Summit Therapeutics Inc. (SMMT) Q4 FY2025 Earnings Call Transcript & Summary

Good afternoon, and welcome to some Summit Therapeutics Q4 and year-end 2025 earnings call. [Operator Instructions]. Please refer to the company's website for updates. Please note that today's call is being recorded. [Operator Instructions]. At this time, I would like to turn the call over to Dave Gancarz at Summit Therapeutics, Chief Business and Strategy Officer. You may proceed.

Good afternoon, and thank you for joining us. On today's call, we will provide an update on our fourth quarter and year-end 2025 financial results and operational progress. This afternoon's press release is available on our website, www.smmttx.com. Our Form 10-K was also filed today and is available on our website and via the SEC's website. Today's call is being simultaneously webcast, and an archived replay will also be 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 President and Co-Chief Executive Officer, Manmeet Soni, our Chief Operating Officer and Chief Financial Officer, and Dr. Allen Yang, Chief of R&D Strategy. I'm Dave Gancarz, the Chief Business and Strategy Officer at Summit. 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, including the Form 10-K issued today about these risks and uncertainties. Summit undertakes no obligation to update these forward-looking statements, except as required by law. One item to note, this presentation is being webcast with slides, so we'll be referring to the slides being displayed in the webcast link. I'd encourage you to use the webcast link to see the slides being presented this afternoon that will accompany our comments. Following comments from our team, we will take questions. And with that, I'd like to hand it over to Maky.

Thank you, Dave. Good afternoon, everyone, and thank you for joining us today. I'm very proud of team Summit's ongoing accomplishments and the growing positive data sets and support around ivonescimab, a PD-1 VEGF bispecific, our lead investigational assets. We are highly focused, mission-driven patient-first company with a mission to make a significant difference in improving the lives of patients suffering from cancer. Our team is growing rapidly as we expand our clinical development plan and prepare for commercialization in anticipation of a decision from the FDA on our BLA near the end of this year. We have announced a few significant events today, starting with updates related to our HARMONi-3 study. Last quarter, we announced our HARMONi-3 Phase III trial evaluating ivonescimab plus chemo as first-line treatment for patients with squamous and non-small cell lung cancer was amended to have separate analysis by squamous and non-squamous histologies for primary endpoints of PFS and OS for each cohort. The squamous cohort was planned to complete enrollment in the first half of 2026, followed by the non-squamous cohort in the second half of this year. As announced today, we have now completed screening patients for the squamous cohort of the HARMONi-3 study, and the last patient will be randomized in the next couple of weeks. We have amended our statistical plan to now include an interim PFS analysis for our squamous cohort, and we are planning to conduct the interim PFS analysis during the second quarter of 2026. Overall survival will be immature at the time of this analysis. Therefore, we may not have overall survival results to communicate at that time. As you recall, we initially included PFS as a primary endpoint in this study opened the readout of HARMONi-2 comparing ivonescimab to pembro in PD-L positive frontline lung cancer patients, which showed a highly statistical significant and clinically meaningful benefit in PFS with a hazard ratio of 0.51 and a median improvement in PFS of over 5 months. This point was later validated with HARMONi-6, showing that there was a substantial PFS benefit when comparing ivonescimab plus chemo versus a PD-1 inhibitor plus chemo with a hazard ratio of 0.60. 2 Phase III studies conducted by Akeso in China in frontline non-small cell lung cancer demonstrated a 40%-plus improvement in PFS for the ivonescimab or both the HARMONi-2 and HARMONi-6 PFS results were based on the planned interim PFS analysis of each study. By adding an interim PFS analysis, we opened the door to an earlier discussion with the health authorities for our multiregional Phase III study. The final PFS analysis, if applicable, and an interim analysis for OS is planned to be conducted in the second half of this year, consistent with previous guidance. For the non-squamous cohort of HARMONi-3. We continue to expect enrollment to complete in the second half of this year and to reach a prespecified number of events for the final PFS analysis by the first half 2027. There are several meaningful moments upcoming related to these 2 cohorts, each of which are independent from each other, like 2 separate studies in one protocol where 2026 will be pivotal to providing additional clarity to expand the reach of Ivo to a broader population of lung cancer patients. Additionally, we announced today the first update to the IVO Phase III clinical trial program, which will continue to expand throughout 2026. ILLUMINE, a new Phase III study in PD-L1 positive frontline head and neck squamous cell carcinoma will be sponsored by GORTEC a French cooperative group dedicated to head and neck oncology with initial enrollment expected to begin early next quarter. The study intends to evaluate both ivonescimab monotherapy and in cognition with ligufalimab, Akeso's proprietary anti-CD47 monoclonal antibody against monotherapy pembro in this three-armed randomized study. Approximately 780 patients are intended to be enrolled across the 3 arms in multiple countries in Europe and in China. We may consider potentially expanding the study to include U.S. sites as well. Phase II data supporting the potential use of ivonescimab in this patient population was previously presented at ESMO 2024, where ivonescimab in combination with ligufalimab demonstrated an objective response rate of 60% in 20 patients with median PFS of 7.1 months after a median follow-up of 4.1 months. At the time of this analysis, no patients receiving ivonescimab plus ligufalimab is continued treatment due to the treatment-related adverse events. The data generated in Phase II is encouraging in light of existing standard of care, and Akeso is also running a single [indiscernible] Phase III trial in this population in China. Turning to our clinical collaboration with Revolution Medicines. Today, we announced the first patient has been dosed in the collaboration's initial clinical trial. As a reminder, ivonescimab is being evaluated in combination with 3 RAS(ON) inhibitors, including daraxonrasib, a multi-selective RAS inhibitor, zoldonrasib, a KRAS G12-D selective inhibitor, and elironrasib, a KRAS G12-C selective inhibitor across multiple solid tumor settings with RAS-mutations, including pancreatic cancer, colorectal cancer and non-small cell lung cancer. Finally, as we announced last month, we entered into a clinical collaboration with GSK to evaluate ivonescimab in combination with GSK's novel B7-H3 antibody drug conjugate in multiple solid tumors. The initial study under this collaboration is expected to begin dosing patients in mid-2026. Let's now take a step back and look at ivonescimab accomplishments today. There are many to list, we're just highlighting some of them. Ivonescimab has read out 4 Phase III clinical studies to date, all 4 of which have had positive data leading to 2 approvals in China so far. At this time, a total of 15 Phase III trials have been announced currently ongoing or have read out in multiple tumor types. 44 clinical trials have been initiated since 2019 between Summit and Akeso evaluating ivonescimab in a variety of solid tumors. When considering investigator-initiated and collaborative studies, a total of 142 clinical trials are now listed on clinicaltrials.gov, the enthusiast demonstrated by investigators around the world to generate data and see positive signals for patients facing high unmet medical needs really speaks to the opportunity and optimist surrounding ivonescimab. Together with our partner, Akeso, we have enrolled over 4,000 patients in either Summit-sponsored or Akeso-sponsored clinical trials across the world. Commercially, in China, over 60,000 patients have received ivonescimab based on 2 approved indications by the NMPA in non-small cell lung cancer according to our partners at Akeso, a third indication based on the positive HARMONi-6 study in frontline squamous non-small cell lung cancer is currently under review by the NMPA in China. I wanted to make sure this point is not missed. 4 Phase III trials evaluating ivonescimab have read out to-date and all 4 with positive data readouts. This represents the only Phase III readout that we have seen in the PD-1 VEGF bispecific class today. These positive trials are supported by the -- by the differentiated mechanism of action of ivonescimab. Here is the current ivonescimab development plan across Summit and Akeso. In total, there are 15 randomized Phase III trials 4 of which are global Summit-sponsored studies in non-small cell lung cancer and colorectal cancer, 1 of which is a multi regional cooperative group study announced today and 10 of which are being enrolled by Akeso in China in a variety of solid tumor types, including lung, breast, head and neck, BTC, pancreatic and colorectal cancers. Additionally, Akeso is also currently enrolling multiple Phase II trials evaluating ivonescimab in other tumor types: ovarian, gastric, HCC and others, including non-metastatic setting. Through our partnership with Akeso, we continuously compile a substantial amount of data going us to make faster, more informed decisions fueling the rapid expansion of our global development plan. Focusing on our pipeline at Summit. We have 4 global Phase III trials completed or ongoing. HARMONi, which readout positively last year, HARMONi-3, HARMONi-7, HARMONi-GI3, all 3 of which are currently enrolling and progressing nicely. The HARMONi trial evaluated ivonescimab plus chemo against chemo alone and treatment for EGFR-mutant non-small cell lung cancer after TKI therapy, a population of significant unmet need with few available treatment options. We submitted a BLA filing last quarter, seking approval in this proposed indication and in January, we announced the U.S. FDA's acceptance of the filing and a PDUFA [indiscernible] action date of November 14, 2026. As previously disclosed, the FDA noted that a statistically significant overall survival benefit is necessary to support marketing authorization in this setting. Considering safety and efficacy profile of the current FDA-approved options to patients in this setting, the positive regionally consistent results of this Phase III multiregional study as well as discussions with key opinion leaders and physicians who have administered ivonescimab to patients, we believe that ivonescimab is a potential treatment option with a favorable benefit risk profile. In anticipation of potential approval in Q4 of this year, we continue to ramp up commercial capabilities in preparation for potential launch. HARMONi-3 is evaluating ivonescimab plus chemo against Pembro plus chemo in frontline metastatic non-small cell lung cancer. This patient population represents a significant unmet medical need with nearly 100,000 patients in the United States alone as this trial covers frontline non-small cell lung cancer patients, without genomic mutations, irrespective of histology or PD-L1 status. I spoke a minute ago about the recent changes to this pivotal study. For HARMONi-7, this study is evaluating ivonescimab monotherapy against pembro monotherapy as frontline treatment for patients with non-small cell lung cancer that have high PD-L1 expression levels. HARMONi-7 continues to enroll well, and we look forward to providing additional updates in the future. And finally, last quarter, we initiated and began enrolling patients in HARMONi-GI3 evaluating ivonescimab plus chemo compared to bev plus chemo in first line therapy in patients with [indiscernible] colorectal cancer. Our decision to expand into colorectal cancer was driven by encouraging Phase II data published at ESMO 2024 and subsequent continuing enrollment in this Phase III studies in China and the United States with additional chemotherapy regimens. This data set allowed us to make an informed decision to move forward in CRC, specifically with a [indiscernible] chemo combination. We look forward to providing further updates on the Phase II data set later this year as well as the HARMONi-GI3 study as the trial progresses. Looking beyond our own sponsored trials we are expanding into additional settings with multiple collaborations and other groups. We have the Phase III ILLUMINE study sponsored by GORTEC evaluating ivonescimab in head and neck cancer that I spoke to earlier, with respect to novel [indiscernible] combination. We announced that the first patient was dosed this quarter in our collaboration with Revolution medicine to evaluate ivonescimab in combination with 3 novel RAS-inhibitors across multiple solid tumor setting. We are excited to learn about the opportunity and potential to improve patient outcomes with ivonescimab combined with this novel-targeted therapies and promising molecule. This collaboration is intended to evaluate ivonescimab in combination with one or more of Rev Med RAS(ON) inhibitors in pancreatic cancer, colorectal cancer and non-small cell lung cancer. This collaboration has an opportunity to be mutually beneficial to both Summit and Rev Med by leveraging a combination of potential next-generation assets that individually have promised in each setting, and this may have high promise for patients with RAS-mutant cancers. In our GSK collaboration evaluating ivonescimab in multiple solid tumor settings in combination with their B7-H3 ADC, we expect the trial to initiate in mid-2026. This is another example of promising targets seeking to significantly advance outcomes in settings where both Ivo and B7-H3 ADCs have shown promise. We have over 60 ISTs that we intend to support in various stages of development. Of these, 15 are currently enrolling 5 of this in collaboration with MD Anderson and ivonescimab has now been featured in over 45 publications, presentations and posters. Collectively, this trial enhance and inform our own clinical development activities as we learn more about new settings where neither we nor Akeso have had the opportunity to explore yet. Tremendous interest in ISTs is a testament to the enthusiast. We have heard from many investigators as they consider the potential opportunity that ivonescimab presents across multi tumor types. Over the past 18 months, we have seen 4 positive randomized Phase III trials including the first and only Phase III trials to compare positively against anti-PD-1 therapies. Each of these studies represent a benefit either over a PD-1 inhibitor or in setting where PD-1 inhibitors have failed to achieve a benefit in either PFS or OS. Akeso's HARMONi-2 PFS results showed ivonescimab monotherapy as superior to KEYTRUDA in frontline non-small cell lung cancer. These results represent first time any therapy has achieved a clinically meaningful benefit over KEYTRUDA in randomized Phase III trial. In April of 2025, Akeso announced that HARMONi-2 achieved a clinically meaningful overall survival hazard ratio below 0.8 at this early look. Moving to Akeso's HARMONi-6 frontline small cell lung cancer study in patients with squamous histology, results were announced at ESMO 2025, demonstrating ivonescimab with chemo was superior to PD-1 plus chemo in PFS. With this result, HARMONi-2 and HARMONi-6 represent the first and only known regimen to achieve a clinically meaningful benefit replacing an anti-PD-1 regimen. In EGFR-mutant non-small cell lung cancer, both Akeso's HARMONi-8 trial and our own global HARMONi trial achieved positive consistent results. In HARMONi, a positive overall survival trend was observed with hazard ratio of 0.79, barely missing statistically significant. In a subsequent analysis in September 2025 with longer-term follow-up on western patients, ivonescimab plus chemo showed favorable trends in the overall survival with a hazard ratio of 0.78 and a corresponding nominal p-value of 0.032. In HARMONi-8 final overall survival analysis showed ivonescimab plus chemo achieved a statistically significant hazard ratio of 0.74 with a p-value of 0.019 supporting a treatment profile where OS does not degrade but rather improves over time in this setting. Turning to our market opportunity. The value proposition is clear, ivonescimab on its own has the potential to be a platform blockbuster drug, additionally, novel-novel combinations with IVO could bring potential improvements over current standard of care which could expand market opportunity further. Ivonescimab is well positioned to make a significant impact across the solid tumor treatment landscape. Between JAK-point inhibitors and anti-VEGF therapies, TD Cowen and others estimate the total addressable market to be in excess of USD 100 billion globally, looking only at the JAK-point inhibitor market for non-small cell lung cancer market estimates for immunotherapy are expected to exceed USD 20 billion by 2028. And yet these estimates still do not include the full impact ivonescimab could have as it has already shown promising data in multiple tumor types where checkpoint inhibitors have not been effective including EGFR-mutant non-small cell lung cancer and PD-L1 low-triple negative breast cancer. Ivonescimab differentiated profile supports its platform potential across multiple indications, many of which could be blockbuster opportunities on their own. We have a very exciting year ahead. Here are some of the upcoming milestones we expect to reach in 2026 and into the first half 2027. Our global clinical studies pipeline will continue to expand, and we will provide further details in 2026 as we begin studies in new settings and indications. This will include additional novel-novel combinations as well as the new Phase III studies that we intend to launch in 2026. The first step with respect to this expansion came today with the announcement of the cooperative group led ILLUMINE Phase III clinical study in head and neck cancer. We will continue to expand often the details of our clinical development plan throughout 2026, including sponsored studies. With today's HARMONi-3 update. We anticipate an interim PFS analysis for the squamous cohort to occur next quarter, final PFS and interim OS data are expected in the second half of this year. In the HARMONi-3 non-squamous cohort, we expect to complete enrollment this year. We anticipate final progression-free survival data in the first half of 2027. And as already discussed, we are looking forward to a potential first approval for ivonescimab in the U.S. around our November 14 PDUFA date based on our HARMONi BLA filings. Now I will turn the call over to Manmeet to provide a financial and operational update for the quarter. Manmeet?

Thank you, Maky, and good afternoon, everyone. On the financial front, let me start with our cash position. We ended the year 2025 with a strong cash position of approximately $713.4 million, and to remind everyone Currently, we have no debt. Turning to operating expenses. I will provide details on both GAAP and non-GAAP numbers. You can refer to our press release issued this afternoon for a reconciliation of GAAP to non-GAAP financial measures. As a reminder, non-GAAP expenses exclude stock-based compensation expenses. Total GAAP operating expenses for the fourth quarter of 2025 were $225 million compared to $234.2 million for the third quarter of 2025. This decrease in GAAP-operating expenses was primarily due to the lower stock-based compensation expense of $19.1 million, and this was offset by an increase in our clinical trial-related spend of $8.8 million. Overall, our non-GAAP operating expenses during the fourth quarter of 2025 were $113.3 million compared to $103.4 million for the third quarter of 2025. This increase in non-GAAP operating expenses was primarily related to an increase in R&D expenses related to HARMONi-3 and HARMONi-7 trials. As you will note, we have been very efficient and disciplined in controlling our G&A spend. Our total G&A spend, excluding stock-based compensation expense has been approximately $43 million for the full year 2025 with a run rate of approximately $10 million to $11 million per quarter in 2025. On the operations front, I'm extremely proud that Team Summit has been able to accelerate enrollment of 600 squamous patients ahead of our planned timelines, which will allow us to have interim readout by second quarter of 2026. With the acceptance of our BLA with FDA, we have accelerated our commercial readiness activities to prepare for our potential commercial launch of EGFR-mutant non-small cell lung cancer post TKI therapy. With respect to manufacturing and drug supply readiness, we have successfully transferred and validated the production process of ivonescimab to a U.S.-based manufacturer. And with that, I will hand it back over to Dave.

Thank you, team. And we will now see if there are any questions that our team can help answer. Operator, if you could please open the line for questions.

[Operator Instructions] We'll take our first question from Salveen Richter at Goldman Sachs.

This is Mark on for Salveen. Can you talk about what drove the decision to include the interim PFS analysis for HARMONi-3 for the squamous cohort and also frame expectations for both the initial data in the second quarter and also the potential final PFS analysis in [indiscernible] in the second half, will we see curves in addition to the top line data? And now given the split do you expect OS could reach that -- significance [indiscernible] that final analysis time?

Thanks, Mark. Appreciate the question. This is Dave. So we decided to amend the protocol for the HARMONi-3 study by including an interim analysis for the PFS primary endpoint. If you recall, we previously amended the HARMONi-3 study in order to add PFS as a primary end point in addition to overall survival. The reason for the addition of PFS as a primary endpoint was based on the results of HARMONi-2, which showed the large PFS delta that Maky spoke to a hazard ratio of 0.51, comparing IVO to monotherapy [indiscernible] lung cancer patients. And then this would allow for a -- so this was then seen again in the HARMONi-6 data. So this would allow for an earlier discussion with the agency based on the primary endpoint and now an interim PFS. So it's really about accelerating the timelines with respect to the data based on 2 interim readouts from our partners at Akeso in studies in lung cancer. And so with both studies remaining -- or reading out positively, the overlap and the indication with respect to HARMONi-6, that gives a strong indication in terms of the opportunity that exists here with ivo plus chemo versus a PD-1 plus chemo here. What I would say with respect to your question on survival, and I think Maky emphasized this point a minute ago as well. Overall survival will be a mature at the time of the interim PFS analysis. In terms of disclosure, with respect to when that will take place. That will -- so we plan to run the analysis in the second quarter. And then ultimately from there, what gets disclosed will be determined based on output results as well as traditional major medical conference guidance depending on how results are read out one way or the other. And then with respect to your final question on final PFS interim OS. So that remains no real change in timing. That's the second half of this year again. We're not really guiding -- and we don't really comment historically on our expectations with respect to results. We don't -- we obviously are encouraged by ivonescimab's Phase II data, the Phase III data that took place in HARMONi-6, and so we really are looking to continue to follow in those trends, but don't necessarily guide specifically with respect to our expectations numerically, if you will.

We'll go next to Yigal Nochomovitz at Citi.

Thanks for the comprehensive update key and team. So just to kind of press further on this question around this interim PFS and second quarter now. So it sounds like what you're saying is that this is based on the optimism from HARMONi-2 and HARMONi-6, but I just want to check, was there anything specific that you saw in HARMONi-3 with respect to an event rate, it's faster or other new piece of information that increased your confidence in doing this interim now in the second quarter? Or is it really just a question of providing this update sooner to accelerate development based on, as you pointed out, what you saw with HARMONi-2 and HARMONi-6?

Yes. Thanks, Yigal, for the question. It's really a data-backed decision, as we mentioned, with respect to interim readouts for HARMONi-2 and 6. And then obviously, the significant overlap in setting with HARMONi-6. I would also reemphasize we are not changing the timing in terms of guiding towards final PFS expectations and then the internal [indiscernible] no change there from events. I'll let Allen provide more commentary as well.

Yes, Yigal. I think what you said, it's the latter. Remember, this study was designed way back in '23 right? And since then, we've had the HARMONi-2 and the HARMONi-6 readout. Our mission is always to bring this very important medicine, which we think is a game changer to patients as soon as possible, right? And I think the HARMONi-2 and now the HARMONi-6 data gives us growing confidence, granted both of those studies read out on an intra-PFS, which was very dramatic. And PFS is a surrogate endpoint. So there has to be some regulatory discussion, but we'll need to look at that data before we can make those decisions. But again, I think this is an opportunity to bring patients faster.

Okay. And at this point, are you providing any other details with respect to the office spend or the number of events that are triggering this interim in the second quarter?

No, nothing in terms of a statistical plan at this point has been provided neither for the interim PFS nor the final. But we have provided approximate sample sizes for both cohorts and then obviously, the primary endpoints of both PFS and OS.

Okay. And then a totally separate question. I just want to comment or ask about ILLUMINE. So is there -- you had the data in ESMO in 2024. What do you know about contribution of components with respect to Ivo and ligufalimab? Is there evidence to suggest synergy or not? Or is this just an additive effect. If you could just spend a little bit more time explaining the thinking scientifically to put those two together. I know the ESMO data was a little bit of a time ago and back in 2024.

Sure, Yigal. Thanks for the question. So if you recall from ESMO 2024, we showed data that was generated from our partners at Akeso both in monotherapy ivonescimab as well as ivonescimab in combination with ligufalimab that as Maky explained, was Akeso's proprietary CD47-antibody. And that data was encouraging in both cohorts, but it did show an additional uplift that we've seen with ivonescimab plus ligufalimab. We've seen our partners at Akeso launch a Phase III study with the combination in PD-L1-positive head and neck cancer. And so we've explored and have been encouraged by the data as it continues -- the Phase II data continues to mature. And part of the study being a three-armed study, with IVO in one arm, IVO plus ligufalimab in the second arm and then the control arm being monotherapy pembro. That will help answer definitively that question with respect to contribution of components. But the 2 cohorts within the Phase II each were encouraging. And there was encouragement from the cooperative group in GORTEC and I'd like to obviously thank GORTEC for their enthusiasm in terms of the study. And that's what's led to the progression here.

Yes. I would just add that, as Dave said Yigal, that the data from ESMO showed that the combination of ligufalimab and ivonescimab was -- had a higher overall response rate than ivonescimab alone. We're excited to work with GORTEC, which is a premier cooperative group in head and neck cancers. And they've designed a very rigid, clinically sound scientifically robust study to demonstrate that. And I think Maky's comments in the script showed that -- there are going to be ivonescimab as one group and ivonescimab plus ligufalimab. So you can demonstrate the contribution of components against the standard of care Pembrolizumab. So I think that's going to be very important.

Next, we'll move to Brad Canino at Guggenheim.

Congrats on the screening completion. For me, it's not quite clear yet why adding the interim provides a benefit with regulatory discussions because it seems like you'll reach final PFS before any OS data interim or final? And presumably, you would need the OS to file anyway. So can you help us square that for me I'm starting to beat the horse on this one.

Great. Thanks for the question, Brad. And so I think there's a couple of things in terms of what you said. So first of all, you can't really have a discussion with respect to data with the regulatory agencies without data, right? And so part of the interim analysis allows for the generation of primary endpoint based data. And then as we continue to mature that data, you'll see also no change in our guidance with respect to final PFS as well as interim OS timing in the second half of the year as well. And so when you kind of combine those two points, it allows for the acceleration of the conversation without much delay with respect to -- there's several months in between, obviously, second quarter versus the second half of the year, but it allows for progressing that conversation with the agency with data in hand to allow for next steps.

And I guess when I hear this and along with the regulatory strategy in EGFR-mutant, should we read this as like a company's evolving view that frontline lung could see approvals with just PFS benefits and only OS trends?

Yes. I mean I think there -- depending on -- it's a combination, right? It depends on the timing, right? The magnitude of the benefit is important. And then obviously, there'll be some contribution in terms of overall survival trends. And I think that's where we see dual primary endpoints in this study. And then across solid tumors, you see that in several places as well. the studies to be clear, is certainly powered for both primary endpoints, which is an important point as well.

So Brad, this is Manmeet. I think in other cohorts, right, depending upon this earlier interim PFS data and the magnitude of the PFS that will allow us a potential discussion with the FDA to accelerate our submission, as we submit right, OS may come and mature, and that is a path forward to accelerate, provide this drug to patients much earlier.

We'll go next to Cory Kasimov at Evercore ISI.

This is Josh on for Cory Kasimov. Our question is on the head and neck Phase III. Why opt to go through a co-op group here? And what signal will you want to see before committing to expanding into the U.S. here? And could it be used to leverage for a U.S. approval?

Josh, thanks for the question. So a couple of points there. I think one, we've talked a few times now in terms of expanding our Phase III program more broadly. So I think -- in some ways, there's an opportunity to work with some of the premier cooperative groups in terms of adding additional indications that we see promise in as well. And this is one of those indications. There's a highly competitive space in head and neck cancer, and we think there are multiple opportunities for patients in this setting. And we think ivonescimab presents a strong opportunity in particular, ivonescimab and then potentially ivonescimab in combination with ligufalimab, right? And so working with cooperative groups also expands a number of trials that are able to be performed ultimately. And so it's important that we are taking on as much opportunities as we can with respect to bringing ivonescimab to as broad of a set of patients who are impacted by cancer as we can. So we think that, that is a strong approach overall. It's a strong cooperative group who's run multiple studies as well, and they were highly enthusiastic based on the data that's been presented and obviously working with them since. And so as Maky emphasized, earlier as well, it's important to note that we do plan to continue to expand that Phase III program in 2026, and I think we've been pretty clear that as we plan to launch additional studies, we would wait until we get to the readiness to launch, and we'd have FPI in sight. And so part of this will be over the course of '26, but this is an important concept that we had with respect to working with a highly enthusiastic cooperative group in a setting which they specialize and it was an opportunity to really explore on a multiregional setting, this -- these two regimens, really the monotherapy as well as the combination regimen.

I was just going to add, they approached us, right? So they came to us. Head and neck is an unmet need. It's not the largest unmet need in the PD-1 VEGF space. And so I think we are going to -- as Dave said, focus our resources on the largest unmet needs, and this one was convenient because they came to us wanting to do a study. Yes. Sorry, Josh, I interrupted you.

I was going to ask if there was anything specific you could give us on what may trigger like a U.S. expansion here?

Yes. Not -- I don't know that at this time, we want to start disclosing specific details, but obviously, we'll get enthusiasm with respect to enrollment with several countries in Europe who are enrolling in the study feedback from GORTEC as they operationalize the study, there's also additional data being generated by our partners at Akeso in Phase III in China with respect to the setting. I think there's a multitude of different is continuing maturity of the Phase II, obviously, as well. So there's multiple paths with respect to that, but nothing more specific there, just at this point.

We'll take our next question from Tyler Van Buren at TD Cowen.

Congrats on the squamous enrollment completion and the progress. So should we expect the HARMONi-6 OS data later this year? And how about HARMONi-2 OS data as well? And in general, given the upcoming HARMONi-3 OS data over the next year, can you just reiterate what gives you the most confidence that all the positive PFS data we have seen from the frontline lung cancer trials will ultimately translate to OS benefits in the frontline Western population or global studies?

Appreciate the question, Tyler. I think as we have said many time, so the HARMONi-2 and the HARMONi-6 studies are studies that are conducted by and sponsored by our partners in China and Akeso. So they have not necessarily guided in terms of looks on overall survival readout at this point. It's important to note again, HARMONi-2 is not necessarily powered for overall survival. And what -- was not powered for overall survival at all. That was a PFS primary-endpoint exclusively. HARMONi-6 was also a PFS primary endpoint but obviously a little bit larger in the sample size of over 500 patients. And so I think the protocol for HARMONi-6 was published, and so that would appear at some point to look like 2026 as an event, but they have not guided more specifically to that. I think the second half of your question with respect to translation into HARMONi-3 and then obviously, the confidence that we have with the PFS data translating to OS. So I'd make a couple of points. I don't think there's a better analogy in terms of opportunity with respect to a randomized Phase III study. And in this case, in squamous non-small cell lung cancer, IVO plus chemo versus PD-1 plus chemo, then a randomized Phase III that was nearly identical just run in China, right? And so that was strongly positive. The PFS hazard ratio indicated a 40% improvement in terms of PFS reduction of risk and/or death, and so when we look at translation from China to the global setting, we're obviously very confident in HARMONi helped enforce that very consistent results with respect to OS, both from a media perspective as well as hazard ratio. I think the other thing is we step back, we often talk about the question with respect to PFS and hey, what's the confidence level translating that into OS? And so at this point, 4 randomized Phase IIIs have read out, right? HARMONi-A was the first, and that was in China the EGFR-mutant non-small cell lung cancer after a TKI. And that final OS analysis was statistically significant, and that was displayed at [indiscernible]. The second was the HARMONi study, and we've talked at length there with a very strong showing with respect to overall survival, the final analysis was not statistically significant, but with longer follow-up time given the given the delays in initial enrollment in the follow-up time differences between China and the U.S., we saw a nominal p-value that was below any threshold with respect to what would be required for significance. We saw a p-value of 0.03. When we look at HARMONi-2, the only readout we've seen thus far was the NMPA, the Chinese health authority requested, look. And that's sort of an OS hazard ratio of 0.777 comparing IV to pembro. So at this point, HARMONi-6 has not even hit that point, and it's still -- that application in review is our partners at Akeso have announced. And there hasn't been a look yet in overall survival. But of the 4 that have readout of those studies have shown some data towards OS. All of them have shown a hazard ratio of less than 0.8, which when we speak to KOLs, we speak to physicians globally. That's kind of the generally agreed upon threshold for clinical meaningfulness, if you will. And so the amount of encouragement that we've seen with respect to OS is about as high as you can get with respect to the time that we're at. I appreciate everyone's focus on overall survival but overall survival takes time. in terms of the readout and all of the readouts that we've seen to date have pointed in one direction, which has been highly encouraging. So hopefully, Tyler, a comprehensive answer to your question, but one that answers it.

Tyler, this is Alan. I would just add from a clinical perspective, from the mechanics of the study, they're not a crossover design. The standard of care for both arms is the same, right? And the patients are blinded. So they don't even know whether -- which arm they were on. So they should get balanced standard of care. Now if you start that standard of care in the second line or later line, 5 months later because of the PFS benefit [indiscernible], that should translate to a benefit in OS, right? It's just such a large magnitude in delaying that next line of therapy.

And [indiscernible] your line is open.

More of a commercial question here. So as you're thinking about the commercial footprint you're going to need the EGFR-mutant non-small cell lung that you're building up right now, how much footprint could you -- would be usable for the broader [indiscernible] population. I'm assuming all of that. But then how much more would you have to add on top of that to address the broader squamous population? And then I have a follow-up.

Asthika is Manmeet, and I can take that question on commercial readiness, right? There are a lot of synergies, right? If you see our EGFR and squamous and non-squamous all are coming from the non-small cell lung cancer, right? And as you would note, right, most of them are treated by similar physicians over there -- so our footprint and synergies will come right pretty much. EGFR is a much smaller population base, squamous gets over like 2.5x to 3x bigger than EGFR and then non squamous comes, which is almost double of cues, right? So it keeps expanding, but it gets our foot into the door. We will have to do a lot of education, a lot of learning from our setting our basic infrastructure in next coming quarters, and that will be the backbone off as we expand into squamous and non-squamous because these are all similar physicians. Same indications.

How should we think about, I guess, the ramp-up in your expenditure for the SG&A line item?

Yes, we have been like pretty efficient over there. As I said, EGFR is the smallest one, right, to initiate. We don't have to put a lot of expenditure and most of the expenditure will come right when we hire our sales teams over there. We have been already doing a lot of activities on the medical affairs front, which we initiated right last quarter, and those all are happening. So I would say there will be expense, but that will come a quarter before the PDUFA right, as you get into that, you hire more sales people and other things. But other than that, we are already doing much of the activities and managing that right now very well.

Got it. And then as per -- I like that you guys are offsetting some of the development to these cooperative groups like GORTEC. But of course, these groups are going off the data that's generated in China also with novel agents that are not yet approved in the U.S. and Europe. So I guess, how are you thinking about when you think about these data [indiscernible] for U.S. submissions, how are you thinking about some of the regulatory requirements like Project Optimus that might be required perhaps to be done before a Phase III has started and how are you getting these cooperative groups to kind of play [indiscernible] with that and make sure that the data that they're generating is going to be applicable for a U.S. submission too?

Yes, it's a great question, Osaka. And so importantly, our partner at Akeso have started a Phase III in China in the setting. And so that also speaks to the additional data that exists with respect to some of the work that's been done in this setting. And also, there's optimism, there's contribution of components which we spoke to earlier as well. And obviously, with the novel-novel opportunity here with Ivo and Ligu, it's important to show Ivo as a monotherapy as well as Ivo and Ligu combined. And so I think a lot of the concepts that you're speaking to are something that's permeating both in the U.S. as well as Europe, the cooperative groups are very familiar with those thought processes of the health authorities. And so in general, that's not something -- that is a high concern in terms of pushback or anything like that with the cooperative groups, that's something that's pretty well understood at this point.

Asthika, this is Allen. I'll just add to what Dave said is that we've used Chinese data clearly to satisfy project optimism before. So that shouldn't be an issue.

We'll take our next question from David Dai at UBS.

Just on the HARMONi trial in second line EGFR and also small-cell lung cancer. Just could you provide some additional color on the FDA interactions leading to the BLA submission? And then more importantly, anything you can share on the FDA [indiscernible] on the OS, how has that changed your time?

Yes. This is Allen. So again, I think we've been very transparent that this study is positive with the PFS endpoint. We just missed OS because of delays in enrollment due to sort of post effects from the pandemic. The FDA was clear that they wanted to see the OS to make this a fileable package. And we said, look, we think the data are important. When we look at our data compared to other agents approved in the space, we think that this satisfies an important unmet need patients. And so we wanted them to review the full package of the data. We've submitted it and they've accepted that filing and they're reviewing the data now.

Got it. Okay. That's helpful. And then just on the most recent collaboration with GSK of the B7-H3 ADC in combination with Ivo. And so just maybe help us understand a little more on the initial indication you're exploring. We know that the GSK is currently exploring B7-H3 for small cell lung cancer. Is that an indication you think it will make sense for you explore in combination with Ivo?

Yes. We've specifically talked about in our press release announcing the collaboration in small cell lung cancer, right? And so that is a place -- we've also been clear also that there's multiple solid tumor settings where we believe both B7-H3 as well as Ivo have shown promise. And so -- but there's obviously a place where with the evolving landscape of small cell lung cancer, that's an important place for us to explore. And we think the B7-H3 ADC, that GSK has, is showing a lot of the -- we're not going to go into details with respect to the comparisons we've done against the B7-H3 across multiple companies. But it's important that we did look at that asset and feel that was a very appropriate partner for Ivo with respect to collaborating in small cell as well as a couple of other solid tumor settings.

We'll move next to Mitchell Kapoor at H.C. Wainright.

With HARMONi under consideration from the FDA, could you walk through your high-level thoughts on pricing strategy, given the competitive landscape in EGFR non-small cell lung cancer, but also the benefit of ivonescimab, what could provide in future expansion indications?

Mitchell, this is Manmeet, and it's very early to start talking about pricing. Pricing is dependent on as finally decided, right, based on the final label you have and the indication which we are launching in -- and obviously EGFR, is our first one, but we will not be commenting on the price. Obviously, as you see the other benchmarks, right, and you can easily look at, right, how other second-line EGFR drugs are priced, you could see that there is a big range, and we have the potential based on the benefit of ivonescimab to price it very well. But as you also stated, right, in the long run, we have multiple more indications to come. So we'll have to price it appropriately, but more to come. I think there is no decision or nothing to add over here right now.

Okay. Fair enough. And then on those potential expansion opportunities, obviously, ivonescimab is kind of this pipeline and a drug opportunity, which is rare these days, but what kind of gating items would be there to determine how fast you could initiate more trials? Is it additional partnerships? Or anything that could determine the next steps you take? Are you watching Akeso's next moves? Or what's helping you to decide how fast to initiate additional studies?

Yes, it's a great question, Mitchell. I think -- so I want to emphasize one of the points that Maky spoke to because I think sometimes there's a lot of really positive events that take place with Ivo and sometimes it's important to slow down on a couple. And so over 4,000 patients have been treated with ivonescimab just in clinical trial clinical trials sponsored by either Summit or Akeso, right? So it doesn't include the over 140 total clinical trials listed on clinicaltrial.gov at this point. This doesn't -- such as ISTs and whatnot. But so when we look at the amount of data generated by ivonescimab, there's a significant amount of information that can be really well understood in several different settings. We've also -- it's important that our partners at Akeso have initiated 10 Phase III clinical studies. And so underneath that, you can do the amount of data that has been generated in terms of really understanding where ivonescimab can be successful. And then obviously, there's also a significant place where we can continue to explore where maybe the prevalence of a particular disease in China is not necessarily as high as it may be in the U.S. and vice versa, right? But there's a lot of overlaps with respect to the characteristics of those diseases, that's important for us to be able to kind of translate that inflation across. But because there's so much patient data with respect to how patients who have performed on ivonescimab, that really allows us to triangulate, if you will, the information. So we're not running, hey, we've been able to dose 30, 40, 50 patients with Ivo and now it's very encouraging. So we are trying to figure out how to move forward. There's a plethora of information and data. So much of it truly highly encouraging in terms of what that opportunity can be. And that really gives us the opportunity to really think through the different places, the different standards of care. It's important to also consider what the standard of care is in some of these settings. How is that evolving? How is that evolving in the short term? How is that evolving by the end of what would be a Phase III clinical study. And so we can really look at the information we have internally, what's happening in the market to really, at the end of the day, -- what we're trying to do is provide a medicine that improves outcomes for patients, right? But that takes an ecosystem in order to do. Physicians need to be able to access, understand and have clear answers from that data. Patients need to be able to see what opportunities exist based on data and outcomes from trials. And so when we look at the totality of the landscape across many of the tumor types that are sensitive either to immunotherapy, anti-angiogenic therapy, places where neither have been successful, but there's an opportunity with ivonescimab. We really can look at the totality of landscape, the data generated what physicians will need to see in a couple of years to really come up with the right answer. And that's why some of these even collaborative -- or collaboration opportunities, rather with Rev Med, with GSK, that's important. We'll have more of those coming as well. But when we look at totality of what's out there, it's really important to consider each of those points. And so that's why we really look to expand much further in 2026 as well.

Yes, Mitch, and I want to just address a couple of your comments. So at JPM, Maky announced we're going to be doing multiple new Phase III programs. We will, of course, continue to explore cooperative group studies and collaborations with external partners, and you should expect more of those to come. But our strategy is not dependent on that. We will have sponsored studies based on the Akeso data and moving forward. And so you should expect more of those studies to come as well.

Next, we'll go to Eric Schmidt at Cantor.

I wanted to go back to HARMONi-3 and beat the horse a little bit more. I'm wondering if you've had discussions with the FDA around what you think would be the maximum disclosable set of inflation, given you need to maintain the integrity of the trial? Do you think, for example, you might be able to give us specific ratios or any other meaningful data at that time?

And Eric, just to be clear, you're speaking about the interim PFS?

I am. Thank you, Dave. Yes.

No, I appreciate it, Eric. So I mean, look, I think -- and I think we kind of mutually addressed this across comments from Manmeet, Maky and myself a little bit earlier. But it's important that the analysis is run and then we see the analysis in terms of outcomes in terms of what the next logical steps are in that respect. And so -- and then obviously, positive data requires contemplation with respect to major metal conferences as well. And so it's -- we have several opportunities, if you will, in terms of the data and what that readout will look like. And as we get a little bit closer, we'll be providing a little bit more clarity on what that looks like. But obviously, we thought it was very important now to provide effectively an immediate answer with respect to the analysis being run in the second quarter. And then the amount of that disclosure in some ways depends on what both the data shows and what the next steps are.

You just want to manage expectations here. Once we get the data, the most important thing is trying to provide this agent to patients as soon as possible. That requires a regulatory interaction, right? And as a courtesy to them, we need to demonstrate to them first, right? Then in collaboration with our investigators, we want to present this at a major medical meeting. So unfortunately, sort of a press release with curves for you guys as investors and analysts are not going to be a high priority for us.

Well, I guess my question was even just very specific to maintaining integrity of the final PFS readout from a regulatory standpoint? And whether -- even if you were able to get the interim PFS that would be [indiscernible] rated disclosure making regulators too uncomfortable. But do you have a view on that?

Sorry, Eric, I'm not sure we followed exactly what you're...

I think what he's saying is -- Eric, correct me if I'm wrong, but what you're saying is if we were to release top line interim PFS, would that impact the study scientifically in terms of unwinding it for the final PFS, right?

Exactly.

Yes, I understand what you're saying. And I guess I just don't want to disclose too much about what we're doing at this time. I understand your question. We're, of course, going to take that into consideration. But I just don't want to disclose how we're going to do this right now.

Yes, I would say a couple of key principles, right? We're never going to do anything that puts at risk the final analysis, if you will. And I think part of this becomes an outcomes-driven response as well in terms of what that data shows to be able to provide the clarity and transparency, but also be able to maintain the integrity of the study itself as well as the interactions with the health authorities.

And we'll take that question from [indiscernible] at Jefferies.

I wanted to ask on the FDA review for HARMONi. Have you guys had any interaction with the FDA since having the BLA submitted? And is there anything in the FDA's stance changing on excitability of PFS and read through that to HARMONi-3?

Yes. Thanks, Faisal. I think we addressed most of this a little bit earlier. But yes, we have interactions with the agency. We don't necessarily disclose mean by meeting discussions and whatnot. And so what we don't want to do is we're not looking to leverage external sources in terms of covering the agency or anything like that. We have confidence -- those discussions are intended to be confidential. So we're not necessarily giving step-by-step updates with respect to that. We have -- we do have interactions with the agency, both for this study as well as other current studies and then potential future studies. And so it's important in terms of the totality of what we're looking to accomplish with ivonescimab that -- we have the utmost respect for the FDA. I think that's just a level setting point. That becomes very important in terms of -- with the platform opportunity, if you will, for IVO, there's a lot of studies with a lot of potential settings where ivonescimab may benefit to patients, and we want to make sure that we have a strong relationship with the agency in order to do -- our mission is really to bring ivonescimab to be to as many patients facing an unmet need is possible in doing what's right for ultimately patients facing cancer diagnosis.

And that concludes our Q&A session. I will now turn the conference back over to Dave Gancarz for closing remarks.

This is Bob Duggan. Not only David is correct in saying that we have a tremendous respect for the FDA, is probably America's most respected agency around the world for its integrity the due diligence of its work for putting patients first, and we're really honored to be reporting into them. And lastly, we're also very [indiscernible] with our partner, Akeso. Akeso has almost a few hundred million dollars of investment value in their ownership along with you all, that are owners of Summit, and we're happy that they chose to do that. We're also quite pleased to see that time after time when they introduce new drugs, they get through their own agency, they get clearances. They're doing quite well. If there's any China look like Regeneron, it's Akeso, just a fabulous company with great engineers, great scientists, and we're pleased that they are the source of the bispecific [indiscernible] back in 2013, and we're proud to have that in licensed and we're making great progress with that. So thank you all. We look forward to updating you on our next call, unless there's great late breaking news in between.

This concludes today's conference call. Thank you for your participation. You may now disconnect.