randomized double-blind placebo sites suggest that this is not exclusively VEGF.
Congrats on the impressive HARMONi-6 data. So I think there's a lot of great questions on HARMONi-6 already. So I want to actually talk about your plan for colorectal cancer. So for the Phase III study, are there any plans to stratify or analyze outcomes based on the presence of liver versus non-liver mets given some prevalent evidence of their impact on treatment responses in MSS CRC? And then you mentioned the global components of the Phase II FOLFOX combination study. So what's the expected timeline for the next update on whether we should expect some U.S. data from this trial in the next update as well?
Thank you, Clara. Those are all important questions. We do have stratification factors in our current trial, but we aren't ready to disclose all the specific factors just yet. Your comments about the patient characteristics are noted. Regarding the publication of additional data, particularly from U.S. patients, we are considering the right timing for that. The ongoing Phase III readouts are key for us in this decision-making process. Publishing data related to different chemotherapy options is crucial for our strategies, but we don't feel the need to go through each one individually. The results from the Phase III study will be significant to publish, and our partner Akeso is also conducting a Phase III trial, which will provide valuable additional insights once it concludes.
Also my congrats on all the progress and the great data presented yesterday. To start off on HARMONi, the takeaway from World Lung was that your OS benefit would become more pronounced with the appropriate level of follow-up. So the HARMONi filing with the FDA, do you need to take a new data cut or are you filing what you have right now? And then I have a follow-up.
Yes. Thanks for the question, Asthika and appreciate the words at the beginning. I think we haven't publicly spoken to the specific details with respect to how we'll work with the agency. As Urte mentioned earlier, we maintain communication with the agency. It's important to work through the submission process. So I think that is clearly just given where we are today, only 1.5 months later from the data cut based on what we saw at World Lung. In terms of next steps with that, I think part of that will involve discussions with the agency.
Got it. Regarding the amendments to the HARMONi-3 study, the original study was limited to squamous patients and had a recruitment of around 400 or 450 patients. The HARMONi-6 data indicated a significant benefit in a similar patient population. Now, you are increasing the recruitment for the HARMONi-3 squamous cohort to 600 patients, which aligns with what KEYNOTE-407 recruited. I would like to hear your thoughts on the rationale for this increase in target size.
This is Urte. We are basically splitting the cohorts into 2 parts. There will be separate analysis and it's very important that we are powering for both endpoints for PFS and OS. This is a very good sample size. We have high confidence in the readout of the squamous cohort, but this is appropriate to cover those endpoints.
I also want to add my congrats on the great data here. So a couple of questions. One, just a clarifying question on HARMONi-3 Phase III trial update. So Dave, you mentioned that the trial update derisks regulatory aspects. I just want to clarify that, does that mean that you're able to file each histology separately? I'd say if one histology failed while the other succeeds, then you can file for the successful one irrespective of the failed histology?
In short, yes, they're independent ITTs. So they're independent analyses.
It's just the nature of what has happened. So they will not need on executives.
Congratulations on the very impressive data yesterday. I guess the first question is the HARMONi-6 safety profile, I mean, really reaffirms to us like ivonescimab's tolerability especially given it's largely comparable control arm. Were there any specific like squamous-specific related events that's different from the non-squamous cohort in HARMONi? And related to that, I think there's just an apparent kind of underdepreciation for the safety profile, specifically bleeding. I think discussion brought that up. I'm kind of curious as to how you guys are addressing that especially with KOLs?
This is Jack West. There are differences between squamous and non-squamous tumors based on their characteristics. Squamous tumors are generally larger and more centrally located compared to non-squamous tumors, and the occurrence of brain metastases is less common in squamous cases than in adenocarcinoma, particularly among patients with EGFR mutation positive non-small cell lung cancer, where brain metastases are a significant concern. As I mentioned in the presentation yesterday, our approach is not just limited to patients with advanced squamous lung cancer; we made a bold decision to enroll patients with multiple features that have typically made using bevacizumab challenging or even unfeasible. Clinicians outside of China, or in regions with less experience, will need to consider this data carefully. It's essential that we move beyond historical limitations tied to different drugs with distinct safety profiles. We're in a new era where eligibility criteria should be adapted and more flexible. It will require a combination of education and gradual experience for oncologists to become comfortable treating these patients and to be bolstered by their own positive experiences over time.
Yes. We think this is a good package. We have statistically significant PFS. We have supportive OS data, which we think is very meaningful and will be evaluated in context. We have supportive efficacy data from OR and duration of response. So all seems to be a good package for full approval. We cannot foresee what exactly the comments and the opinions of the FDA are. As we said, as we're going through the review process and very specific information we get, then we will provide color on that. We will be watching that along with you.
Congrats on the data. Can you point to relevant regulatory precedents where a strong PFS benefit without a statistically significant OS benefit at the time of filing was still enough for FDA approval? How were these situations handled by the FDA? Also, could you comment on the changes in the volume and types of business development discussions you've been having lately?
I will take the first part. In this exact setting in EGFR-positive previously treated patients, there were 2 relevant approvals, both of them occurred last year. The first one is for the amuvatinib molecule based on the study, which was approved on statistically significant efficacy, and was accompanied by a positive trend in OS. The other approval that happened as the accelerated approval is for a molecule. Wording is slightly different, but it's previously treated patients with both chemo as well as therapy, and that accelerated approval was based on ORR with the duration of response. I can also note that the confirmatory study for that module in EGFR-positive in the frontline setting is coming. So there isn't going to be any additional generation of statistically significant PFS.
We want to thank you for your attendance today. I only wish you could be at ESMO. There's at least 25,000 people here. We were really honored and Akeso was honored to be the first presenter at the presidential presentation with 9,000 people packed into a very large hub program. They gave resounding applause as they heard the data. This is a breakthrough. It's a break of magnitude. Undeniably, we have an excellent product. Lung cancer is the #1 killer. It's not going to be that way for long. We really are in the mitigation and hopefully, in some areas, we would move this forward even into more advanced settings. Our team is very excited. We're very excited to have the product in our hands. The doctors and physicians that support them are really excited. We've seen them in the hallways and in other meetings. We've been just packed with attendance and appreciation. You have to kind of be here to see. It's my first trip to Berlin, I must say it's a beautiful city, even for someone who lives in Miami. So yes, we're going straight ahead here, and we're enjoying ourselves. The future looks incredibly bright. Opportunities like this I haven't seen in my brief investment lifetime. I'm just really excited about helping patients here and making a significant difference. I will say you see people from all cultures, all walks of life here. This health care business is one that brings the world together, not separates it. And we're just really happy to play a significant role, and we're thankful to our Akeso partners from China and to the FDA for giving us the platform from which to really move forward. So thank you for being on the call. We look forward to talking to you soon. Have a great day.
Ladies and gentlemen, that concludes today's call. You can disconnect. Thank you, and have a great day.