Summit Therapeutics - Earnings Call - Q4 2024

Executive Summary

• Q4 2024 was a pivotal execution quarter: Summit announced a clinical trial collaboration with Pfizer to evaluate ivonescimab with multiple vedotin ADCs (trials expected to start mid-2025), advanced Phase III programs (HARMONi enrollment complete; HARMONi-3 expanded to include non-squamous), and activated initial HARMONi-7 sites in the U.S.
• Balance sheet strengthened: cash and short-term investments ended Q4 at $412.3M; management stated the company is debt free, having paid $31.8M in principal and interest in Q4 2024.
• Q4 P&L stepped up with ongoing trial expansion: GAAP operating expenses were $65.8M; GAAP net loss was $(61.2)M; GAAP EPS was $(0.08). Non-GAAP operating expenses were $54.8M; Non-GAAP net loss $(50.2)M.
• Catalysts into mid-2025: topline HARMONi (global Phase III EGFRm post-TKI) results expected mid-2025, with FDA Fast Track designation already granted for this setting; management reiterated plans to expand development beyond NSCLC via ISTs and MD Anderson collaboration.
• Estimates comparison unavailable: S&P Global consensus estimates for Q4 2024 (EPS, revenue) were not available through our data service at this time; thus no beat/miss determination can be made.

What Went Well and What Went Wrong

• What Went Well

  • Expanded HARMONi-3 to include non-squamous histologies, significantly increasing the addressable first-line NSCLC population in the U.S.; enrollment for non-squamous began in the U.S. and squamous enrollment continues globally.
  • Strategic acceleration via Pfizer ADC collaboration: “Clinical trials associated with this collaboration are expected to start by the middle of this year” and Pfizer will run operations and cover associated costs, with Summit providing ivonescimab.
  • Balance sheet/financial execution: “We have paid off our debt… and now we are debt free,” enabling execution of Phase III trials without leverage risk.

• What Went Wrong

  • Operating expenses rose with trial expansion and stock-based comp, lifting quarterly GAAP OpEx to $65.8M and GAAP net loss to $(61.2)M; Non-GAAP OpEx increased to $54.8M and Non-GAAP net loss to $(50.2)M.
  • Estimates benchmarking unavailable; inability to contextualize earnings against Street (S&P Global) limits near-term performance framing versus expectations.
  • Continued cash burn inherent to late-stage development: FY 2024 net cash used in operating activities was $(142.1)M, reflecting increased clinical activities around ivonescimab.

Transcript

Operator (participant)

Good morning and welcome to Summit Therapeutics' fourth quarter and year-end 2024 earnings and update call. All participants will be in listen-only mode until the question-and-answer portion of this call. We do not expect any technical difficulties today. However, in the event that we lose this webcast connection and are unable to provide any updates, please wait up to 10 minutes for resolution. Please refer to the company's website for updates. Please note that today's call is being recorded. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to address your question, press star one again. Thank you. At this time, I would like to turn the call over to Dave Gancarz, Summit Therapeutics' Chief Business and Strategy Officer. You may proceed.

Dave Gancarz (Chief Business and Strategy Officer)

Good morning, and thank you for joining us. Two press releases were issued earlier this morning and are available on the homepage of our website. Our Form 10-K was also filed earlier this morning and is available on our website. Today's call is being simultaneously webcast, and an archived replay will also be made available later today on our website, www.smmttx.com. Joining me on the call today is Bob Duggan, our Chairman of the Board and Chief Executive Officer; Dr. Maky Zanganeh, our Chief Executive Officer and President; Manmeet Soni, our Chief Operating Officer and Chief Financial Officer; and Dr. Allen Yang, our Chief Medical Officer. Before we get started with the rest of the call, I would like to note that some statements made by our management team and some responses to questions that we may make today may be considered forward-looking statements based on our current expectations.

Summit cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Please refer to our SEC filings for information about these risks and uncertainties. Summit undertakes no obligation to update these forward-looking statements except as required by law. Following comments from Bob, Maky, and Manmeet, we will take questions. With that, I will turn the call over to Bob.

Robert Duggan (Chairman and CEO)

Thank you, Dave. Good morning, everyone, and thank you for joining us today. I am very pleased with recent accomplishments of Team Summit and the accelerating positive information and enthusiasm surrounding ivonescimab, our lead investigational asset. In Q4 of last year and to date in 2025, we have reached several meaningful milestones around the development of Ivonescimab, importantly with our partners in China as well as here in the U.S. and Western markets. We continue to progress towards our mission of building an organization making a significant positive difference in serious unmet medical needs. Specifically, earlier today, we announced a clinical trial collaboration with Pfizer, which will evaluate ivonescimab in combination with multiple Pfizer antibody-drug conjugates, or ADCs, in unique solid tumor settings.

Rapidly developing novel mechanisms that go beyond what is currently available to patients and physicians is what we believe will make the most significant impact for those facing the greatest challenges from cancer today. We believe this collaboration with Pfizer will accelerate the advancement of potentially landscape-changing therapeutic combinations, which intend to improve the standards of care for patients facing serious unmet needs. Clinical trials associated with this collaboration are expected to start by the middle of this year. In October of last year, we completed enrollment in and received Fast Track designation for Harmony, 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, or TKI. Top-line data from ivonescimab's first global registration of phase III trial Harmony is expected in mid-2025.

Additionally, in October of last year, we announced a study amendment to the Harmony III protocol, expanding the study to include patients with both squamous and non-squamous histologies. With this amendment, Harmony III is a multi-regional registrational phase III trial assessing ivonescimab as first-line treatment for patients with metastatic non-small cell lung cancer with both squamous and non-squamous histologies. Enrollment is ongoing globally for patients with tumors of squamous histology, and we have begun enrollment in patients in the United States with non-squamous tumors. Harmony III now addresses a patient population two to three times larger than prior to the amendment, significantly expanding the numbers of patients with cancer that Ivonescimab can potentially help. Towards the end of the year, we announced our third global phase III trial, Harmony VII, would be initiated in early 2025.

Initial trial sites have begun activating in the United States, and Harmony VII continues to progress as planned. As a reminder, Harmony VII is evaluating Ivonescimab monotherapy against pembrolizumab monotherapy in first-line metastatic non-small cell lung cancer patients whose tumors have high PD-L1 expression without actionable genomic alterations. Maky will further discuss these accomplishments, including additional strides taken to drive our continued belief in what could be accomplished by Team Summit, as well as our conviction in the potential of Ivonescimab in non-small cell lung cancer and, very importantly, indications beyond lung cancer. We are a mission-driven organization with an overriding patient goal to improve quality of life, increase potential duration of life, and resolve serious medical needs. We are the right team, and we believe we have the molecule in Ivonescimab to realize this goal.

With that, I will turn the call over to Maky for additional context and recent highlights for consideration. Maky.

Maky Zanganeh (CEO and President)

Thank you, Bob, and good morning, 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. Before providing some additional detail and reviewing the current pipeline, I would like to touch on the clinical work that has been conducted with Ivonescimab and some of the interest and recognition received last year. Since first entering the clinic with our partner, Akeso, back in 2019, more than 2,300 patients have been treated in clinical trials with Ivonescimab. In 2024 alone, Ivonescimab was featured in 14 publications across seven tumor types and selected for five oral presentations at major medical conferences. Currently, between our partners at Akeso and our team at Summit, four Phase III trials have been completed enrollment, two of which are awaiting top-line data readout, including the Summit-sponsored Harmony trial.

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 start a clinical study in pancreatic cancer later this year. A significant amount of additional data is being generated in additional indications, including colorectal cancer, ovarian cancer, gastric cancer, and hepatocellular carcinoma, in addition to more data to support the lung cancer program. Turning specifically to the Summit-sponsored pipeline, as Bob mentioned last quarter, Harmony completed enrollment in the fourth quarter with top-line data expected in mid-2025. This data is expected to contain data for both primary endpoint, progression-free survival, and overall survival.

Harmony III was amended by significantly expanding the addressable patient population to include all front-line metastatic non-small cell lung cancer patients without driver mutations by including patients with non-squamous tumors in addition to squamous tumors. Squamous tumors represent approximately 25%-30% of non-small cell lung cancer in the United States, with non-squamous tumors representing a large proportion of the rest. As a reminder, this trial includes patients with tumors that are PD-L1 negative, PD-L1 low expressing, and PD-L1 high expressing. We announced our intention to initiate Harmony VII in early 2025, for which we have begun to activate clinical trial sites in the United States. Later this year, we expect to announce additional details around expanding our clinical development plan around Ivonescimab, specifically beyond lung cancer.

After receiving interest from more than 75 investigator-sponsored trials in the most recent open window, we have approved over 30 ISTs to date, which will either enhance our sponsored clinical development activities or can show signals in settings where Ivonescimab has not yet had the opportunity to explore. In 2024, we started our collaboration with MD Anderson, which now has studies that are activated and open for enrollment in Houston. We have committed $15 million to this collaboration to quickly discover additional opportunities for Ivonescimab, including several tumor settings outside of its current development plan, as well as the possibility of identifying biomarkers through additional research activities. Finally, as we announced this morning, our clinical trial collaboration with Pfizer will look at Ivonescimab in combination with several Pfizer Vedotin-based ADCs in multiple tumor types.

As we seek to accelerate the development of Ivonescimab across non-small cell lung cancer and other solid tumor settings, this collaboration would allow us to quickly advance beyond our promising late-stage development plan to evaluate Ivonescimab in combination with some of the most innovative ADCs from Pfizer. Clinical trials as part of this collaboration are expected to start mid-2025. Pfizer will be responsible for the operations and costs associated with these trials. We will provide Ivonescimab and jointly oversee the study. As a reminder for those new to the Summit story, Ivonescimab has a significant lead in the clinical development of this novel class of compound. Ivonescimab brings two highly validated targets together into one novel bispecific antibody that targets both PD-1 and VEGF. Next, I would like to review upcoming catalysts for this year and beyond.

As we touched on a moment ago, we are expecting Harmony top-line data in mid-2025, which we expect will include both primary endpoints of progression-free survival and overall survival. This will be the first global phase III clinical trial readout for Ivonescimab, which provides a potential path to applying for marketing authorization in our territories, including potentially the United States. Secondly, we intend to expand our sponsored clinical development plan to go beyond non-small cell lung cancer in 2025 and 2026, in addition to continuing engagement with a rapidly increasing number of investigators seeking to conduct investigator-sponsored trials at various institutions across a large number of different tumor types. And you will see continual activation of additional ISTs in a variety of solid tumor settings.

This is in addition to Akeso continuing its execution of its phase III studies, including completing the enrollment of Harmony VI in front-line squamous non-small cell lung cancer with Ivonescimab combined with chemo, as well as continuing the enrollment of its phase III biliary tract cancer, triple-negative breast cancer, and head and neck cancer studies. Over the course of this year, we will continue to see clinical trial data readouts from Akeso in a variety of tumor types. And finally, we expect to see more phase III initiations from Akeso in non-small cell lung cancer and beyond, likely in indications in which phase II data has been generated, which we touched on earlier. We are excited for the catalyst-rich path ahead of us, our conviction, and belief in the potential for Ivonescimab to improve patient lives for the better remain strong and consistent.

Now, I would like to take a moment to review study design for our two ongoing global phase III trials, Harmony II and Harmony VII. Here we have the study design for Harmony III. Harmony III is a randomized, double-blind, global phase III clinical trial evaluating Ivonescimab in combination with chemotherapy against pembrolizumab 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 histologies with no activating genomic alterations regardless of PD-L1 expression, including high, low, and negative PD-L1 expressing tumors. Dual primary endpoints for Harmony III include progression-free survival and overall survival, and results will be stratified by squamous and non-squamous histology. Next, we have the study design for Harmony VII.

Harmony VII is a randomized double-blind global phase III clinical trial evaluating Ivonescimab monotherapy against pembrolizumab monotherapy as first-line treatment for the metastatic non-small cell lung cancer patients with tumors with high PD-L1 expression. Dual primary endpoints for Harmony VII include progression-free survival, overall survival, and results will be stratified by squamous and non-squamous histologies. As a reminder, our Harmony VII study shares similarity with Akeso-sponsored Harmony II phase III trials, which reported data last year, but specifically targeted the PD-L1 high expressing tumors consistent with the standard of care for monotherapy immunotherapy in the U.S. and Europe. Turning to the market opportunity for Ivonescimab, the value proposition here is clear. 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.

Specifically, in non-small cell lung cancer, there are a combined six announced or ongoing Phase III studies conducted by either Akeso or Summit. Non-small cell lung cancer alone has an addressable market that could ultimately approach $20 billion for checkpoint inhibitors, according to the third-party research from the likes of TD Cowen and others. But this is just the start. There are more than 50 indications where PD-1, PD-L1, or VEGF therapies have been approved. Ivonescimab will continue to be rapidly tested and developed beyond non-small cell lung cancer across all checkpoint inhibitors indications. The addressable market approaches $90 billion globally in the next couple of years, according to IQVIA Research.

However, this still excludes the full impact that Ivonescimab could have, where it has shown promising data in multiple tumor types where checkpoint inhibitors have not been effective, including microsatellite stable colorectal cancer, PD-L1 low negative triple-negative breast cancer, and EGFR mutant non-small cell lung cancer after targeted therapy. We are excited to continue to progress our development in non-small cell lung cancer in 2025. Additionally, data shared in 2024 showed that Ivonescimab has a market potential much larger than non-small cell lung cancer and our current ongoing global phase III clinical studies that we are sponsoring at Summit.

There are multiple phase II trials that have been conducted, providing encouraging data to continue to explore Ivonescimab and its opportunity to become a standard of care across several solid tumor settings, which we intend to continue to explore with the goal to improve the lives of as many patients as possible facing high unmet medical needs. I would also like to take the opportunity to thank, most importantly, the patients in our clinical studies, as well as our investigators, hospitals, including our collaborators at MD Anderson and our partner in China, Dr. Michelle Xia, and the entire Akeso team, as we continue to pave the way for rapid development of Ivonescimab globally. And of course, the Summit team.

As Bob and I look back on all of the many achievements over just the past two years, Team Summit has done a tremendous job across every department in making our goals a reality and appropriately condensing time when and where possible. We continue to look at opportunities to accelerate our timeline in bringing additional therapeutic options to patients with high unmet cancer needs. It's an honor and privilege to work with each member of Team Summit, and I would like to express my heartfelt thanks to every one of our team members. With that update, I will now ask Manmeet to provide details on our financial position and operations update.

Manmeet Soni (COO and CFO)

Thank you, Maky Zanganeh, and good morning, everyone. This morning, we issued our earnings release for the fourth quarter and year-ended 2024.

Today, in addition to providing you with an update on our cash position and operating expenses, I will also be providing an update on our progress on clinical trial enrollment on Harmony III, Harmony VII, and an update on tech transfer for manufacturing in our licensed territories. On the financial front, let me start with our cash position. We ended the year 2024 with a strong cash position of approximately $412 million. Let me remind you that we have paid off our debt in entirety, and now we are debt-free. With a strong cash position and zero debt, we are well-positioned to continue to execute on our clinical trials. Turning to operating expenses, I will be providing details to both GAAP and non-GAAP measures. You can refer to our press release issued this morning for a reconciliation of GAAP to non-GAAP financial measures.

Just to remind you, non-GAAP expenses exclude stock-based compensation expense. Our GAAP R&D expenses during the full year 2024 were $150.8 million, compared to $59.4 million for the previous year. And non-GAAP R&D expenses were $134.8 million during the full year 2024, compared to $55 million for the previous year. The increase in the R&D expenses reflects the expansion of our clinical trials related to ivonescimab. Our acquired in-process R&D expenses during the year 2024 were $15 million, compared to $520.9 million for the previous year. To remind, acquired in-process R&D expenses for the year 2023, which were $520.9 million, were related to the upfront payments made to Akeso for the licensing agreement. And $15 million expense in the year 2024 is related to the amendment of the licensing agreement with Akeso to include Latin America, Middle East, and Africa regions into our licensed territory.

Our GAAP G&A expenses during the full year 2024 were $60.5 million, compared to $30.3 million for the previous year. Non-GAAP G&A expenses were $25.5 million during the full year 2024, compared to $20.6 million for the prior year. Our GAAP G&A expenses primarily increased due to an increase in the stock-based compensation charges related to achievement of certain market conditions on performance milestones which vested during 2024. Overall, our non-GAAP operating expenses during the full year 2024 were $175.3 million, compared to $596.5 million for the previous year. The decrease in non-GAAP operating expenses was primarily related to the decrease in acquired in-process R&D expenses, as mentioned earlier, which were offset by the increase in R&D expenses due to the expansion of clinical studies and development costs related to Ivonescimab.

To remind that last quarter, we announced that we plan to expand Harmony III study to include non-squamous patients in addition to the squamous patients. I'm very pleased that our Summit team was able to activate non-squamous arm in a record time, and we recently started enrolling patients for non-squamous in the United States. We expect to start activating sites to enroll non-squamous patients in other regions during the second quarter of 2025. We continue to enroll squamous patients in all the territories. Additionally, during last quarter, we had given guidance that we will initiate our newly announced global trial, Harmony VII, in front-line non-small cell lung cancer for PD-1 high patients in early 2025. Ahead of our schedule, Team Summit has already begun to activate sites in the United States. We expect to initiate activating sites in the other regions during the second quarter of 2025.

Turning to tech transfer for manufacturing, we continue to make progress in transferring relevant know-how to third parties to establish additional supply sources in our licensed territory, and with that, I will hand it back over to Dave. Dave.

Dave Gancarz (Chief Business and Strategy Officer)

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

Operator (participant)

At this time, I would like to remind everyone, in order to ask a question, press star, then the number one on your telephone keypad. We will pause for just a moment to compile the Q&A roster. Your first question comes from the line of Yigal Nochomovitz with Citi. Please go ahead.

Yigal Nochomovitz (Analyst)

Hi, great. Thank you so much for taking the question.

Obviously, we're getting a lot of inbounds on Harmony II, and Akeso has provided some comments on the timing of the OS. If you could help us understand what you believe to be the timing for the Harmony II OS, and given the fact that it may be approved in China as early as the third quarter of this year for the second indication for front line, what is the potential, or is there any expectation that we could see a glimpse of some early OS data in that China label? Thank you.

Dave Gancarz (Chief Business and Strategy Officer)

Thanks, Yigal. And this is Dave. So appreciate the question, and I know there's a bit of commentary with respect to Harmony II. As our partners at Akeso have mentioned, they expect to reach the number of events required for their interim analysis by the end of the year 2025.

We ultimately don't have more information on that front other than continuing partnership with Akeso. But at this point, there's been nothing new on that front with respect to any additional information. But appreciate the question.

Yigal Nochomovitz (Analyst)

Okay. No worries. And then on the second-line EGFR, the Harmony trial, I think Maky mentioned you will have the OS data in the top-line readout. What is your understanding as to whether you need that to be only a trend or actually hit on statistical significance in order to be in a good position for approval in the U.S.? Thank you.

Allen Yang (Chief Medical Officer)

Yeah, Yigal. This is Allen Yang. Thanks for the question. So I think there's two things. I think we would, of course, want to hit OS and be statistically significant.

However, if you look at the precedents of previous approvals in this space, they have not required OS. PFS has been adequate.

Yigal Nochomovitz (Analyst)

Okay. And then I know Manmeet just mentioned that you're starting to add the patients for non-squamous in the second quarter for Harmony III. Is there any possibility you could provide even a rough guideline as to the timing for the top-line readout for Harmony III? And if you can't do that, anything you can say around Harmony VI, given that's possibly helpful in terms of a read-through to Harmony III? Thank you.

Manmeet Soni (COO and CFO)

Yeah. Hey, Yigal. This is Manmeet. You heard it correct, right? We have just initiated our sites in the U.S., and we have started enrolling for U.S., the non-squamous arm.

It's too early to give clarity on the completion of the enrollment until we complete all the sites in other territories, which is obviously in Europe and other regions, which we plan to initiate. We would be able to provide once all those sites are activated, and we have a quarter or two of the run rate, then we will have clarity in our timelines over there. Related to Harmony VI, you're also correct, right? That trial has been completed enrollment, which was fully in China in the squamous arm. And what I believe, as per the guidance from Akeso, that should read out sometime in the middle to end of this year. We don't have visibility into any more details further than that.

Yigal Nochomovitz (Analyst)

And then the last quick one, I would be remiss if I didn't ask you about the news this morning on the Pfizer collab.

Anything you could say there in terms of additional details? Which of the Vedotin ADCs, what tumor types, how big would these early studies be, and things of that nature? Thank you so much.

Dave Gancarz (Chief Business and Strategy Officer)

Yeah. Thanks, Yigal. This is Dave. Really appreciate the interest there. I think so what we've said this morning, multiple ADCs from Pfizer. We plan to go into multiple solid tumor settings and expanding that beyond just non-small cell lung cancer, obviously. We haven't given specifics in terms of which ones just yet, but they are likely to be phase 1b/2 level trials at this point. These are the first combinations that we'll do with Ivonescimab in these specific ADCs. So normal course operations there. But we'll give additional details as we get closer. But we are very excited to get moving here.

I think, as we've mentioned before, this is one of the strategic advantages that we feel we have in terms of the opportunity to combine ivonescimab with a number of different products from a number of different organizations, pharmaceuticals and biotechs. And so this is one of the first steps in terms of moving forward from that perspective. But we will be giving additional details as we continue to get closer to the beginnings of these trials, which are expected in the middle of this year. So short-term from that perspective.

Yigal Nochomovitz (Analyst)

All right. Thank you very, very much.

Dave Gancarz (Chief Business and Strategy Officer)

Thanks, Yigal.

Operator (participant)

Your next question comes from the line of Brad Canino with Stifel. Please go ahead.

Bradley Canino (Analyst)

Good morning. Thanks for the questions.

In the Pfizer ADC collaboration, do you think about this more from the perspective of providing further therapeutic enhancement beyond the KEYNOTE-189 benchmark, or more from the perspective of bringing Ivonescimab outside of lung with a better probability of success?

Allen Yang (Chief Medical Officer)

Hi, Brad. Thanks for the question. Both, but probably the latter more. So clearly, ADCs are going to be important across solid tumor oncology. I think the data in lung cancer is interesting, but the data outside of lung cancer has been stronger. And I think the fact that there's multiple ADCs involved in this is important.

And maybe just a quick follow-up on that. In lung specifically, as I look at the Pfizer pipeline of ADCs, can I check your confidence level in integrin beta-6 for an ADC target over TROP2, where obviously competitors have front-line phase III is reading out this year? Yeah.

Robert Duggan (Chairman and CEO)

So I appreciate the question, Brad. And I think we'll be in a better position to give a little bit more details as we get closer to launching the phase 1b/2 clinical trials. But at this point, we're not really getting into the specifics just yet in terms of the design as we want to allow for these trials to get up in the activation portion and then ultimately get up and running. Brad, for what it's worth, it's an important question. Love to answer it, but we can't do it yet.

Bradley Canino (Analyst)

All right. Maybe last for me. With the Harmony EGFR data coming mid-year, how do you plan to show the data to investors to demonstrate that there is comparable efficacy and safety and its effect in Western patients relative to Akeso's China patients?

Robert Duggan (Chairman and CEO)

Thank you. Thanks, Brad. Yeah.

I mean, I think that is going to be a key component. I think we, and especially Allen, have been talking about this for over the course of the past year or so. One of the key components will be showing the comparability of the data, to your point, both efficacy and safety in the Eastern and Western population. So while we haven't explicitly described the ways in which we will show this, we'll obviously have presentations at major medical conferences. And the granularity will be there so that that data can be interpreted.

Bradley Canino (Analyst)

Thanks again.

Robert Duggan (Chairman and CEO)

Thanks, Brad.

Your next question comes from the line of Kelly Shi with Jefferies. Please go ahead.

Kelly Shi (Analyst)

Congrats on the progress. Thank you for taking my question. Maybe a couple of questions on Harmony trial, global trial design.

Regarding the prior assumptions on both PFS and OS, should we assume it is designed based on a total of 420 patients, but not a subgroup of ex-China patients?

Allen Yang (Chief Medical Officer)

Yeah. Kelly, this is Allen Yang. Yes. It is a primary analysis of the total study population. Of course, as Brad alluded to, that there will be looks at the regional differences. We have had discussions on this from a regulatory standpoint about how the data should be analyzed and presented. But then, of course, during the analysis and then during the review process, they could always ask for additional studies as well. Okay.

Kelly Shi (Analyst)

Thank you. Okay. Thanks. And you guided me the year for data disclosure. I just want to confirm this is referring to June, July, or actually could it be the entire Q2, Q3 timeframe?

Robert Duggan (Chairman and CEO)

Yeah. Yeah. I appreciate the question, Kelly.

I think we're probably a little bit broader on that, more in the Q2, Q3 timeline. But obviously, as we get closer to that, we'll be letting people know.

Kelly Shi (Analyst)

Okay. Terrific. And one more on Pfizer's collaboration. So regarding EV in bladder cancer, just curious, is there a possibility to add some combo arm to the ongoing or the initiating phase three trials running by Pfizer, or should we expect more early phase trials?

Allen Yang (Chief Medical Officer)

Yeah. I don't think we've disclosed anything. We're exploring every opportunity to move as quickly as possible. We haven't said anything about EV specifically, but we believe that EV is important in bladder cancer. And yeah, more to come. Yeah.

Robert Duggan (Chairman and CEO)

We're excited to give you a little bit more details in the upcoming couple of months.

Kelly Shi (Analyst)

Okay. Great. Thank you for the callers.

Robert Duggan (Chairman and CEO)

Thanks, Kelly.

Operator (participant)

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

Saadia Raman (VP)

Hi. This is Saadia Rahman on for Mohit. Thanks for taking the questions and congrats on all the progress over the year. So I wanted to ask on the Pfizer collaboration, curious how you're thinking about the overlapping toxicities with VEGF inhibition and Vedotin-based ADCs and how this could differ from combinations with ADCs using topoisomerase payloads.

Robert Duggan (Chairman and CEO)

Yeah. I appreciate the question there. I think part of so if I take a step back, one of the things that we've expressed more broadly is that we want to be able to take ivonescimab and combine it with the best available treatments on a tumor-by-tumor level, right? And so part of what we will be doing is doing safety run-ins with any combination in which we combine with Ivonescimab. And that'll be the same here.

I don't think we're in a position to comment specifically on each of the different types of ADCs, whether it be MMAE-based, whether it be topoisomerase-based. We've seen data historically, whether it be in combination with immunotherapy like pembrolizumab in some of these ADCs, whether it be, again, MMAE-based or topoisomerase-based. But at this point, we're excited about the profile that's been shown to date for ivonescimab. We're very aware of the profile to date for many of the progressing ADCs. And I think that's where we're going to take the opportunity to do rational step-by-step combinations. And then we'll take that to the next step as we see the data.

Dave Gancarz (Chief Business and Strategy Officer)

Yeah. And I would just add that there's emerging data in combination with pembrolizumab that these types of ADC combinations are feasible.

We have good safety data comparing Ivonescimab to pembrolizumab, so we don't expect any additions or surprises in the combinations.

Saadia Raman (VP)

Got it. Thank you. And then on the upcoming readout this year in EGFR mutant lung cancer, I think you said the majority of those patients are coming from the China Harmony study. And the majority of those patients received a first or second-gen TKI before getting a third-gen TKI. Would all of the patients recruited into the Harmony study receive only a third-gen TKI in that first-line setting? And can you talk about any differences in those populations that we could expect in terms of time from diagnosis or survival after that third-gen TKI and whether that could result in any differences in efficacy when looking at the next line of treatment?

Dave Gancarz (Chief Business and Strategy Officer)

Yeah.

But just to be clear, the majority of patients in Harmony did receive a third-generation TKI as part of the standard of care. And those patients will be included. Whether they received a first or second generation before receiving a third generation, they would still be eligible. And in terms of differences in responses in those that got first or second versus third generation and where they got them, that's outlined in the Lancet publication by Zhang et al., and we don't expect any differences.

Saadia Raman (VP)

Okay. Thank you. And then maybe one more on the Harmony II trial and your global trial. So the time to separation on the PFS curve in Harmony II happened very early on. Can you talk about what you would expect for the global study since it adds on chemo combination?

Just trying to understand how much the curves could shift and how that could affect timing of when you hit on PFS relative to when Harmony II hit on PFS.

Dave Gancarz (Chief Business and Strategy Officer)

Yeah. I think we've put out a decent amount of data with respect to AK112-201, which was the phase two, which looked at ivonescimab plus chemotherapy in multiple settings, including both squamous and non-squamous in the front-line setting. That's probably the earliest, or best rather in terms of an early thought process with respect to what we would see from data with Ivonescimab plus chemo and comparing that against the historical benchmarks that you would see from trials such as KEYNOTE-189, KEYNOTE-407, etc. So I think those are probably the landmarks that I would look at from an early read in terms of what's publicly available.

And then obviously, as we get continuing data, including Harmony VI from our partners at Akeso in the squamous front-line setting, those will be additional inputs that will provide more color.

Saadia Raman (VP)

All right. Great. Thank you so much.

Dave Gancarz (Chief Business and Strategy Officer)

Thank you.

Operator (participant)

Your next question comes from the line of Mitchell Kapoor with H.C. Wainwright. Please go ahead.

Mitchell Kapoor (Analyst)

Hey, everyone. Thanks for taking the questions and congrats on this deal. Can we just talk about kind of when you were searching for a BD transaction like this, you just talked about what you were looking for before you came to this arrangement with Pfizer. And now that this deal is on the table, do you foresee additional BD opportunities, or does this kind of preclude those for a while? And could you just talk about if you expect future business development to be i

n the pursuit of combinations similarly like this?

Robert Duggan (Chairman and CEO)

Importantly, if there are any particular BD opportunities that you're not considering. Yeah. Thanks for the question, Mitchell. I think if I, again, take a step back here, I think one of the things that we've talked about as the strategic advantage for Summit and ivonescimab is that we don't have that pipeline internally that we're kind of almost committed to combining with and will almost force through combinations as much as possible to try to keep internal synergies. In general, our approach will be to look out and say, "What are the best therapies? What are the standards of care across each of the different solid tumor settings?" To the extent that Ivonescimab plus one of those, whether antibodies or small molecules, makes sense, then that'll be an opportunity where Ivonescimab can combine there.

So I would say, as a whole, we don't believe that there's a single ADC platform that individually is the only way to move forward. But we do believe that multiple companies have multiple different types of ADCs, whether it be topoisomerase-based, whether it be MMAE-based, whether it's switching out the linkers of the antibodies in different settings. Obviously, there's a number of, for example, TROP2 ADCs with different antibodies. So what we can do is really explore different combinations of Ivonescimab plus X, Y, or Z ADC, antibody, small molecule. So we're not really giving guidance in terms of we plan to do X additional collaborations like this or whatnot.

In general, what we certainly feel well-positioned for is that we will take Ivonescimab and look to combine it with the best possible alternative, if you will, out there from a standard of care perspective to bring the most potential value to Ivonescimab and ultimately help patients in any way that we can there.

Allen Yang (Chief Medical Officer)

Yeah. Mitch, this is Allen Yang. I would just add that we just want to pursue the best science to help patients, right? And so I think there was a lot of interest in combining with Pembro in terms of combination therapies with different immunotherapies and different other agents. And based on the Harmony II data, as we had suspected that now companies are interested in sort of pairing with Ivonescimab, and that's where the puck is going.

Mitchell Kapoor (Analyst)

Okay. Great.

And just to clarify the last point, are there any particular BD opportunities that you're not open to at this juncture?

Robert Duggan (Chairman and CEO)

No, I wouldn't say that there's specific things we're not open to. I think it's more about what is possible with Ivonescimab.

Allen Yang (Chief Medical Officer)

Yeah. And I would just add if there was some clear safety issue or something like that. But we have not seen that signal yet. So we're pretty excited that we have a lot of opportunity.

Manmeet Soni (COO and CFO)

And Mitch is Manmeet. Okay. Great. Sorry, Manmeet. Sorry, Mitch. This is Manmeet. And I would just clarify, yes, to answer your question very specifically, this transaction with Pfizer doesn't preclude us to do any other regional or any partnerships or any other activities.

Mitchell Kapoor (Analyst)

Very helpful. And the last one for me, just on the first-line trials, can you talk a little bit more about the Harmony IIi enrollment?

I know you briefly touched upon that, but does Harmony 7 site activation compete for patients for the PD-L1 high enrollment for Harmony III at all?

Manmeet Soni (COO and CFO)

Yeah. Hey, Mitch. This is Manmeet again. Yes. Obviously, there is a segment of patients, right, PD-1 high patients, which will be covered in our Harmony III also, right? So there is some sort of that. But as you know, we are much ahead in our schedule on Harmony III activations. And there will be not a full overlap of the sites, right, as compared to Harmony 7. So we have just taken Harmony 7 initiation in the last few weeks, and Harmony III is already enrolling, right, patients. So there will be obviously, there is an overlap, but we don't expect there is a competition because of the new sites which we are planning to add in Harmony 7.

Mitchell Kapoor (Analyst)

Great.

Thank you all very much for taking the questions and congrats again on this collaboration.

Manmeet Soni (COO and CFO)

Thanks, Mitchell.

Operator (participant)

Your next question comes from the line of Asthika Goonewardene with Truist Securities. Please go ahead.

Asthika Goonewardene (Analyst)

Hey, guys. Thanks for taking my questions and congrats on all the progress as well. I want to dig into Harmony III a little bit, please. Will the primary statistical analysis for that study are you doing the primary analysis on the combined non-squamous plus squamous population, or will you do it more in a stepwise manner, kind of looking at the squamous and non-squamous subgroups individually first and then looking at the overall population? I ask this because I believe the BioNTech study is structured more like the latter. I'm curious to know if you're taking a different approach and if so, why you prefer your method.

Allen Yang (Chief Medical Officer)

Yes. Thanks for the question. This is Allen.

Yeah. So our plan is to do a primary analysis of the combined population, and we believe that that was the best way to bring this product to patients as fast as possible from an operational perspective. Of course, there is always data and ongoing data coming out. The Harmony VI will be informative as well. But our current plan is to do a combined analysis.

Asthika Goonewardene (Analyst)

Got it. Thanks, Allen. Have you discussed with the FDA any way to accelerate a filing with Harmony III? I'm wondering if you're seeing a strong PFS signal. Have you talked to the FDA about maybe doing accelerated filing based on that?

Allen Yang (Chief Medical Officer)

Of course, we want to bring this to patients as fast as possible. We've had several discussions with them on this study, but I can't disclose our discussions at this time.

Asthika Goonewardene (Analyst)

Got it. Okay.

And then on the Pfizer collaboration, do you feel ivonescimab could better leverage the immunogenic cell death versus PD-1, or is the rationale behind this deal mainly about layering on a classical anti-angiogenic pressure in addition to PD-1 with the ADC?

Allen Yang (Chief Medical Officer)

Yeah. That's a great question. We could talk a lot about that. But with that said, part of it is empiric. We know that both of these drugs, a lot of these drugs, are active in different tumor types, and then you clearly want to add those efficacies. Whether there would be some synergistic effect through the immune system for the profile, would it be different from Pembro's sort of additive or synergistic effect? We think all of those are actually possible, and we're looking forward to these combinations. But yeah, it's very interesting.

Asthika Goonewardene (Analyst)

Great. Thanks for taking my questions, guys.

Allen Yang (Chief Medical Officer)

Thanks very much.

Operator (participant)

Your next question comes from the line of Reni Benjamin with Citizens JMP. Please go ahead.

Reni Bejamin (Managing Director)

Hey, guys. Thanks for taking the questions, and congratulations on all the progress. With Harmony III and 7 kind of off to the races, can we talk a little bit about the next solid tumor indications you plan to invest in? And we had some ongoing study data reported last year. Can you talk a little bit about when we might see some updated results from those studies? And I guess just as a sticking with this theme, I guess broadly, do you kind of strategically follow Akeso based on their data, their solid tumor data, and kind of do global studies based on what they've reported, or do you kind of broaden exposure and go after indications that maybe they're not addressing?

Robert Duggan (Chairman and CEO)

Sure, Fran. Thanks very much for the question.

In reality, everything that you mentioned resonates, right? And so if you think about the last part of your question, which is, do you follow Akeso or do you look to branch out? As Maky talked about, part of our MD Anderson collaboration looks to accomplish parts of that as well as our IST program. If you look at some of the phase two data generated by our partners at Akeso, which were released over the course of last year, whether it be BTC, colorectal cancer, head and neck cancer, and triple-negative breast cancer, there are some promising signals that we see in that phase two data. There are also additional indications that have been explored in phase two where data hasn't yet been fully disclosed from that perspective, which give us opportunities.

Then obviously, we can run additional signal-seeking or phase two studies as well, whether on our own or through things like the clinical trial collaboration with Pfizer here, which we'll look to do that as well. So as a whole, I think, as Maky mentioned in her comments earlier, we're very keen to, in addition to the significant work being done in non-small cell lung cancer, look beyond lung cancer as well. And that's part of our 2025, 2026 development plan.

Reni Bejamin (Managing Director)

Got it.

Allen Yang (Chief Medical Officer)

Yeah. Sorry, go ahead. No, Fran, I was just going to add. So we haven't disclosed it. We're in the midst of multiple regulatory discussions around that. I would just say that we have been thinking about this for a long time.

So we did this exercise even before the Harmony II data read out, shortly after the deal was done, looking at all the prior checkpoint inhibitor approvals, looking at all the anti-angiogenic approvals, looking at what we think the population size would be, what the comparator arm would be. And then you layer on top of that the phase two data coming out from Akeso. That all goes into the calculus of how we make those decisions. And hopefully, we'll be able to disclose some exciting opportunities soon.

Reni Bejamin (Managing Director)

Outside of the opportunities, could we expect updated results from any of those studies, or do you feel like they're largely concluded and really it's about the phase three studies that are up and running?

Manmeet Soni (COO and CFO)

Yeah. Hi, Ran. This is Manmeet.

Yes, you will continue to hear more updates as we progress on all the studies which we had given some initial top-line data earlier in the last year. But I would also mention that, right, colorectal cancer, right, where we are pretty excited. And we have just recently partnered with Akeso also on the phase two study which we are beginning to activate over here on our side. And that would be the first one which you would hear more details in the next coming quarters.

Reni Bejamin (Managing Director)

Excellent. Okay. Thank you for that. And just one last one for us. I think ct.gov said that there are three active sites for Harmony 7. Can you talk a little bit about how many sites globally you expect to have on board by the end of 2025 for both Harmony III and Harmony 7?

Manmeet Soni (COO and CFO)

Hi, Ran. This is Manmeet again.

I think we don't give the specific number, but on the sites which we activate, because we go into multiple regions, right, this is a global multi-regional study, but I would expect by end of 2025, almost most of the sites or near to 100% of the sites should be activated.

Reni Bejamin (Managing Director)

Great. Thanks for taking the questions, guys, and congrats.

Manmeet Soni (COO and CFO)

Thanks very much.

Dave Gancarz (Chief Business and Strategy Officer)

Thank you.

Operator (participant)

I will now turn the call back to Dave Gancarz for closing remarks.

Dave Gancarz (Chief Business and Strategy Officer)

Thanks very much, and I'd like to hand it over to Bob Duggan just for a couple of remarks before we close.

Robert Duggan (Chairman and CEO)

Yeah. I just want to weigh in on the question of business development. Business development has a couple of arms. One is to optimize IVO and make it the best product monotherapy combination therapy that the world can get from us and our partner, Akeso.

We're daily looking at that and evaluating that. There's plenty of room to go, as you see with the trials that we're entering into. The second aspect of business development is what's the timing of gaining markets, additional market space, additional market opportunity, and then how much share can you get, and how do you go about doing that? That's also a major part of business development. We're very active on two footprints. Pfizer is footprint one. How do we optimize the product? Other activities, we're constantly working on those here also. I just want to make clear that Pfizer is not the beginning and end of business development at Summit. Not that it isn't for most of you, but even for some of you. Back over to Dave.

Dave Gancarz (Chief Business and Strategy Officer)

Really appreciate it, Bob. Thanks very much.

I want to thank everyone for attending today's earnings call. An archived version of the webcast will be available later today on our website, www.smmttx.com. Thank you very much for your participation, and we hope you enjoy the rest of your day. Thank you.