Summit Therapeutics Inc.SMMTNASDAQ
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Operator: 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. [Operator Instructions] I would now like to turn the call over to Dave Gancarz. Please go ahead.
Dave Gancarz: 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.
Howard West: 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 [indiscernible] 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 statistically significant 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 irAEs, serious irAEs and irAEs 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, 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.
Mahkam Zanganeh: Thanks, Jack. I would like to echo Jack's comments around our gratitude for the patients who enrolled on 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 resource 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 first-line 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 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 diagnosis 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 a 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 for 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 separate analysis conducted 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 analysis within the HARMONi-3 study, the analysis for squamous tumors and non-squamous tumors may be conducted at separate time 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 short time 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 monocolonal 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 with 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 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 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 continue 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. Manmeet?
Manmeet Soni: Thank you, Maky, and good morning, everyone. Today, in addition to providing with 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 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. Dave?
Dave Gancarz: 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.
Operator: [Operator Instructions] Your first question comes from the line of Yigal Nochomovitz with Citi.
Yigal Nochomovitz: 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?
Mahkam Zanganeh: Very good question. Dave?
Dave Gancarz: 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.
Yigal Nochomovitz: And then just the other follow-up. Obviously, Maky, you talked a lot about new studies, CRC, and then you mentioned 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?
Dave Gancarz: Maky prefers that I answer the questions.
Mahkam Zanganeh: [indiscernible].
Dave Gancarz: She doesn't have [indiscernible]. Yes, we have an ATM out there with give or take $350 million. I have already had some inbound interest in additional capital. I'm interested. I've invested a few weeks ago additional capital. So yes, we'll move straightforward on that. And I'm happy to have the opportunity and I think others are too. So you'll see that as it plays out. I won't predict the amount right yet, but I'm aware of all the numbers and aware of the plans going forward. We have empirical evidence that this is a product that is crying out for significant investment. It is to demonstrate its capacity to enter into a business that the leading player is generating roughly $34 million in revenue over the next 3 years, $17 million, $18 million, [ $3 billion ] in free cash flow. So this is a significant opportunity, and we do not want to miss it. We have -- we also feel that the key to making that happen is for this team to have control to be able to start, stop and change a number of variables leading to our ultimate success, and we're happy with the position that we have. So I hope that gives you some addressment to the issues of finance.
Mahkam Zanganeh: And as soon as we have more information regarding other clinical trials, for sure, we are going to communicate as time allows.
Operator: Your next question comes from the line of Tyler Van Buren with TD Cowen.
Tyler Van Buren: 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?
Urte Gayko: Thanks for the question. So yes, we announced today [indiscernible] 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 doctor's approval backwards, as you mentioned, [indiscernible], the approval of [indiscernible] previously treated EGFR patients that [indiscernible] actual approval in also previously EGFR patients. And as you are aware, and obviously we are fully aware that neither of those other people included a significant OS benefit. We have also disclosed previously, but I'm just repeating that 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.
Tyler Van Buren: 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?
Urte Gayko: 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.
Operator: Your next question comes from the line of Brad Canino with Guggenheim Securities.
Bradley Canino: 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 second half '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.
Urte Gayko: Sure. So we have had certainly many discussions just to confirm internally and there are many open scenario. 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.
Bradley Canino: 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?
Dave Gancarz: Sure, Brad. This is Dave. And so I think one of the things that Maky spoke about was we had previously presented data with our partners at Akeso in 2024 at ESMO. And that was validating with respect to not just colorectal, but head and neck as well as triple negative breast cancer. What then has since happened, both Akeso as well as an expansion of that Phase II to include patients in the U.S. was conducted. And so with that, we've had multiple backbones of chemotherapy, which have been reviewed with ivonescimab as well as a novel-novel combination with ivonescimab in this setting. And so what that's done is it's given a bit of exposure to the drug as well as the ability to compare historical results with different chemo backbones in order to kind of validate what we're seeing and the consistency of that data. And so we ultimately chose based on the standard of care that exists in the strong preference for both patients and physicians to move forward with the FOLFOX regimen. But there's quite a bit of data that's been generated across a number of different backbones, which gives us quite a bit of confidence. And it is -- I'm sure you're aware but also to note our partners, Akeso, are running a Phase III study in this setting as well. And so it's another -- just another data point with respect to confidence that we have in terms of ivonescimab's opportunity in this setting.
Operator: Your next question comes from the line of Salveen Richter with Goldman Sachs.
Salveen Richter: With regard to HARMONi-6, the PD-LI by status was interesting, and we see -- PD-L1, sorry, negative outperformed PD-L1 positive. Could you just help us maybe understand what's playing out there and then the translational work that you're going to be doing to kind of help the oncologists with determining how to best position here?
Howard West: In terms of HARMONi-6 and the PD-L1 expression, I would say that it's not -- I don't see it as necessarily that the negatives are outperforming the others, but rather that the differential effect is a little greater in the PD-L1 negative patients. To me, that's not that surprising. I would say that as a clinician talking with all of my other clinician colleagues, we've long recognized that although other regimens that are FDA approved here have some incremental benefit from the addition of the checkpoint inhibitor that benefit is tepid. It's rather minimal, and these are patients -- this whole group is one that has disappointing outcomes even with our current standard of care. And so there's really a lot of room to do better. In this case, I would say that it may be suggested that this is a setting where there are -- I'm sorry, this may be a setting where VEGF components may be especially relevant. And I will say that it's important to also recognize that these are subsets. We're going to have additional information to look at these, whether it's consistent trends between HARMONi-6 and HARMONi-3, but that it's important to note that in the patients, particularly with the high PD-L1, that group had a smaller -- that was about half of the size of the other groups. And so I wouldn't want to put too fine a point on any of these subset analyses. They're just suggested and all of them showed the same trend or the same overall conclusion of being superior with [indiscernible] just to varying degrees.
Dave Gancarz: Brad, if I may just touch back on your question on EGFR. We were really pleased that the FDA approved or taking that trial on. There were a number of major issues to hand on that trial. One of them was China versus U.S.A. data translatability. That was -- we put a real feather in the cap that there is some significant translatability. That's obviously a very dynamic issue. There was also the issue of bleeders in EGFR and we certainly put that one to rest. There was also the issue of brain mets, something very serious, that's members of my own family. We put that issue to rest. Then there was the bispecific, very novel, and we put that issue to rest. So that would not have happened had the FDA not allowed us to move forward. Now in a continuation, our trials will always have China patients. It won't be 2/3 to 1/3, it will be more like to 1/3 to 2/3, and we're very pleased about that. But on the record ivonescimab performed incredibly well. We had a progression-free survival hazard ratio of 0.52. We did better than any other drug in that marketplace. On the p value. We had [ 0.57 ]. [indiscernible] It's important to note that when you receive feedback from the FDA, it's a game you got to play and we played it. We needed 150 at least patients from outside of China, and we were able to get to 175. What really wasn't told was we underestimated the degree of difficulty to get the to doctor to take this trial on. There was an inertia there. And that inertia caused us to get off to a very slow start. So we think as all that becomes incredibly available to others, they will look at it as a very successful human patient trial and we certainly appreciate the fact that the FDA allowed us to move forward on that. So that gives you a little background on why we'll submit. We feel -- we are a patient-based company, and we feel patients can benefit and did benefit, and we would like to see more of that, and the FDA will make the final decision. There probably isn't a U.S.A. agency today that has more respect around the world than the FDA, and we totally support that. So I hope that gives you a little bit of color as to we've made the investment, and we'll make a further investment. And if it goes well and we get into patients' hands, everybody will have a win on it. If it doesn't, we certainly will try to make [indiscernible].
Operator: Your next question comes from the line of Cory Kasimov with Evercore.
Cory Kasimov: 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?
Dave Gancarz: 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. And 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 ITT 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. And so -- and additionally, we've seen advisory committees from the FDA earlier this year that there's an increased importance on the results of U.S. patients, which becomes a subset of the 2 histologies. So without the change, U.S. patients are effectively a subset of a subset at that point. And now we have individually powered squamous and separately powered non-squamous histologies for both primary endpoints of PFS and OS. And so they're individually powered at the histology level now, and so 2 ITTs. So separately powering the individual histologies is effectively a cleaner assessment of the data. And three, it allows us to keep pace in non-squamous as well because given the PD-1 plus chemo therapy 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. So we -- again, we increased the sample size. But because we're rapidly enrolling the cohort, 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. So we don't see a change in probability of success in either of the opportunities. We view them both as being cleaner. However, really specifically to your question, Cory, with respect to what we saw with HARMONi-6 yesterday, what that does is allows for a direct read-through now to an ITT population in the HARMONi-3 study. So it's effectively the same comparison now, ivo plus chemo versus PD-1 plus chemo in the squamous population. 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 rest of world. And so 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.
Operator: Your next question comes from the line of Mohit Bansal with Wells Fargo.
Mohit Bansal: Congrats on all the progress. One repeated question we get from experts is that when you compare a VEGF PD-1 to PD-1, or previous PD-1 VEGF combo, it is very clear that the VEGF component is better than the VEGF component that was tested before, but it's not clear that if PD-1 component is better. Now where do you stand on that? And if that is the case, isn't that an issue for OS benefit here because it does seem like PD-1s are the ones which are causing the -- using the long tail in those trials. So I think that's the biggest issue right now. If you could help us understand the confidence around OS here.
Howard West: Yes. This is Jack West. I think it's difficult to impute too much into the value of one side of a molecule or another. We don't -- we haven't historically done that with other molecules that target met and EGFR and say, well, that -- you don't dismiss or minimize that because, oh, this is just working on the met side. I would say that the most important thing is, we should see what the data show at the subsequent final ongoing reading. So if the efficacy is there, and the tolerability is favorable, you look at the totality of the data, and you decide whether that is enough to change from whatever you're competing current standards. And I don't think that we have or should have a separate set of criteria for a presumption that this is working through a VEGF action or immunotherapy action. I think we just make inferences. And I think different clinicians or others make inferences based on their own suppositions or biases. So I would say that -- yes, I'm not sure it really matters. I think that the reality is you look at the efficacy, you look at the tolerability and you weigh all of that against what the current prevailing options and standards are. And if it bubbles up is better, we have lots and lots of therapies that have a benefit that is not sustained over many, many, many years, and that's still valuable. So there are many different kinds of efficacy benefits that have varying degrees of appreciated utility to clinicians and patients. So I think I would focus more on what the actual clinical outcomes are than a supposition of which side of a molecule is more important in one setting or another.
Allen Yang: 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. So 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 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, that was probably indicative of the VEGF, 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, that 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 [ VEGF ].
Operator: Your next question comes from the line of Clara Dong with Jefferies.
Yuxi Dong: 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 time line for the next update on whether we should expect some U.S. data from this trial in the next update as well?
Dave Gancarz: Thanks, Clara. I think all good questions. And I think we do -- we certainly do have stratification factors within our current trial. I don't think at this point quite this early we're looking to make public all of those individual factors just yet. Your points are well taken in terms of the specific patient characteristics that you mentioned. And I would say with respect to the publishing of additional data, including those data that were based on U.S. patients, we're determining the appropriate time if and when that -- if and when we do that. And part of that is we continue to have Phase III readouts that becomes important to prioritize that. Publishing data across multiple different chemotherapy lines for us or chemotherapy options important for us to make decisions. It is not necessarily something that we need to individually go through. And so I think there's a piece where the Phase III will become very important to publish. And obviously, our partners at Akeso are running a Phase III as well, which will provide significant additional context when that study concludes.
Operator: Your next question comes from the line of Asthika Goonewardene with Truist Securities.
Asthika Goonewardene: 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.
Dave Gancarz: 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. And so as she mentioned, currently working on the application at this point. 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. And I think in terms of next steps with that, I think part of that will involve discussions with the agency.
Asthika Goonewardene: Got it. And then just on the amendments to the HARMONi-3 study. So the original HARMONi-3 study, which was in -- originally was restricted to just squamous patients, that had about a trial recruitment of about 400 or 450 patients or so. The HARMONi-6 data came out showing a really great benefit in similar kind of patient population. But now you're expanding the recruitment for the HARMONi-3 squamous cohort to 600 patients. I know that's also in line with what KEYNOTE-407 recruited. But I just want to get your guys' thoughts on the rationale for increasing the target size?
Urte Gayko: This is Urte. [indiscernible] 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. And this is a very good sample size. We have obviously high confidence in the readout of the squamous cohort, but this is appropriate to cover those endpoints.
Operator: Your next question comes from the line of David Dai. with UBS.
Xiaochuan Dai: 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 derisk 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?
Dave Gancarz: In short, yes, they're independent ITTs. So they're independent analysis.
Xiaochuan Dai: Got it. [indiscernible].
Urte Gayko: It's just the nature of what has happened. So they will not need on executives [indiscernible].
Xiaochuan Dai: Got it. Okay. Great. And then secondly, just on the combo strategies for non-small cell. I know a lot of other companies are thinking about doing ADCs and chemo combos. What are your thoughts around like combination strategies with ivonescimab in different solid tumors?
Dave Gancarz: Yes. And David, I think you talked about novel-novel combinations, if I understood that right. And so yes, I think we've talked about this a little bit in the past, but we're very excited in terms of our clinical trial collaboration with [ RevMed ] in terms of evaluating multiple RAS inhibitors in combination with ivonescimab. And so I think we'll be able to, in collaboration with [ RevMed ] dosing patients earlier, early in 2026. But in addition, there too, I think we're planning on multiple additional combinations, and those would likely be with ADCs to where I think you were heading with that, David. And so part of what we believe is a strategic advantage for Summit as a whole, ivonescimab, in the global development of ivonescimab is because we don't have specific ADCs that are part of our portfolio as well. It allows us to follow the data. And so we're working with multiple other companies in terms of collaborating in order to test ivonescimab in combination with multiple ADCs that are multiple targets with multiple different payloads, different structures. And that will allow us ultimately to follow the data. I think you've heard us speak to in the past in reality. What we don't believe -- and similar to -- if you look at solid tumor therapy today, there is not a single chemotherapy or chemotherapy regimen that is applicable across solid tumors, right? There are different regimens that are applicable even in non-small cell lung cancer. Pemetrexed is used very frequently in non-squamous tumors and it is not used in squamous tumors and paclitaxel as the backbone. And so as we think about -- just within non-small cell lung cancer, key difference is in terms of the chemo regimens. That implies, as you keep going beyond into additional histologies and additional solid tumor settings, but certainly different payloads will be very important in terms of being most effective for the tumors in those settings. And so the MOA will be very important. The safety will be very important. There are different tolerability thresholds within different tumors in different settings. And so what we want to do is follow the data. So what we won't be is encumbered by maximizing our own internal pipeline, if you will. And we think there have been mistakes made in the past on that. And we think we have the opportunity to follow the best data, follow the right combination with ivonescimab and ultimately maximize the potential for patients in terms of what can be done to take the power of ivonescimab with some of the novel components that are in development that are exciting right now, whether it be a RAS inhibitor like [ RevMed ] has, multiple RAS inhibitors or different ADCs with [ many structures ]. And obviously, Akeso has multiple ADCs in their pipeline as well that they're going to be taking a look at, in particular, in their own trials to start. And so that will also inform us going forward as well.
Operator: Your next question comes from the line of Ren Benjamin with Citizens.
Reni Benjamin: 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?
Howard West: This is Jack West. I would say there's differences between the squamous and the non-squamous largely based on the characteristics. Squamous tumors tend to be larger and more central than non-squamous tumors and then the fraction of proportion of brain metastases is present. There are some in HARMONi-6 and in other squamous cohorts. But it's far less common in patients with squamous than with adenocarcinoma and especially patients with EGFR mutation positive non-small cell where brain metastases are leading concern. But I would say, as I had alluded and the presentation yesterday as well, this is not just allowing patients with advanced squamous lung cancer, but this was bold and courageous in enrolling patients with several features that have historically been challenging, if not prohibitive with bevacizumab. And frankly, in China, they have years of experience, many of these investigators and growing comfort with that, that I would say that clinical oncologists outside of China or anywhere where they have less experience will need to not only look at these data, it's definitely going to be a point of education that we cannot be limited by and should not be limited by the historical precedence of a different drug with a very different safety profile. These are new times as the eligibility should be very different and liberalized. And yes, I think it will take both a combination of education and gradual experience for oncologists to get it, treat patients and reassure -- be reassured by their own favorable experiences with it over time.
Reni Benjamin: Got it. And then just as a follow-up, do you think that the filing, has the FDA kind of indicated that this goes to ODAC. Will you be applying for accelerated or full approval? And your thoughts on European filings?
Urte Gayko: Yes. We think this is a good [ small ] 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 [indiscernible] package for full approval. We cannot foresee what exactly the comments and the opinions of the FDA are. And as we said, as we're going through the review process and very specific information we get, then we will provide color on that. Other policy issues, I cannot comment on. We look all forward to FDA end up sharing with us what their plans are in terms of external feedback and those kind of things. So we will be watching that along with you.
Operator: Your next question comes from the line of Mitchell Kapoor with H.C. Wainwright.
Mitchell Kapoor: 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 sufficient for FDA approval? And how do you think that -- can you just remind us how these situations were handled by the FDA? And then separately, can you just comment on the business development front on the change in the volume and the types of BD discussions you've been having lately?
Urte Gayko: I will take the first part. So 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 [indiscernible] study, which was approved on statistically significant [indiscernible], and was accompanied by a positive trend [indiscernible] OS. The other approval that happened as the accelerated approval is [indiscernible] molecule. Wording is slightly different, but it's previously treated patients with both chemo as well as [indiscernible] therapy, and that accelerated approval was based on ORR with the duration of response. And I can also note that the confirmatory study for that module in EGFR-positive in the frontline selling. So there isn't going to be any additional generation of statistically significant PFS, OS [indiscernible] was coming. Business development question?
Mahkam Zanganeh: Bob do you want to conclude with the business development.
Robert Duggan: This is Bob Duggan. 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 [indiscernible]. Our team is very excited. We're very excited to have the product in our hands. The doctors, physicians those 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 [indiscernible]. 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 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.
Operator: Ladies and gentlemen, that concludes today's call. You can disconnect. Thank you, and have a great day.