Good morning. And welcome to Summit Therapeutics' Q3 2024 Earnings and Update Call. All participants will be in a listen only mode until the question-and-answer portion of the call [Operator Instructions]. Please refer to the company's Web site for updates. Please note that today's call is being recorded.

After the speakers' remarks, there will be a question-and-answer session. 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..

Good morning, and thank you for joining us. Our press release was issued earlier this morning and is available on the homepage of our Web site. Our Form 10-Q was also filed earlier this morning and is available on our Web site.

Today's call is being simultaneously webcast and an archived replay will also be made available later today on our Web site, 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 of the statements made by our management team today and some responses to questions that we will make 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. And with that, I'd like to turn the call over to Bob..

Thank you, Dave. Good morning, everyone. Thank you for joining us today. I'm very proud of the recent accomplishment of Team Summit and the continuing positive information to be shared surrounding ivonescimab, our lead investigational asset.

There have been several meaningful achievements around the progress of ivonescimab since our last earnings call, both with our partners in China as well as here in the US 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, we intend to amend the protocol for our multi-regional Phase 3 trial HARMONi-3 to now evaluate patients with first line treatment for metastatic non-small cell lung cancer with both squamous and non-squamous histologies. The prior trial design previously included only tumors of squamous histology.

This is a significant immediate expansion of total addressable market of our current Phase 3 clinical trial portfolio. We will provide additional context in a few moments around HARMONi-3's expanded patient population.

We have completed enrollment of our global Phase 3 HARMONi trial in patients with EGFR mutated advanced non-small cell lung cancer who have progressed after treatment with the third generation EGFR tyrosine kinase inhibitor or TKI. As previously announced, we expect HARMONi top line data in mid-2025.

In addition, we received fast track designation from the FDA for this setting in the United States.

Following the positive results of HARMONi-2, we announced our intentions for launching a third global Phase 3 trial, HARMONi-7, studying ivonescimab monotherapy in patients with first line metastatic non-small cell lung cancer whose tumors have high PD-L1 expression.

Additionally, encouraging Phase 2 data featuring ivonescimab from China was featured at World Lung and the 2024 European Society for Medical Oncology or ESMO annual meeting in perioperative non-small cell lung cancer, as well as indications outside of non-small cell lung cancer, including advanced triple negative breast cancer, recurrent metastatic head and neck cancer and microsatellite stable metastatic colorectal cancer.

Each of these Phase 2 studies were sponsored by Akeso with data generated and analyzed by Akeso. These encouraging data reflect why we are continuing to explore the expansion of our clinical development of ivonescimab outside of metastatic non-small cell lung cancer.

In addition, we raised $235 million from leading biotech investors and individuals, including insiders, extending our cash runway and increasing our resources to execute upon expansive goals. Manmeet will provide more details about our financial position in a few minutes.

These accomplishments have been foundational to our 2024 goals of successfully executing on our registrational Phase 3 trials while expanding our clinical development plan.

Maky will further discuss these accomplishments, including additional strides taken to drive our continued belief and conviction in Team Summit and the potential of ivonescimab in non-small cell lung cancer and indications beyond lung.

We are a mission driven organization with the 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 help us realize this goal.

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

Thank you, Bob. And good morning, everyone. As Bob said, I remain incredibly enthusiastic about the accomplishments of Team Summit and our partnership with Akeso. Before providing on some of the highlights, as Bob mentioned, I would like to discuss the clinical work that has been conducted with ivonescimab.

There are more than 25 clinical trials around the globe evaluating ivonescimab across 17 tumor settings, including nine Phase 3 trials planned, ongoing or completed either in China or globally.

While six of the Phase 3 programs across Summit and Akeso are currently focused in non-small cell lung cancer, three additional Phase 3 clinical trials have been announced by Akeso evaluating our lead candidate in solid tumor settings beyond non-small cell lung cancer. This include BTC, head and neck cancer and pancreatic cancer.

At Summit, we are sponsoring two ongoing Phase 3 clinical trials, HARMONi and HARMONi-3. We are planning to initiate HARMONi-7 in early 2025.

Based on the data Bob mentioned that was released at ESMO that I will speak more to it in a moment, we are excited to and are actively exploring expanding our Summit led clinical development plan beyond metastatic non-small cell lung cancer. As a reminder, ivonescimab is the only PD-1 VEGF bispecific antibody in Phase 3 in our licensed territories.

Ivonescimab brings these two highly validated mechanism of action together into one novel molecule targeting simultaneously both PD-1 and VEGF. Next, I would like to review the many achievements completed as well as discuss some upcoming catalysts for the remainder of this year.

The third quarter of 2024 was a landmark moment for ivonescimab and its development with significant catalyst events in the form of data related in September at the World Lung and ESMO conferences.

Last month at the World Lung Conference, HARMONi-2 results were featured as part of the Presidential Symposium and received a tremendous response from leading KOLs.

In this head to head trial comparing ivonescimab versus pembro, both as monotherapy, HARMONi-2 met its primary endpoint of progression free survival with ivonescimab achieving a 49% reduction in the risk of disease progression or death compared to pembro.

Ivonescimab showed consistent clinically meaningful benefit across key subgroups, including patients with either PD-L1 low or PD-L1 high expressing tumors and in squamous and nonsquamous histologies. Consistent with previous studies, ivonescimab demonstrated an acceptable and manageable safety profile.

With the additional Phase 2 data released in the third quarter at both World Lung and ESMO, we continue to expand the meaningful data that has been generated with ivonescimab in various solid tumor settings beyond non-small cell lung cancer.

We are fortunate to have created such a strong partnership in our ongoing collaboration with Akeso as we leverage data from multiple solid tumor studies, supporting and informing Summit's own late stage clinical development strategy in our licensed territories.

In addition to touching on our current clinical development plans, we initiated our strategic alliances with the University of Texas MD Anderson Cancer Center this quarter, providing additional opportunities to evaluate ivonescimab in tumor types and settings in which we have not yet tested its potential.

Patients are expected to soon begin treatment and clinical development effort will soon begin via this collaboration. After the HARMONi-2 data was announced, we have received inbound interest from physicians regarding approximately 75 proposed investigator sponsored trials or ISTs in a wide range of cancer types.

With meaningful updates this past quarter from Akeso’s HARMONi-2 study and several Phase 2 studies, we wanted to take the opportunity to review the respective study designs and further highlight key results. We will start with HARMONi-2.

HARMONi-2 is a randomized, double blind clinical trial, evaluating frontline monotherapy, ivonescimab, as compared to monotherapy, pembro, in patients with locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression. This is a single region multicenter Phase 3 clinical trial conducted and sponsored by Akeso in China.

Our partners at Akeso generated and analyzed the data in HARMONi-2.

Here is the primary endpoint of progression free survival by blinded independent radiologic review committee for the entire study at the time of the first planned interim analysis, with a median follow-up of 8.67 months demonstrating a significant improvement for ivonescimab with a hazard ratio of 0.51 corresponding to a 49% improvement over the control arm.

The median PFS was 11.1 months versus 5.8 months in the ivonescimab and pembro arms respectively. Of note, the curves begin to separate at the first point of radiographic assessment and maintain separation over the entire duration of follow-up thus far.

The analysis of PFS subgroups reveals that the PFS benefit with ivonescimab was observed across nearly all subgroups. Specifically, the benefit is quite comparable across the spectrum of PD-L1 expression with a hazard ratio of 0.54 for patients with PD-L1 low expressing tumors and 0.46 for patients with tumors of high PD-L1 expression.

As previously discussed, and this is particularly true in the United States and Europe, monotherapy checkpoint inhibitor usage is a standard of care for patients with high PD-L1 expression.

With regard to non-small cell lung cancer histology, the benefit was also similar for patients with squamous non-small cell lung cancer who showed a hazard ratio of 0.48 favoring ivonescimab and those patients with tumors of non-squamous histology with a hazard ratio of 0.54 favoring ivonescimab.

This slide is a strong indicator that the benefit was seen across clinical subgroups and underscores that the success of the trial overall was not driven by an especially strong performance of a subgroup. For safety, we see that there was a numerically higher rate of serious treatment related adverse events with ivonescimab 20.8% compared to 16.1%.

This did not translate to greater treatment discontinuation or treatment related adverse events leading to death, both of which were numerically higher in the pembro arm.

This pattern held true in patients with squamous non-small cell lung cancer as well, a place where anti-VEGF therapy has historically demonstrated safety risk where there were comparable rates of serious treatment related adverse events, discontinuation and death in the ivonescimab arm compared with the pembro arm.

This is the first randomized Phase 3 clinical trial evaluating the safety profile of ivonescimab in the squamous population, especially confirming its tolerability in this group.

In more detail, we see that nearly all of the higher rate of treatment related adverse events were lab related abnormalities, hypertension and proteinuria but generally did not lead to discontinuation of dosing. These are conditions that are often seen by oncologists who in general are experienced managing these [AEs].

Finally, looking at the immune related and possibly VEGF related adverse events, in the table to the left, we see comparable immune related AEs with ivonescimab compared to pembro. On the right, we see that, as expected, ivonescimab was associated with more possibly VEGF related AEs, both in all grades and grade 3 or higher.

Importantly, however, all grade 3 or higher AEs were all classified as grade 3. There were no grade 4 or grade 5 AEs that were possibly VEGF related in either arm of the study. The table in the bottom line shows that most of the possible VEGF related adverse events represented proteinuria and hypertension.

There is no evidence of life threatening or fatal bleeding complications, including among patients with advanced squamous non-small cell lung cancer and in patients with central tumors, cavitory lesions and/or tumor encasing large blood vessels in this Phase 3 study.

As a result of the successful HARMONi-2 study and our analysis of the underlying data, we announced our plan to initiate HARMONi-7, a randomized global Phase 3 study evaluating ivonescimab versus pembro, both monotherapy in frontline non-small cell lung cancer in their PD-L1 high expression population.

HARMONi-7 is planned with the two primary endpoints, progression free survival and overall survival. We are planning for an estimated 780 patients in this registration enabling study. Turning to HARMONi-3.

As Bob mentioned, we intend to amend this randomized global Phase 3 clinical trial to include patients with tumors of non-squamous histology in addition to continuing to enroll squamous patients.

As part of the trial amendment, the primary endpoint is intended to be updated to include two primary endpoints of progression free survival and overall survival. The total sample size for this randomized multi-regional Phase 3 clinical trial has been adjusted to include an estimated 1,080 patients.

Expanding HARMONi-3 is the most efficient way to cover all metastatic non-small cell lung cancer patients without [driver] mutation.

HARMONi-3 will now cover metastatic non-small cell lung cancer, both squamous and non-squamous tumors in combination with chemotherapy and HARMONi-7 intend to cover PD-L1 high expressing tumors via monotherapy ivonescimab now providing the opportunity to capture a significantly broadened addressable market as quickly as possible.

Supporting this proposed amendment, in part, is both the result of HARMONi-2 showing benefit to patients with both squamous and non-squamous tumors as well as the Phase 2 data that has been previously presented.

As a reminder, updated Phase 2 data for this setting was announced at the 2024 European Lung Cancer Conference in March from the AK112-201 clinical trial centered around the cohort of patients in which ivonescimab is combined with chemotherapy for first line treatment of squamous and non-squamous advanced or metastatic non-small cell lung cancer in patients without actionable genomic alterations.

This data was generated and analyzed by Akeso. First line patients with advanced or metastatic non-squamous tumors experienced a median progression free survival of 13.3 months. In addition, first line advanced or metastatic squamous patients experienced median progression free survival of 11.1 months.

Both metrics are encouraging considering the expectation for the current standard of care in this patient population largely driven by PD-1 inhibitors plus chemotherapy. Median overall survival was not reached in either subset of patients after a median follow-up time of approximately 22.1 months.

The frequency of treatment emergent adverse events leading to the discontinuation of ivonescimab was 11.1% and 2.8% respectively in patients with squamous and non-squamous tumor. We are highly encouraged by the opportunity of ivonescimab to demonstrate its potential across non-small cell lung cancer in multiple clinical settings.

Finally, as we have stated, we are evaluating opportunity to expand our clinical development beyond metastatic non-small cell lung cancer. We will review the encouraging Phase 2 data announced this past quarter at World Lung and ESMO, starting with an overview of the respective study design.

At the World Lung, perioperative non-small cell lung cancer Phase 2 data was featured from AK112-205, a single region, multi-center, open-label study of patients with Stage II or III resectable non-small cell lung cancer with data generated analyzed by Akeso.

The study was designed to assess patients receiving either ivonescimab monotherapy or ivonescimab plus chemotherapy prior to surgical resection and then ivonescimab monotherapy after surgery. Due to the maturity of the data and the timing of the data cut-off, the results were mature for the neo adjuvant portion of the clinical trial.

In September 2024, promising antitumor activity and safety data for ivonescimab were presented at ESMO. Featuring updated data in advanced triple negative breast cancer, recurrent metastatic head and neck squamous cell cancer carcinoma and metastatic microsatellite stable colorectal cancer.

The head and neck study assessed patients who received ivonescimab with or without ligufalimab with PD-L1 positive locally advanced or metastatic recurrent head and neck squamous cell carcinoma.

Note that ligufalimab, or AK117, is Akeso’s proprietary investigational product that is not approved by any regulatory authority and to which Summit does not have any license or ownership rights.

The colorectal study was designed to assess patients who were randomly assigned to receive ivonescimab plus FOLFOXIRI with or without ligufalimab, an investigational anti CD47 monoclonal antibody.

The triple negative breast cancer study assessed patients who received ivonescimab plus chemotherapy, either paclitaxel or nab-paclitaxel with locally advanced or metastatic TNBC. Turning now to anti-tumor activity and safety data from this Phase 2 study.

In perioperative non-small cell lung cancer at the time of data cut-off, 49 patients had been enrolled into the ivonescimab plus chemotherapy arm in the neo adjuvant setting. Of these 49 patients, 39 went on to complete surgery.

Of the 39 patients who received ivonescimab plus chemotherapy in the neo adjuvant stage and completed surgery, 71.8% of patients experienced a major pathological response and 43.6% of patients experienced a pathological complete response.

In the 49 patients enrolled in this cohort, median event free survival was not yet reached after 8.9 months of the median follow-up time. The 12 months event free survival rate was 80.3%. These results are encouraging compared to the historical data that has been observed in global pivotal studies in a similar setting.

The safety profile in this Phase 2 study was acceptable and manageable. No surgeries were delayed or canceled due to the treatment related adverse events. In colorectal cancer, at the time of data cut off, 22 patients received ivonescimab plus FOLFOXIRI with a median follow-up time of nine months.

18 patients received ivonescimab plus ligufalimab plus FOLFOXIRI with a median follow-up time of 9.6 months. All patients in both groups experienced a reduction in their tumor burden compared to their baseline tumor assessment.

The overall response rate and DCR for the 39 patients combined from both groups who had at least one post baseline tumor assessment was 84.6% and 100% respectively. Median progression free survival was not reached in either group at the time of this analysis. The safety profile in this Phase 2 study was acceptable and manageable.

These response rate are very encouraging considering historical benchmarks in this setting. In addition, these patients have tumors that are considered microsatellite stable, a setting where PD-1 therapy has not been historically successful. This is another indicator of ivonescimab potential beyond the current PD-1 landscape.

In triple negative breast cancer, at the time of data cut off, 30 patients received ivonescimab plus chemotherapy with median follow-up time of 10.2 months, 60% of patients had previously received taxane based chemotherapy in either the neo adjuvant or adjuvant settings in this Phase 2 data set.

All patients experienced a reduction in their tumor burden compared to their baseline tumor assessment. The overall response rate and DCR for the 29 patients who had at least one post baseline tumor assessment were 72.4% and 100% respectively. Median progression free survival was 9.3 months at the time of this analysis.

The safety profile in this Phase 2 study was acceptable and manageable. The PD-L1 low or negative TNBC is yet another clinical setting without PD-1 therapy as a standard of care.

Moving to head and neck, at the time of data cut off, 10 patients received ivonescimab with median follow-up of 3.3 months and 20 patients received ivonescimab plus ligufalimab with median follow-up 4.1 months. All patients had tumors with PD-L1 expression. The overall response rate and DCR for the 30 patients combined was 50% and 86.7%, respectively.

The safety profile in this Phase 2 study was acceptable and manageable. The third quarter of 2024 was a pivotal moment in cementing the growing confidence of ivonescimab. Before I turn it over to Manmeet to provide a financial update, I would like to take a moment to thank our incredible team at Summit.

As Bob and I have described all of the accomplishments we have achieved over the past seven quarters with ivonescimab, this team has done a remarkable job across every team in making our goals a reality and condensing time where and when possible to accelerate our timeline in bringing additional therapeutic options to patients with cancer.

It is a tremendous honor and privilege to work with each member of Team Summit, and I would like to express my heartfelt thanks to everyone of our phenomenal team member. With that update, I will now ask Manmeet to provide details on our financial position and operational update..

Thank you, Maky. And good morning, everyone. We issued this morning our earnings release for the third quarter of 2024. Today, in addition to providing you with an update on our cash position, recent financing and third quarter operating expenses, I will also be providing an update on our clinical operations.

On the clinical operations front, I'm really proud of the Team Summit for completing the enrollment ahead of schedule for our first registrational global trial HARMONi in patients with EGFR mutations post targeted therapy. We expect to have the top line data from our HARMONi trial, including patients from US and Europe in mid-2025.

Also, since the release of ivonescimab data during September 2024 at World Conference on Lung Cancer and ESMO Annual Meeting, we have seen an increase in the screening and enrollment activity for the squamous patients at our existing sites in our HARMONi trial.

Additionally, we have seen lots of excitement and outreach from both academic and community physicians to participate in the development of ivonescimab. We believe this interest will help us in accelerating activation of additional sites and ultimately enrolling patients faster for the two planned trials.

HARMONi-3 for addition of non-squamous arm and also for recently announced HARMONi-7 trial, which we had in 2025. On the financials front, let me start with our cash position. We ended the third quarter of 2024 with a cash position of approximately $487 million.

This cash position was strengthened at the end of third quarter with the closing of a $235 million private placement in September 2024 from multiple leading biotech institutional investors and insiders. Turning to operating expenses, I'll provide details to both GAAP and non-GAAP numbers.

You can refer to our press release issued this morning for a reconciliation of GAAP to non-GAAP financial measures. To remind, non-GAAP expenses exclude stock based compensation and one time charges related to acquired in process R&D expenses.

Our GAAP R&D expenses during the third quarter were $37.7 million compared to $30.8 millon for the second quarter of 2024. And non-GAAP R&D expenses were $31.9 million in the second quarter of 2024 compared to $27.3 million for the second quarter of 2024.

Turning to G&A, our GAAP G&A expenses during the third quarter 2024 totaled $20.4 million compared to $14 million for the second quarter of 2024. And non-GAAP G&A expenses were $6.8 million during the third quarter of 2024 compared to $6.4 million for the second quarter of 2024.

The increase in GAAP operating expenses was primarily related to the increase in stock based compensation expense during the quarter related to charges from the achievement of certain market conditions on Performance Stock Option Awards and an increase in R&D expenses due to expansion of clinical study and development costs related to ivonescimab and increase in people cost as we continue to build our R&D team.

On a non GAAP basis, which excludes stock based compensation, our non-GAAP operating expenses during the third quarter 2024 were $38.7 million compared to $33.7 million for second quarter of 2024.

We have been executing efficiently on our two registrational studies, HARMONi and HARMONi-3 with quarterly cash burn in our operating activities keeping it below $35 million.

Finally, to conclude, we believe our current cash balance at quarter end aggregating to $487 million provides us enough cash to continue to invest in the ivonescimab trials planned to be expanded and initiated in 2025. And with that, I'll hand it back over to Dave..

Thank you, Bob, Maky and Manmeet. Now we'd like to see if there are any questions that our team can help answer.

Operator, would you please open the line for questions?.

[Operator Instructions] Our first question comes from the line of Mitchell Kapoor with H. C. Wainwright..

Just wanted to know on the expansion of the HARMONi-3 trial.

Who are the likely first line non-squamous patients that you could likely enroll? And specifically, how do you think about recruiting patients who would otherwise be good candidates for KEYTRUDA? How do you think about getting those patients to participate in this study?.

So the expansion is basically similar to the population that was treated in the KEYNOTE-189 study. So these are going to be non-squamous patients, probably [adeno] patients. And I think Maky reviewed the trial. I think the key here will be the chemo will be slightly different, it will be platinum pemetrexate for these patients.

However, we have extensive experience with that from the HARMONi studies, HARMONi-A and HARMONi..

And do you have a target enrollment for the split between non-squamous and squamous for this trial?.

We have not disclosed that..

We're just in the planning phase right now. As we said, we did the -- we gave the combined number, 1,080 patients, which we plan to enroll in both squamous and non-squamous, we have not given further splits yet..

And then the last one for me is just on HARMONi.

Can you talk about the potential for accelerated approval? Could you file on PFS? And how does that differ in terms of the unmet need from the strategy with HARMONi-3 and HARMONi-7?.

HARMONi has always been our path to market strategy. And as you know, we announced that we completed the enrollment earlier this month and now we expect the data in mid-2025. Obviously, based on the data we’re -- obviously we'll be assessing our regulatory strategy and then providing further updates..

And just to clarify, there's two parts to that question in terms of the PFS, right? So there's could you file only on PFS data and then the timing of which could you file with the PFS data before you have the OS readout.

And so just for the precedent in this EGFR second line space, the approval has been on PFS, right? And unfortunately, it is second line. It's a large unmet need.

So the time between PFS and OS readouts may not be significantly different, right?.

The only thing I would add to that, Mitchell, just to round it out. I think you asked the question in terms of the difference between the HARMONi and the HARMONi-3 perspective. So just to reiterate. So HARMONi-3 is, when we -- with our intention to expand that population, that is patients already with squamous, so we'll keep that cohort.

We'll add patients who are non-squamous but they'll be without actionable genomic alterations, right? So without driver mutations. Our HARMONi trial, will -- is focused on those with EGFR mutant driver -- the driver mutation of EGFR mutations, right? So that is they are separate, they're not overlapping populations, HARMONi and HARMONi-3.

I just want to make sure that that's clear..

And just to further clarify, I just want to clarify for the HARMONi-3, as Maky mentioned, now the endpoint is PFS and OS and the question around PFS filing versus OS timing of the filing is relevant for that study..

Our next question comes from the line of Brad Canino with Stifel..

On the addition of PFS to the primary endpoint of HARMONi-3, can you talk about what types of regulatory feedback and clinical investigator feedback that went into that decision? And then related and sorry to push with a question like this, but we all know that investors are keenly aware and awaiting for an OS answer from your partner, Akeso.

And a change like this before we get that naturally makes one wonder what the confidence of management is to achieve a clinically meaningful OS benefit in the frontline among setting.

So can you talk about both of those elements?.

So let me answer the last one first. There's no change in our confidence for the HARMONi-2 data around the OS, right? I think the opportunity was, and it was unrelated, but the magnitude of the PFS benefit in HARMONi-2 was so striking.

You don't want to have a therapy that provides such a significant benefit and not make that benefit available to patients, right, just based on that number.

Granted, there's a lot of issues that we won't get into about payer reimbursement and the value of OS versus PFS but we think that this is a positive thing in addition of the PFS endpoint as a primary endpoint for the HARMONi-3 study in both timing and availability and benefit to patients..

And just to answer the other part of your question that Brad you asked about regulatory feedback. So as we've promised from the beginning of this relationship with Akeso and our licensing of ivonescimab, we would be speaking, in particular with the FDA prior to these changes. So that we have had communications with the FDA here..

Especially for such an important change..

And now that HARMONi-3 does have both histologies. Do you plan to wait for them both to have data to do the top line or can they be reported separately? Right now, the NCT before you've updated says the primary completion estimate is September 27.

Now that the trial has changed, how should we think about data flow, both histologies together et cetera?.

So at the highest level what I would say there, Brad, is this is a single trial. So it's a single analysis set. So we wouldn't necessarily look to break out timing in there.

Now we did say in the slides that we presented this morning that like -- and as would be expected from a stratification perspective, we would stratify it by histology, but it wouldn't be from a timing perspective broken out.

I would say without going too far into the details, just given that we're intending to amend this shortly, there's a significantly broader population of non-squamous patients as well. And so from a timing perspective, there's more availability of those patients and there's a broader availability to enroll patients with non-squamous tumors..

And then last from me, I think as we see multiple PD-1 and L1 by VEGF bispecifics advance across multiple companies. I mean every day there seems to be a press release.

It would be great to hear your thoughts on whether other designs and constructs, be they those that leverage PD-L1 or maybe broader VEGF isoform inhibition, are viewed internally as close replications of ivonescimab and its incredible profile to date or are viewed as potentially different?.

So what I would say, when we enter into the deal with Akeso, we naturally expected to see a few more assets emerge with a similar construct in general as you mentioned, given the data that had been produced to date and our willingness to enter into a deal of that size and magnitude that we did.

Of course, once the data from HARMONi-2 emerged, we expected to continue to see a rapid emergence of products looking to capitalize on the potential that ivonescimab had created at that point. And so most of these assets, I would point out are very early. A majority, a vast majority of preclinical with no in human data.

However, we do review the construct of each of these compounds individually. And while we're not going to comment on any individual asset particularly, what I would say is that ivonescimab was specifically engineered to improve anti tumor activity and reduce toxicities associated with these two targets.

And this specific engineering was not accidental, it was not serendipitous. And we're very happy with ivonescimab in its construct in particular and that ivonescimab is our asset and we have yet to find one that we would rather have versus ivonescimab.

Two successful randomized Phase 3 clinical studies involving ivonescimab only kind of bolster that perspective..

Our next question comes from the line of Yigal Nochomovitz with Citi..

So just thinking a little bit more about the HARMONi-3 amendment which you announced.

I'm just curious, did you consider just simply starting a new study in non-squamous so you could preserve the timelines for HARMONi-3 or is the argument that because you're amending to PFS, you're going to win back time on the time to primary endpoint since you're no longer looking at OS?.

So we totally understand and we evaluate it.

But as you know, right, in order to capitalize on our existing sites, which we already have on the squamous and this timeline to amend was much faster to add the non squamous arm, and as Dave just mentioned, right, non-squamous is almost double the population and it increases our total market size, right, and the potential and there are long lead times if we have to start another trial with new sites and new clinical trial agreements, the lead time is much longer.

So this would allow us to enroll patients on both arms quicker and expand our market like almost like tripling our market opportunity. Yes, we had not provided you timelines because we were still enrolling and activating sites for squamous, so we had not provided you earlier.

So we don't see this as a material change in delaying squamous but it adds non-squamous opportunity and get non-squamous much faster and earlier into the market..

If I can give some physician feedback that we've been receiving, they very excited about this change, they see the logic in this change. This is a type of patient that they see more commonly in their practices. So it just increased sort of participation and excitement around the study..

I mean, clearly, it makes sense given you fill the gap in terms of the spectrum of all the non-small cell patients that are addressable. The other question I had was regarding, we've gotten a lot of questions on HARMONi-2 hitting on OS. As you know, it's been a significant debate.

I'm just wondering if you could kind of walk through the logic as far as the confidence you have that HARMONi-2 will eventually hit on OS? Obviously, people have been making comparisons, perhaps inappropriate comparisons to HARMONi-A and the strong PFS there and then the OS which is trending well, but obviously not hitting stats yet.

So just wondering if you could frame that and talk about how you see the path to confidence on hitting OS in HARMONi-2, which would obviously be a very big win and translate positively to everything you're doing over in the United States?.

Again, I think our confidence hasn't changed. I think if you look back at data from multiple frontline non-small cell lung cancer studies, remember the HARMONi-A study was a second line study in patients with refractory osimertinib or other TKIs.

If the -- probably the classic study, if you look at the criticism around bevacizumab the ECOG study that led to the approval of bevacizumab had a strong hazard ratio, I think, but it was well above 0.6 and it still hit its OS endpoint, the atezo bev studies as well the EMPOWUR studies as well.

And so with this strong of a hazard ratio in PFS, it's unlikely that the OS won't be there, the OS benefit won't be there. But I just want to remind everybody for HARMONi-2 the primary endpoint was PFS and this study was designed for PFS. And the question around statistical significance, that's a numeric value that the people are after.

And the question is, how long will it take to show that given the sample size..

There are no further questions at this time. I would like to hand things back over to Dave Gancarz for some closing remarks..

Thank you, Ian. I just want to take the time to thank everybody for attending today's earnings call. An archived version of this webcast will be available on our Web site www.smmttx.com. Thank you for taking the time to join us and enjoy the rest of your day. Thank you..