Summit Therapeutics Inc. Q1 FY2025 Earnings Call

Thank you for standing by. Hello and welcome to the Summit Therapeutics Q1 2025 Earnings Conference Call. I would now like to turn the call over to our Chief Business and Strategy Officer, Dave Gancarz. Please go ahead, sir.

Good afternoon and thank you for joining us. A press release was issued earlier this afternoon and is available on the homepage of our website. Our Form 10-Q was also filed earlier and is available on our website. Today's call is being simultaneously webcast and an archived replay will 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 Co-Chief Executive Officer and President; Manmeet Soni, our Chief Operating Officer and Chief Financial Officer; and Dr. Allen Yang, our Chief Medical Officer and Dr. Jack West, Vice President and our Thoracic Oncology TA Head. Before we get started with the rest of the call, I would like to note that some of the 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 the 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. Following comments from Bob, Maky and Manmeet, we will take questions. With that, I would like to turn the call over to Bob.

Thank you, Dave. Good afternoon, everyone, and thank you for joining us today. As you can imagine, I'm very proud of as well as encouraged by the ongoing accomplishments of Team Summit and the continuing positive information and enthusiasm surrounding ivonescimab, our lead medicinal investigational asset. We have begun 2025 with excellent progress and continue to take meaningful steps in the development of ivonescimab. We continue to advance our mission of building a viable organization, making a significant positive difference in serious unmet medical needs. Specifically, last week, our partner, Akeso, made two important as well as material announcements. First, ivonescimab received approval from NMPA, the health authority in China as frontline monotherapy treatment for patients with NSCLC whose tumors have positive PD-L1 expression. This marks an important regulatory milestone for our partners at Akeso and adds to the growing evidence of ivonescimab's differentiated profile and its potential to make a significant difference in the lives of patients dealing with hard-to-treat cancers. On behalf of the Summit team, we want to extend our congratulations to our partners at Akeso for this achievement and our gratitude for our strong ongoing partnership. This approval was based on positive PFS results from Akeso's HARMONi-2 trial which was disclosed at last year's World Conference on Lung Cancer. Additionally, to supplement this groundbreaking PFS data that represented the first drug to achieve a statistically significant benefit over pembrolizumab in a Phase III clinical trial, the NMPA requested that Akeso perform an interim analysis of overall survival. Last week, Akeso reported on the health authority's requested early interim analysis. The analysis showed a clinically meaningful and strongly positive trend favoring ivonescimab at 39% data maturity with a hazard ratio of 0.777, implying a potential 22% reduction in the risk of death compared to pembro. To be clear, at Summit, we are pleased and excited about this remarkable outcome. Maky will discuss this a little further in a few moments. Additionally, Akeso's HARMONi-6 Phase III clinical trial met its primary endpoint of progression-free survival at a prespecified interim analysis conducted by an independent data monitoring committee. This trial evaluated ivonescimab in combination with chemotherapy against tislelizumab, a PD-1 inhibitor in combination with chemotherapy in patients with advanced squamous non-small cell lung cancer regardless of PD-L1 expression. Conducted in China by our partners at Akeso, the trial showed statistically significant and clinically meaningful improvement in progression-free survival for ivonescimab plus chemotherapy. Akeso noted that no new safety signals were identified. This marks the first known Phase III trial in NSCLC to show significant improvement over a PD-1 or PD-L1 inhibitor combined with chemotherapy in a head-to-head setting. Following the success of Akeso's HARMONi-2 study, this is the second instance where ivonescimab-based regimens have demonstrated significant benefits in frontline treatment in non-small cell lung cancer. The full data set for HARMONi-6 is planned to be presented at an upcoming major medical conference later this year. Turning to our own global Phase III trials. We expect top line data in mid-2025 from HARMONi, our global Phase III trial in patients with EGFR mutated advanced non-small cell lung cancer who have progressed after treatment with a third-generation EGFR tyrosine kinase inhibitor. As a reminder, HARMONi is Summit's first global registrational Phase III trial and received Fast Track designation from the U.S. FDA. We are also excited to see progress in the expansion of ivonescimab studies through collaborations with leading organizations for which Maky will provide additional data. We will provide details in the future on additional catalysts, including top line results from our first registrational Phase III HARMONi trial and our clinical development plans beyond non-small cell lung cancer, both of which will be provided later in 2025. Maky will further discuss these accomplishments, driving our strong unyielding belief in what can be accomplished by Team Summit and our conviction in the potential of ivonescimab. We are a mission and purpose-driven organization with a collective goal to improve quality of life, increase potential duration of life and resolve serious medical needs. We believe we have the right team and the right molecule in ivonescimab to realize this goal. Not only do we have the right team, we have the right partner. The courage displayed by Michelle Xia and the Akeso team to conduct a head-to-head study against pembro was rewarded by the results and well-deserved second approval for ivonescimab in China. However, it also served to raise the awareness of ivonescimab globally when ivo became the first drug to demonstrate an improvement head-to-head in a Phase III trial versus pembro. Blockbuster drug development takes courage. And Akeso has demonstrated this courage on more than a few occasions, unlike many companies that have tried to but failed. With that, I will turn the call over to Maky for additional context and recent highlights for your consideration. Maky, are you ready to jump in?

Yes. Thank you, Bob, and good afternoon, everyone. As Bob said, I remain incredibly enthusiastic about the future of Summit and the possibilities of what can be accomplished with our lead candidate, ivonescimab, especially as we approach our first global Phase III readout and begin to grow our commercial team. Before providing some additional detail and reviewing the current pipeline, I would like to highlight our current progress in developing ivonescimab and dive a bit deeper on a few concepts that Bob touched upon. Since 2019, more than 2,300 patients have been treated in clinical trials with ivonescimab. Currently, combined between our partners at Akeso and our team at Summit, four Phase III trials have completed enrollment, three of which have had top line data readout and the other, the Summit-sponsored HARMONi trial, we expect top line data in the middle of this year. Five Phase III trials are currently ongoing; two of these are Summit-sponsored trials in first-line non-small cell lung cancer; and three are Akeso-sponsored trials studying ivonescimab in head and neck, biliary tract, and triple-negative breast cancers. Akeso has also announced its intention to conduct Phase III clinical trials in pancreatic cancer as well as immunotherapy refractory non-small cell lung cancer patients. With the addition of these trials, the cumulative number of Phase III trials for ivonescimab that have been announced or ongoing or have completed is now 11. On top of this, a significant amount of relevant data is being generated in additional indications, including colorectal cancer, ovarian cancer, gastric cancer, and hepatocellular carcinoma to further support our broad platform cancer program. Turning specifically to the Summit-sponsored pipeline. Our first global Phase III trial, HARMONi, is evaluating ivonescimab in patients with EGFR mutant non-small cell lung cancer after progressing on a third-generation TKI such as osimertinib. While this is a limited market opportunity compared to frontline treatment for non-small cell lung cancer, HARMONi represents our initial fast-to-market strategy with ivonescimab. Historically, PD-1 inhibitors, including pembro, have tried and failed to demonstrate a benefit in PFS or OS in the EGFR-mutant non-small cell lung cancer setting. This provides ivonescimab the opportunity to differentiate itself from current PD-1 therapies as well as a novel mechanism and a new treatment option for patients. The enrollment for the HARMONi trial completed in October of last year and top line data is expected mid-2025. This data is expected to contain data associated with both primary endpoints, progression-free survival and overall survival. Subsequently, we started two additional global Phase III studies, HARMONi-3 and HARMONi-7, which both evaluate ivonescimab head-to-head versus pembro, either with or without chemotherapy in frontline non-small cell lung cancer. HARMONi-3 evaluates ivonescimab in combination with chemotherapy and HARMONi-7 evaluates ivonescimab as monotherapy. Last October, HARMONi-3 was amended by significantly expanding the addressable patient population to include all frontline metastatic non-small cell lung cancer patients without driver mutations by including patients with non-squamous tumors in addition to squamous tumors. With this amendment, HARMONi-3 is now an all-comer study from a histology perspective and a PD-L1 expression perspective in frontline non-small cell lung cancer, covering an addressable patient population 2x to 3x larger than prior to the amendment. As a reminder, this trial enrolls patients irrespective of PD-L1 expression, including those patients whose tumors do not express PD-L1. Additionally, we have now begun enrolling patients in HARMONi-7 as we continue to activate clinical trial sites in the United States and will expand beyond the U.S. in the coming months. Later this year, we expect to announce additional details expanding our clinical development plan around ivonescimab, including beyond lung cancer. We continue to receive strong interest for investigator-sponsored trials, including in the most recent open window which closed just two weeks ago. To date, we have approved over 30 ISTs with a review of meaningful submissions from the last window to be performed shortly. These collaborations enhance our sponsored clinical development activities and can show signals in settings where ivonescimab has not yet been explored. Our strategic collaboration with MD Anderson, which commenced in July 2024, now has two studies that are activated and are enrolling in Houston with either cutaneous squamous cell carcinoma or glioblastoma. We committed $15 million to this collaboration to quickly discover additional opportunities for ivonescimab, including several tumor settings outside of this current development plan as well as the possibility of identifying biomarkers through additional research activities. Separately, we continue to support investigator-sponsored trials or ISTs, two of which have begun enrolling at the Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute. We are also looking forward to the initiation of clinical trials as part of our collaboration with Pfizer, which are expected later this year. This collaboration allows us to quickly advance beyond our current promising late-stage development plan to evaluate ivonescimab in combination with some of the most innovative ADCs from Pfizer. Pfizer will be responsible for the operations and costs associated with these trials. Summit will provide ivonescimab, and both parties will jointly oversee the studies. As you recall, ivonescimab brings two highly validated targets together into one novel bispecific antibody that targets both PD-1 and VEGF and holds a meaningful lead in terms of time and data generation in the clinical development of this novel class of compounds. Next, I would like to review some of the catalysts that we previously announced for this year. As we touched on a moment ago, we are anticipating HARMONi top line data in mid-2025, which we expect will include data related to both primary endpoints of progression-free survival and overall survival. This will be the first global Phase III clinical trial readout for ivonescimab which will provide information related to the clinical profile of ivonescimab beyond China, as well as data that may lead to a potential path to applying for marketing authorization in our territories, including the United States. As we stated previously, this trial was conducted with patients whose non-small cell lung cancer was positive for EGFR mutations and had progressed after third-generation TKI therapy. This is a setting where PD-1 inhibitors, including pembro, had failed to show an improvement in either progression-free survival or overall survival, providing an opportunity to demonstrate the differentiated mechanism of action for ivonescimab beyond currently available immunotherapy options. As a reminder, this study contains a subset of patients from the HARMONi-A study conducted by Akeso in China who received a third-generation EGFR TKI. HARMONi-A led the first approval and commercial launch of ivonescimab in China in patients with EGFR mutant non-small cell lung cancer. Additionally, HARMONi-6 as a catalyst event is intended to answer a proposed question as to whether the PFS benefits seen with ivonescimab monotherapy compared to PD-1 monotherapy would carry over to chemo combination settings, in this case, in frontline non-small cell lung cancer. As was announced last week, in HARMONi-6, ivonescimab in combination with chemotherapy achieved statistically clinically meaningful PFS benefit over tislelizumab in combination with chemotherapy in frontline patients with squamous non-small cell lung cancer patients. Tislelizumab is a standard of care anti-PD-1 therapy in China and Europe, and PD-1 or PD-L1 therapy plus chemotherapy is standard of care for first-line patients without driver mutations in non-small cell lung cancer in nearly all major markets globally. The full HARMONi-6 data set is planned to be presented at a major medical meeting later this year. Finally, data from the HARMONi-2 trial conducted by our partners at Akeso in China provide insights regarding how the benefit seen with ivonescimab in progression-free survival can translate to overall survival. After its groundbreaking PFS benefit over monotherapy pembro, an early look at OS requested by the health authorities in China showed a strongly positive overall survival trend with a hazard ratio of 0.777 at 39% data maturity, implying a potential decrease of more than 22% in the risk of death for those patients receiving ivonescimab compared to pembro. I would like to pause a moment to expand on these results. The early interim analysis for HARMONi-2 was conducted at the request of the Chinese health authorities during the review of the study overall, which led to the second approval and label expansion for ivonescimab in China. This early look was conducted at just 39% data maturity in the trial because it was conducted at the request of the health authorities and had so few total events, the alpha allocated to this analysis was minimal at 0.0001. When we say alpha, this is statistical nuance but effectively, the goal was to provide the planned interim analysis and final analysis with the best statistical chance of success. Recall as well that this trial was sufficiently powered to show a statistically significant PFS benefit in order to gain approval in China, which it has already done. It was not powered and the design was not intended to show a statistically significant OS benefit. When considering what an early look at OS requested by the Chinese health authorities with few relative events in the trial not powered for overall survival means, statistical significance was not part of our consideration, focus, or expectation as indicated by Akeso's minimal alpha spend. As we previously announced, a planned interim analysis is expected roughly by the end of this year, which will have a greater number of OS events. Note that HARMONi-7, our global study of frontline patients with PD-L1 high expressing non-small cell lung cancer, which intends to enroll 780 patients, nearly doubled the enrollment of HARMONi-2, is sufficiently powered to show a benefit in both PFS and OS. Context matters here. What this health authority requested interim analysis did show was that at this early stage and early look at the data, if you will, overall survival already shows a strongly positive trend that is clinically meaningful. If HARMON-7 were to show similar results at its final OS analysis, it is highly probable that this would result in a statistically significant overall survival benefit being achieved. This first look at overall survival data for HARMONi-2, combined with a strong PFS result in HARMONi-6, is remarkable. This data in totality with previously disclosed data for HARMONi-A and PFS data for HARMONi-2, as well as earlier phase trials in and outside of non-small cell lung cancer conducted by Akeso, further validate that ivonescimab is mechanistically distinct from PD-1 inhibitors and has the potential to make a meaningful positive impact for patients facing difficult cancer diagnosis. We are thrilled with the data released last week in both the statistically significant PFS results from the first interim analysis in HARMONi-6 and the early look requested by NMPA at survival in HARMONi-2. In speaking with the key opinion leaders, we have received very positive feedback. Our KOLs are highly encouraged by the potential of ivonescimab. This is consistent with the published feedback of multiple top thoracic KOLs in media articles over the past week. Additionally, Akeso continues to enroll multiple Phase III clinical trials, including biliary tract cancer, pancreatic cancer, triple-negative breast cancer, and head and neck cancer, and intends to launch an additional Phase III study in second-line or later non-small cell lung cancer after progression on immunotherapy. Now, I would like to take a moment to review study design for our two ongoing global Phase III trials, HARMONi-3 and HARMONi-7. For those on the webcast, this slide shows the study design for HARMONi-3. HARMONi-3 is a randomized, double-blind, global Phase III clinical trial evaluating ivonescimab in combination with chemotherapy against pembro in combination with chemotherapy as first-line treatment for patients with metastatic non-small cell lung cancer. This trial includes patients with squamous or non-squamous histology with no activating genomic alteration regardless of PD-L1 expression, including high, low, and negative PD-L1 expressing tumors. Dual primary endpoints for HARMONi-3 include progression-free survival and overall survival, and results will be stratified by squamous and non-squamous histology. As we have discussed, HARMONi-6 from our partner, Akeso in China met its primary endpoint, achieving statistically significant and clinically meaningful improvement in progression-free survival for ivonescimab with chemotherapy against PD-1 therapy with chemotherapy in frontline treatment of patients with squamous non-small cell lung cancer regardless of PD-L1 expression. These results from the Akeso trial conducted in China further validate our conviction in the potential for this study. We look forward to the full HARMONi-6 data set being presented at a major medical conference later this year. Next, we have the study design for HARMONi-7, a randomized double-blind global Phase III clinical trial evaluating ivonescimab monotherapy against pembro monotherapy as first-line treatment for metastatic non-small cell lung cancer patients with tumors with high PD-L1 expression. Dual primary endpoints for HARMONi-7 include progression-free survival and overall survival, and results will be stratified by squamous and non-squamous histologies. As a reminder, our HARMONi-7 study shares similarities with the Akeso-sponsored HARMONi-2 Phase III trial but focuses on those patients whose tumors have a high PD-L1 expression for which monotherapy pembro is the current standard of care in the United States and other major Western markets. Turning to the market opportunity, ivonescimab has the potential to be a platform blockbuster drug and is well positioned to make a significant impact across the treatment landscape of non-small cell lung cancer and beyond. In non-small cell lung cancer alone, there are combined seven announced or ongoing Phase III studies conducted by either Akeso or Summit. According to third-party research, including TD Cowen and others, the non-small cell lung cancer addressable market is expected to approach $20 billion for checkpoint inhibitors. With the recent data announced by our partner, Akeso in China, our belief is further validated in the potential for ivonescimab to make a significant difference for patients with non-small cell lung cancer. Beyond non-small cell lung cancer, across all checkpoint inhibitor indications, the addressable market approaches $90 billion globally in future years according to IQVIA research. But as we have been discussing, while the checkpoint inhibitor market opportunity is significant, the potential opportunity that I just mentioned does not include the full impact that ivonescimab could have, given it has shown promising data in multiple tumor types where checkpoint inhibitors have not been effective. This includes microsatellite stable colorectal cancer, PD-L1 low and negative, triple-negative breast cancer and EGFR mutant non-small cell lung cancer after targeted therapy based on the Phase II studies conducted by Akeso. In total, there are more than 50 indications where PD-1, PD-L1, or VEGF therapies have been approved, all areas for ivonescimab to potentially offer patients with cancer improved treatment options. Ivonescimab will continue to be appropriately rapidly tested and developed beyond non-small cell lung cancer. I continue to applaud the work of Team Summit and its rapid advancement in the development of ivonescimab which only two years ago began to open the first clinical site ever in the United States for ivonescimab. We persistently evaluate opportunities to accelerate our timeline in bringing additional therapeutic options to patients with high unmet cancer needs and look forward to upcoming announcements regarding expansions to our clinical development pipeline. With that update, I will now ask Manmeet to provide details on our financial and operational update.

Thank you, Maky, and good afternoon, everyone. We issued this afternoon our earnings release for the first quarter of 2025. Today, in addition to providing you with an update on our cash position and operating expenses, I will also provide you with color on our clinical, commercial, and manufacturing operations. Let me start with an update on the clinical operations front. As Maky mentioned earlier, we expanded the HARMONi-3 clinical trial during the fourth quarter of 2024 to add non-squamous patients. We are very pleased with the rate of enrollment across the HARMONi-3 trial for both squamous and non-squamous patients in the United States and Europe. In addition, very recently in 2025, we have initiated enrollment for patients in the HARMONi-7 clinical trial in the United States. We expect to initiate enrollment for the other regions during the next quarter based on the regulatory clearances to begin activating sites later this quarter. With our expected top line results from HARMONi trial during the middle of this year, we have initiated preparations for our first potential commercial launch of ivonescimab. We recently strengthened our leadership team with the appointment of Robert LaCaze as our Chief Commercial Officer. Robert is a seasoned biopharmaceutical executive with over 30 years of extensive leadership experience in commercial strategy and execution. Prior to joining Summit, he held senior positions at major pharmaceutical companies, including Bayer Healthcare and Bristol-Myers. With a proven track record of launching and growing blockbuster oncology franchises, Robert joins our team at the right time as we continue to refine our commercial strategy and expand our capabilities. In addition to Robert, we have also hired key hires for market access, marketing, and sales to optimize the commercial launch strategy. On the drug manufacturing front, in addition to our current supply source for ivonescimab from Akeso, our collaboration partner, we have made significant progress in transferring relevant know-how to certain third-party contract manufacturers in our licensed territory. Also, we are very pleased with the first approval of Akeso's PD-1 inhibitor penpulimab by the U.S. FDA, which demonstrates Akeso's capability to adhere to global manufacturing and quality standards. On the financial front, let me start with our cash position. We ended the first quarter of 2025 with a strong cash position of approximately $361 million. Let me remind you that we paid off our debt in entirety during the fourth quarter of 2024 and are now debt-free. Turning to operating expenses. I'll 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. Our GAAP R&D expenses during the first quarter of 2025 were $51.2 million compared to $51.4 million for the fourth quarter of 2024. And non-GAAP R&D expenses were $47.1 million for both the first quarter of 2025 and for the fourth quarter of 2024. Our GAAP R&D expenses for the first quarter of 2025 remained flat as compared to the last quarter of 2024. Our GAAP G&A expenses during the first quarter of 2025 were $15.6 million compared to $14.2 million for the fourth quarter of 2024. And non-GAAP G&A expenses were $8.6 million during the first quarter of 2025 compared to $7.5 million for the fourth quarter of 2024. Our GAAP G&A expenses primarily increased due to an increase in professional services to support the development of ivonescimab. Overall, our non-GAAP operating expenses during the first quarter of 2025 were $55.7 million compared to $54.6 million for the previous quarter. The increase in non-GAAP operating expenses was primarily related to an increase in G&A expenses as noted above. And with that, I'll hand it back over to Dave.

Thank you, Bob, Maky, and Manmeet. We will now see if there are any questions that our team can help answer. Justin, please open the line for questions.

And the first question comes from the line of Salveen Richter from Goldman Sachs.

This is Mark standing in for Salveen. Congratulations on the quarter. I have a couple of questions regarding the upcoming HARMONi EGFR data set. I believe everyone will be focused on the subgroup data to see if Akeso's previous results from China are applicable in Western regions. What do you see as the benchmark for success in this scenario? How closely does the data need to align with HARMONi-A to validate its applicability? Additionally, regarding RYBREVANT's approval on MARIPOSA-2, what profile are you looking for from HARMONi, and what level of benefit do you think would persuade doctors to prescribe ivo in the second-line EGFR setting?

Thank you, Mark, for your question. I will say a few words and then turn it over to Jack West, our Thoracic Oncology lead. Regarding your first question, we do not intend to set a specific target or number that we are aiming to achieve. The key focus will be the consistency of the overall data package, particularly the alignment with data from China and ensuring global consistency. We do not want to establish a benchmark that would be part of our discussions with the agency. As for the second part of your question, I will pass that along to Jack.

This is Jack West. So I would comment that, obviously, the entire field of EGFR mutation-positive non-small cell has become much more complex over the last couple of years with a lot of new options but that still leaves plenty of open space for new choices. One would be that with the potential for amivantamab and lazertinib to be used in the first-line setting, that leaves a need for another option that is very appropriate for the HARMONi platform to fill. Obviously, that's not going to be everybody, and there's going to be patients who get osimertinib monotherapy or the FLAURA2 approach with a combination of chemotherapy and osimertinib. But obviously, amivantamab with chemo has a combination of efficacy with toxicity liabilities that looks very different from what chemo and ivonescimab offers. I have had extensive discussions with clinicians in all sorts of settings, academic and community-based. And there's really a strong sense that there is a value and a great need for alternatives that have a very different and potentially less challenging toxicity profile. Obviously, efforts are made in ways to ameliorate the toxicities with amivantamab, but there will always be a value in choices.

Our next question comes from the line of Yigal Nochomovitz from Citigroup.

Congrats on the very positive recent developments. My question also on HARMONi. Could you just be more specific in terms of what will we see with respect to the geographic data, meaning China versus ex-China patients? Are we going to be getting separate hazard ratios on PFS and OS for each of these geographies? Would it be something in the form of a forest plot? Or would it just be some kind of a more qualitative statement around potential comparability? That's my first question.

Thanks, Yigal. This is Dave. I think I would break that down into two points. One is the actual top line data, which tends to be a bit more qualitative. Major medical conferences will provide presentations that include more details. These will definitely offer some context regarding geographic breakdowns, and a forest plot is one way to achieve that. We'll make those final decisions, but the aim is to provide appropriate context regarding the differences between North American and European patients compared to those enrolled in China.

Okay. And then two more on HARMONi. With respect to timing, you consistently said mid-2025. Is it fair to assume that we would see HARMONi before we see HARMONi-2 and HARMONi-6 which you've alluded to would be at the fall medical meetings? And then also with HARMONi, what is your view on whether you need OS to be stat sig for a competitive filing in the United States?

Sure. The timing of the data releases will depend on which conference takes which presentation, particularly in the fall. It involves some strategic considerations regarding where and when to display the data. I can't provide a specific order for the presentations, but we anticipate top line data for HARMONi to be available by mid-2025. The ESMO conference is in October, so that data will come later. While I cannot specify which conference will host different data, we expect to have top line results before the end of Q3 or the beginning of Q4. Hopefully, that helps. Can you repeat your second question?

I was just curious about the relative importance of hitting on OS in HARMONi to have a competitive BLA filing.

Yes. I think at this point, it's important to say we have two primary endpoints. We want to be clear on that. I think the other piece becomes the totality of the package. Importantly, I'll ask Jack or Allen to add any context here. But in the second-line EGFR mutant non-small cell lung cancer space post the TKI, overall survival hasn't been seen at this point to show a statistically significant benefit in any regimen. And so that will be part of the context. But importantly, as you noted, we have two primary endpoints. So it will be a total package consideration there.

Yes, this is Allen Yang, Yigal. I don't have much to add except that historically, it hasn't been necessary to achieve overall survival to gain approval in this area. We certainly want to demonstrate a clear benefit for ivonescimab in this field. However, it's great for patients that there will be several options available to them, as Jack mentioned. Unfortunately, this is a palliative setting, so physicians will consider various factors such as efficacy and toxicity profiles when deciding on treatments.

And maybe if I could just squeeze one in, maybe for you, Allen, maybe Jack. Obviously, the Pfizer partnership for the ADCs is great. However, that one is missing some of the more perhaps relevant targets in non-small cell lung cancer, such as TROP-2 or HER2, HER3. So how are you thinking about that aspect of a longer-term strategy in lung cancer to combine potentially down the road with those types of ADCs?

Yes, Yigal, that's a great question. So again, I think the landscape of cancer is changing very quickly, which is terrific. I think Pfizer is a great partnership. They have a great pipeline of ADCs. We're not sort of wedded to the pipeline. We're open to it; ivonescimab is our only child really. And so we are open to other collaborations as well. And so we continue to follow the lung cancer landscape and we're open to whatever is the best treatment for our patients.

Yigal, this is Jack West. We have other combinations being evaluated and potentially developed in settings like ISTs and cooperative group efforts. We are open to a variety of options that will provide us with numerous combination opportunities.

Our next question comes from the line of Cory Kasimov from Evercore.

I'll stick to two of them. I guess, first one is for HARMONi-2; you obviously showed pretty profound PFS benefits across all cuts of the data and histologies, everything else. Would you expect that to broadly hold for overall survival as well? And then I have a follow-up.

Cory, great question. This is Dave. At this point, the only data that's been released publicly from our partners at Akeso has been the top line hazard ratio for HARMONi-2. So to your point, you are correct in the consistency of the PFS data within HARMONi-2. But I don't want to get in front of our partners in terms of data release with respect to subgroups or anything like that but going beyond the top line overall survival hazard ratio that they provided.

Okay. Understood. And then a question we get a lot. I wanted to ask you is, do you expect safety trends in the global population, whether it's the HARMONi study or some of your follow-on ones to match what's been seen in the data sets coming out of China? What would be the rationale as to why it could be different?

So Cory, I just want to make sure I understand your question. You're asking for the rationale in terms of why the data would be different between China and...

Yes, this is Jack West. I would say the main concerns for clinicians will be serious bleeding issues or straightforward questions that wouldn't allow for much interpretation. The data we've seen has been solid enough that any significant divergence from what has been observed in larger trial settings would need to be quite notable moving forward.

Okay. Yes, we found the safety language in the Akeso press release on HARMONi-6 to be very reassuring. But that answer is very helpful.

Our next question comes from the line of Kelly Shi from Jefferies.

Congratulations on the progress. My first question is about the HARMONi-3 trial, specifically the chemotherapy combination trial in the frontline setting. Do you have enrollment targets for squamous versus non-squamous patients? Will the enrollment be expected to be evenly split between the two subtypes? I also have a follow-up question.

Yes. We do have sort of enrollment objectives for both the pathologies so that we would have enough scientific information to have an informed decision on both histologies. We haven't disclosed the exact numbers and they're not precise. They are sort of ranges of the expectations. So there will probably be equal amounts of squamous and non-squamous at the end of the study.

Great. And also for HARMONi-7, the global trial running by Summit in the PD-L1 positive patients, what kind of a median overall survival benefit in terms of how many months of improvement over PD-1 would be considered transformative and replace PD-1 standard of care in this frontline setting?

Kelly, this is Dave. I would just want to say we haven't given our statistical plan yet in terms of this. I'll let the physicians comment on the clinically meaningful threshold and whatnot. But in terms of what we're like gearing the trial for and whatnot, that's not necessarily a plan we've given. The only thing I would say from a top line perspective, I think we've been pretty clear publicly that as we look at overall survival being around or under the 0.80 hazard ratio has been a focus for us. But I'll let Jack, if there's anything else or Allen, you want to add to that?

Yes, this is Jack West. I believe Dave emphasized all the key points. Generally, if the trial is statistically significant, it is very likely to also be clinically significant and could lead to changes in the standard of care. The statistical plan will probably be more rigorous than what clinicians or patients typically consider a clinically meaningful improvement. Generally, most clinicians expect at least two to three months of improvement in overall survival. This is not specific to this trial but serves as a general benchmark for practice changes.

Yes. I'll just underscore what Jack said, that we haven't really released those specifics around our statistical analysis plan. But if the HARMONi-7 study is positive as designed, it would be very clinically meaningful and an important change in the standard of care. I'd also add, like if you look at the HARMONi-2 data presented to date, if those numbers hold up, I think that's very clinically meaningful and important data.

Our next question comes from the line of Asthika Goonewardene from Truist Securities.

This is Karina for Asthika. Congrats on the progress. First one is, when do you guys expect the Chinese NMPA label to be publicly available by Akeso for HARMONi-2? And have you seen what the OS curves look like? And since it's now approved in China, can you tell if they show consistent or widening separation over time?

Karina, this is Dave. Regarding the availability of the label from the NMPA, the process differs somewhat from what we see in the U.S. It's not usually published on the FDA website like in the U.S. Instead, it becomes part of the next shipment of the physical product as the official update. However, it typically becomes available in a shorter timeframe than that. Could you please repeat your second question, Karina?

Yes. If you've seen the OS curves, what they look like since it's already approved in China, can you tell whether they're consistent or they're widening over time?

Yes. Similar to what I mentioned earlier, this is Dave again. The trial was sponsored and conducted by our partners at Akeso, so we will allow them to release the information regarding their clinical trials. We won't discuss specifics that have not yet been disclosed publicly. However, I appreciate the interest, and that information will likely be shared when they choose to do so at a medical meeting or another event.

And also one more on HARMONi-3. Have you guys had discussions with the FDA about leveraging project front-runner for accelerated approval?

In general, we don't usually delve too deeply into our discussions with the agency as we want to respect their processes. We have had multiple conversations with them regarding HARMONi-3 to ensure our trials align with their feedback. However, we prefer not to go into the specifics of those discussions. Thank you for your question.

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

Congrats on all the progress. I have two questions. I'll ask one by one. So regarding HARMONi-2, is it fair to assume that the majority of the OS events would have happened only among the low PD-1 patients given that OS for Keytruda tends to be significantly longer for PD-1 high patients and by extension, ivonescimab?

Mohit, this is Dave. I very much appreciate that question in the sense of the expectation that you set there and your baseline comment is true in the sense of the difference in the medians on the pembrolizumab side. But at this point, that becomes kind of a subgroup analysis piece. And so again, we'll defer to our partners at Akeso in terms of the timing of the detailed releases there.

Got it. Okay. So let me ask you the other one. I appreciate that. So look, I mean, in the lung cancer, especially non-small cell lung cancer, you are going after an indication where pembro is pretty strong. Are there other indications where the delta for VEGF/PD-1 combination could be much more pronounced versus a PD-1 inhibitor, where VEGF could add a lot more value than just lung cancer? And where are you in terms of pursuing those indications outside of lung cancer?

Thanks, Mohit. Yes, I’ll address the first part and then pass it to Allen for further details. I would point you to the ESMO 2024 Phase II data released by Akeso. There are specific tumor settings where PD-1 inhibitors have historically faced challenges. Examples include microsatellite stable colorectal cancer and low or negative PD-L1 triple-negative breast cancer. Regarding the specifics of our development plan, as Maky mentioned earlier, we plan to provide more context throughout this year rather than releasing details gradually. We also want to ensure we have the right alignment with the regulatory agencies. Allen, would you like to add any further insights?

No, I think it's a good question. Again, we've sort of boiled the ocean. We've looked at the PD-1 approvals. We've looked at the VEGF approvals. And then there's clearly tumors where the VEGF and PD-1 activity overlap, and we're looking at those. The thing to consider about that is what would be the control arm for that study, and what regions are those tumor types more prevalent in? And I think you can sort of guess what I'm alluding to if you look at the specific tumor types. And then what is the Phase II data that Akeso generates? That's probably the most important thing in how we're thinking about which tumor types to go into next. So we do have a very clear plan of where we want to go next and we're very excited about the ivo data, and all of those considerations, including the PD-1 and VEGF activity, are taken into consideration.

I would just potentially add that in addition to specifically the VEGF component, the cooperative binding is relevant here that if we look at settings where we've demonstrated success, you have EGFR mutation-positive. It's a setting, yes, where VEGF may be particularly relevant. It's also a setting where other PD-1 inhibitors have not proven successful. You can also look at HARMONi-2 and see that in the setting of high PD-L1 where pembro has been very favorable, we also saw great success for ivo relative to pembro but also see benefit for ivonescimab in the low PD-L1 setting against pembro where pembro has not been as commanding of a choice. And so I think that can be extrapolated potentially into other settings, whether that is because specifically of the VEGF component that it brings but it also may be because of the cooperative binding that may render ivonescimab a more effective immunotherapy.

Next question comes from Mitchell Kapoor from H.C. Wainwright.

Congrats on the recent progress. I wanted to ask, so the NMPA granted the first-line approval in PD-L1 positive non-small cell lung cancer patients in China based on HARMONi-2. But I wanted to understand what it's going to take to get approval in the PD-L1 low patients. Why didn't they grant this approval? Did they indicate anything like they need to see more data? Or is that indicative of anything they're seeing in the HARMONi-2 trial so far?

Mitchell, it's Dave. Let me clarify that because I just want to make sure this is clear. So in - so we generally break down PD-L1 expression by negative, less than 1, low 1 to 49 or high 50 plus. And then in the case of HARMONi-2, when we say PD-L1 positive, that was really 1 plus, if you will. So the high and the low but not the negative. So the approval, as we understand it in China from the NMPA was in PD-L1 positive. So PD-L1 expression greater than 1, if you will, if you use the TPS scoring system. And so that is what the HARMONi-2 trial was designed as PD-L1 positive. For HARMONi-7, because of the standard of care in the Western markets, our trial is designed as a PD-L1 high expressing patient population. Just want to clarify and make sure that's clear, Mitchell.

Yes. Sorry. So what I meant to ask is the PD-L1 negative patients, is there something that needs to be shown there that would be able to gain approval in that population?

That aspect wasn't included in the HARMONi-2 study. What would be necessary to demonstrate is essentially a separate trial, for lack of a better term. Additionally, it's crucial to note that the HARMONi-6 data announced by Akeso relates to all-comers for PD-L1. This means it involves patients who are PD-L1 negative or have less than 1% according to the TPS score. This study focuses on a chemotherapy combination. Now, I'll let Jack provide further comments. However, when considering the PD-L1 negative population, it aligns more with chemotherapy combinations or something similar to either our HARMONi-3 for squamous and non-squamous or Akeso's HARMONi-6, which is exclusively for squamous.

Yes, I believe Dave explained it very well. HARMONi-2 does not address that population. It simply does not clinically cover it, but HARMONi-6 and our own data from HARMONi-3 will encompass the entire spectrum of metastatic and advanced non-small cell lung cancer.

Yes. And this is Allen, Mitchell. So just to be clear, there is some variability in what physicians do based on the PD-L1 expression levels. But to be clear, HARMONi-3 and HARMONi-7 will cover the whole gamut of metastatic and advanced non-small cell lung cancer.

Perfect. I appreciate that. Lastly, can you provide any updates on HARMONi-2? I understand the nominal alpha, but will the p-value be reported alongside that nominal alpha level?

Just to make sure I'm clear, Mitchell, are you asking when the next analysis would be or when the more detailed data for the NMPA requested analysis would be?

Sorry, yes. So basically, the next overall survival update, obviously, the 39% data maturity. But at the next update, would we be able to see the p-value in addition to that nominal alpha level trying to search for statistical significance?

Yes. I think part of this depends on the decision made by Akeso regarding their trial. The next analysis will likely involve more planned analysis with a focus on intent, which means we would have more mature data. This should also lead to increased alpha spending associated with that data.

Our next question comes from the line of Eric Schmidt from Cantor Fitzgerald.

One on HARMONi and one on HARMONi-2. First, on HARMONi, when we see the data in mid-2025 on overall survival, will that OS result be a mature one? And what is required via your conversations with the FDA around the U.S. approval, either in terms of what you need to see with OS or PFS in the Western population?

Yes. I think, Eric, this is Dave. I believe what we mentioned earlier still stands regarding not delving into the specific details of our discussions. However, I want to remind you that we have two primary endpoints. Ultimately, it will be reviewed as a total package, regardless of the decisions made. I think I'll stop there.

And the OS maturity?

We haven't commented on that, Eric. What we've indicated is that we will have data related to both primary endpoints. However, we haven't disclosed the specifics regarding the maturity of different points. We do anticipate data on both endpoints.

Great. Second question on the HARMONi-2 HR that you've given 0.7777 the pre-interim analysis, let's call it. I guess the number one question I get is whether with time, that hazard ratio is likely to mature in a favorable or unfavorable direction? Do you have a view on that?

Sure. I think it's important to note that there is a bit more variability at the lower side of maturity. However, I wouldn't expect it to move in only one direction. It's also crucial to avoid drawing direct comparisons from the HARMONi-A data, which we've heard some discussion about regarding the initial NMPA request that reported a hazard ratio of 0.72 followed by a 0.80 on overall survival. There are significant differences between these trials, such as second line versus first line, EGA positive versus EGFR specific, and whether they involve chemotherapy or are monotherapy. Overall, while we've seen fluctuations in PD-1 inhibitors, it's encouraging to see a clinically meaningful positive trend so early in the maturity process. Jack, do you have anything to add?

I would add that in my extensive discussions with clinicians since the initial release, they do not view the overall survival as strictly binary, particularly when considering early preliminary data. They recognize that this is compared to pembrolizumab, which is a highly respected treatment with proven effectiveness. Thus, observing a hazard ratio of 0.78 or better against an active and well-regarded comparator, while not demonstrating significant differences in toxicity, is something that clinicians are very receptive to and view positively. This is true both for this specific context and for its potential implications beyond this particular monotherapy test in PD-L1 positive cases. Given the wide-ranging application of pembrolizumab historically in lung cancer and other areas, showing improvement with a hazard ratio below 0.8, especially in preliminary data, has truly captured attention. They are not deterred by any statistical challenges or the preliminary nature of the data. Generally, clinicians are quite impressed and satisfied with these results.

And our last question comes from the line of Ren Benjamin from Citizens.

I guess, one, in the HARMONi study, is the PFS and OS going to be evaluated as a co-primary endpoint? Or as Maky mentioned, with HARMONi-3 and 7 dual endpoints? And can you remind us why you would favor, let's say, one over the other? And a more broader question, just given recent geopolitical tensions, can you kind of give us your thoughts on how you're thinking about the potential impact of tariffs, how you're thinking about manufacturing, and any IP and API-based scenarios?

Yes. Thanks, Ren. So for the first question, I think we look at it more as dual primary endpoints in terms of passing the alpha in hierarchical testing, PFS first and then OS. With respect to the second question, I will hand that over to Manmeet to speak to.

Sure. This is Manmeet. On the manufacturing side, we currently have our supply source from our partner, Akeso. Additionally, we have made significant progress in transferring knowledge to certain contract manufacturers in the U.S., Europe, and other regions, which is ongoing. This addresses our concerns regarding manufacturing. Concerning intellectual property, we are confident as our IP extends until late 2039 and into the 2040s, so we have no worries on that front either.

And just as a follow-up, I mean, the manufacturing from the CDMOs, will that product find its way into the HARMONi-3 and HARMONi-7 trials so that upon potential approval, this is going to be quite kind of seamless in terms of utilizing the material? Or will there need to be a bridging study? How do we think about that?

No, it's similar to what any manufacturer or pharmaceutical company will do, as they typically have multiple sources of production, and we are planning to add more. Akeso is one of the sources, and we will also have another source from our contract manufacturers. Regulatory filings will be necessary to compare the production batches and ensure they align with the specifications. Initially, these will be used for clinical supplies, which is a standard practice among pharmaceutical companies.

There are no further questions. I turn the call back over to Dave Gancarz for final remarks.

Thank you, Justin. And thank you, everyone, for the amount of interesting questions. I think the last thing I'd like to do just to make sure we fully address is I'll hand it over to Jack West for just given his extensive experience, obviously, in thoracic oncology and whatnot. Any final comments, Jack, that you have with respect to the announcement with respect to the hazard ratio and the overall survival of the early look for HARMONi-2.

I have had the opportunity over the last few months to have numerous conversations with various experts in thoracic oncology. Some of the most pressing questions regarding ivonescimab, especially after a successful year, focus on its performance outside of China. We will receive information on this in the coming months, as well as whether the benefit remains when combined with chemotherapy, and how the addition of chemotherapy influences the differences in both treatment arms. HARMONi-6 is set to explore this, and we already know that the results are favorable and are clearly not due to monotherapy. Another important question that we can partially address with HARMONi and HARMONi-2 revolves around progression-free survival to overall survival, which is always a concern in lung cancer and other types of tumors. This has been particularly challenging with VEGF inhibition. My colleagues and I have considered that irrespective of the specific p-value, particularly early on and in a trial like HARMONi-2—which was not designed to evaluate overall survival—the key detail is whether the hazard ratio for overall survival following the observed progression-free survival will be around 0.7 or 0.9. That has been my consistent message. No one knew where it stood until the recent press release confirmed it is in the 0.7 range. This is what people have been wanting to understand — whether the results align or not, and they absolutely do. To me, this answers that question and alleviates many concerns. We will provide more detailed information soon, but at a high level, this is what we aimed to clarify regarding whether it holds up or not. While we expect some erosion with subsequent treatments, my colleagues and I have specifically been looking for a 0.7 value, which is exactly what we were hoping to see.

Really appreciate it, Jack. And I want to take the time to thank everybody for attending today's earnings call. We are unfortunately out of time now at this point but I want to say thank you, and an archived version of this webcast will be available on our website. Thank you very much, and enjoy your evening.

The meeting has now concluded. Thank you all for joining. Have a pleasant day, and you may now disconnect.