Bicara Therapeutics Inc. ($BCAX)

Good day, and thank you for standing by. Welcome to the Bicara Therapeutics ASCO 2026 Corporate Call. [Operator Instructions] Please be advised that today's conference is being recorded. I'd now like to turn the conference over to Rachel Frank, Vice President of Investor Relations and Corporate Communications.

Thank you, and good morning, everyone. It's a pleasure to welcome you to Bicara Therapeutics investor conference call to discuss an update that we will be presenting at the 2026 American Society of Clinical Oncology Annual Meeting. You can access the press release as well as the slides that we'll be reviewing today by going to the Investors section of our company website. Before we begin, please note that this call will include forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Please refer to our most recent SEC filing for important risk factors that could cause our actual performance and results to materially differ from those expressed or implied in these forward-looking statements. Any forward-looking statements made on this call represent our views only as of today, and we disclaim any obligation to update any forward-looking statements. Joining us on the call today are Claire Mazumdar, Chief Executive Officer; and Bill Schelman, Chief Medical Officer. Ryan Cohlhepp, President and Chief Operating Officer; and Tanya Green, Chief Development Officer, are also on the line and will join us for Q&A. I'll now turn the call over to Claire.

Thank you, Rachel, and good morning, everyone. Today, we're pleased to share new data from 2 posters being presented at ASCO 2026 that collectively represent the most comprehensive mature clinical data set assembled for Piterapist Alpha or Fisterra in first-line recurrent or metastatic HPV negative head and neck cancer. These data spend approximately 90 patients across 3 dose cohorts with up to 3 years of follow-up with our 1,500-milligram weekly pivotal dose, the longest follow-up presented of any investigational agent in the HPV negative head and neck cancer space. Before we jump in, a quick reminder on the mechanistic differentiation of Viterra, a potentially first and best-in-class bifunctional EGFR-directed antibody combined with a TGF-beta like MTAP. FICERA combined tumor targeting with tumor modulation, where the EGFR arm localizes to the tumor, while the TGF-beta arm serves as the treatment modulator, designed to deliver superior efficacy, improve safety and enhance durability directly at the tumor site. FICERA specifically addresses a key challenge in solid tumor treatment by enabling immune cell penetration into tumors reducing fibrosis and immunosuppression, while reversing TGF-beta-driven resistance mechanisms, ultimately designed to drive the deep, durable responses that may translate into better outcomes and survival for patients. For patients with recurrent metastatic head and neck cancer, there remains a significant unmet need for improved treatment outcomes. The current standard of care pembrolizumab provides response rates of only 19% as a single agent and 36% in combination with chemotherapy. The median overall survival remains poor at only 12 to 13 months. Importantly, for people living with HPV negative disease, real-world data consistently show worse survival outcomes as low as 7 to 9 months compared to the overall population when treated with stand with care. The biology tells us why. These tumors overexpress both EGFR and TGF-beta. TGF-beta creates a hostile fibrotic tumor microenvironment that excludes immune cells, driversistance to checkpoint inhibitors, such as pembrolizumab and limits the durability of any response. Standard EGFR antibodies don't address this, that's precisely [indiscernible] was designed the way it was. The opportunity ahead is significant. Head and neck cancer is a fast-growing global market projected to exceed $5 billion in sales in 2030 and growing with roughly 50,000 annually incident patients across major markets. including 18,000 patients in the United States alone. Today, we are presenting long-term data across 3 dose expansion cohorts from our Phase Ib study. The 1,500-milligram weekly dose, which is currently being evaluated in our pivotal Phase III study, fortifying channel 1 represents our most mature clinical data set. The additional dose cohorts of 750 milligrams weekly and 2,000 milligrams every other week were evaluated as part of the broader dose optimization effort to support dose selection and explore alternative dosing strategies. Importantly, what we'll show today is that results across all the cohorts [indiscernible] demonstrated deep and durable responses consistent with our underlying mechanism of action to inhibit TGF-beta. We've taken together today's data further differentiates FICERA's clinical profile. I would like to highlight 3 key points. At a median follow-up of 3 years, 1,500 milligrams weekly of FICERA plus pembrolizumab doubled overall survival versus standard of care, demonstrating a 31% overall survival versus pembrolizumab monotherapy which demonstrated approximately 15% overall survival at nearly 3 years in a real-world study of HPV negative patients. Across all doses of FICERA, there were no new safety signals observed up to 3 years of follow-up and FICERA continues to demonstrate a generally well-tolerated safety profile. Three, TGF-beta inhibition translates to unprecedented depth of response, which yields clinically differentiated long-term outcomes, including duration of response, progression-free survival and overall survival. Collectively, these data provide further confidence in the differentiated clinical profile of FICERA driven by the TGF-beta mechanism and continue to derisk our pivotal study. I'll now turn the call over to our Chief Medical Officer, Bill Schelman, who will walk us through the data.

Thanks, Claire. Before I review the efficacy and biomarker data, I want to draw your attention to the patient demographics and baseline characteristics. In line with what has been previously presented, baseline characteristics are consistent with those seen in HPV negative head and neck cancer. Notably, patients with large bulky tumors with low CPS and local regional recurrence were enrolled into these cohorts. As of the data cutoff, March 31, 2026, the safety profile of FICERA continues to be generally well tolerated and consistent across all 3 dose cohorts with no new safety signals a profile, we are pleased to see maintained as the data set matures and patients have extended treatment exposure. Hypophysis TGF-beta-related AEs, specifically mucosal bleeds, sendable bleeds and epistaxis remain generally low grade. Additionally, there has been no meaningful increase in treatment discontinuation due to treatment-related AEs even with longer follow-up and the combination of FICERA with pembrolizumab demonstrated a favorable benefit/risk profile. Updated biomarker analyses confirm that FICERA sustained TGF-beta neutralization in plasma across all 3 dose cohorts. Importantly, we saw intratumoral reduction in postomats, a pharmacodynamic marker for TGF-beta pathway inhibition across all 3 doses. We also saw a regulation of CD8-positive T-cell infiltration in paired biopsies, reaching statistical significance in the 1,500-milligram weekly and 2,000 milligram every other week dose groups confirming that TGF-ss inhibition enables immune cells to penetrate the tumor and drive meaningful immune activation at the site of disease. When comparing median depth of response in the proportion of deep responders at the same 24-week follow-up, the data are clear. The deeper responses are observed at doses of FICERA that show greater TGF inhibition and tumor penetration. These data are also important for 3 reasons: first, they confirm target engagement. Second, they provide mechanistic foundation for the depth of clinical responses observed in the cohorts. And third, they strengthen the confidence in our pivotal trial and provide the rationale for our loading and maintenance strategy, which maintain therapeutic exposure while offering greater patient convenience. All 3 dose cords at FICERA demonstrated high and consistent overall response rates. Critically, the depth of response is more pronounced at higher doses and the complete response rates underscore that finding. Since prior presentations of the 750-milligram 1,500-milligram and 2,000 milligram cohorts, complete response rates in each of these cohorts have increased. In the 1,500-milligram weekly cohort, the dose being evaluated in our Phase III study, 80% of responders achieved a deep response, defined as a response of greater than 80% tumor reduction. Similarly, 77% of patients in the 2,000 milligram every other week cohort had deep responses. Taken together, these data demonstrate that greater TGF-beta inhibition at higher doses drives not just responses for responses of meaningful and durable depth. To put our data in further context, we continue to believe that the TGF-beta arm of FICERA is what drives depth of response that translates into durability. By targeting immune exclusion in the tumor microenvironment, we believe FICERA synergizes with immunotherapy to enable immune cell penetration that is driving a 22-month immunotherapy like median duration of response similar to what was shown with pembrolizumab, but with higher response rates and greater overall survival. Beyond standard of care, FICERA's meaningfully differentiated from other investigational combinations, which have not shown durability measures out this long. The median duration of response for the 1,500-milligram cohort was mature at our 2-year update last year, a striking 21.7 months. New data show that while the 750 milligrams and 2,000 milligram cohorts are still maturing, median duration of response has already surpassed approximately 17 and 13 months, respectively meaningfully exceeding what has been observed with pembrolizumab for cetuximab and other investigational combination. This speaks to the mechanism of action of TGF-beta inhibition. When looking at progression-free survival, all 3 dosing cohorts demonstrated clinically meaningful disease control. As a reminder, the median PFS of 3.2 months was shown with pembrolizumab in HPV all-comers. At all 3 doses, FICERA improved upon PFS over standard of care from 6.9 months at 750 milligrams, 9.9 months at 1,500 milligrams and 12.7 months at 2,000 milligrams. The 2,000 milligram every other cohort is particularly noteworthy with a median PFS of 12.7 months more than triple the PFS seem with pembrolizumab which supports further development of our loading and maintenance dosing regimen. This also shows that greater TGF-beta neutralization is associated with enhanced progression-free survival. Turning to overall survival. The mature data in the 1,500-milligram weekly cohort showed a median overall survival of 21.3 months Today, we are still to present updated data confirming that FICERA drives a meaningful overall survival tail, with a striking 31% 3-year overall survival rate. By comparison, pembrolizumab demonstrated that approximately 20% to 25% overall survival rate in the HPV all-comer population and a 15% overall survival rate in the HPV negative population. FICERA doubled the overall survival rate in HPV-negative patients at 3 years versus standard of care. While the 750-milligram and 2,000 milligram cohorts are still maturing. Early trajectory suggests that median overall survival is trending towards the median overall survival we are seeing with the 1,500-milligram weekly dose. As a reminder, our 2,000 milligram cohort enrolled in a bimodal pattern. In the initial 15 efficacy evaluable patients with a median follow-up of 27 months, median overall survival has not yet matured but has already surpassed 23.6 months. The remaining 12 efficacy evaluable patients have a median follow-up of 11.7 months, and we anticipate this group to have consistent efficacy as the data mature. FICERA demonstrated rapid responses and high overall response rates across all doses regardless of CPS score, tumor burden and occurrence of distant metastases. The breadth of activity across CPS scores is particularly noteworthy. In patients with CPS 1 to 19, where pembrolizumab monotherapy yields only a 15% response rate Bisera continues to drive strong responses. This is a result of TGF-beta inhibition, which reverses the fibrotic immune-excluded microenvironment that limits checkpoint activity in this population. This is an area where no other investigational EGFR has shown comparable results, underscoring the potential for FICERA in combination with pembrolizumab to be a chemotherapy-free treatment option. I'll now turn the data from our second poster, which examines how depth of response translates into meaningful durability and survival benefit. To do this, we combined the 3 cohorts in separated patients into deep responders those achieving tumor shrinkage of greater than 80% and responders with tumor shrinkage between 30% to 80%. This slide examines duration of response by depth of tumor shrinkage. What stands out is a clear separation between these 2 groups. Patients who achieve deeper responses experienced substantially more durable disease control with meaningfully longer duration of response in a consistently more favorable clinical course across outcomes. In practical terms, deep responders are significantly more likely to maintain the response over time compared to those with more modest tumor shrinkage. This reinforces that depth of response is a strong predictor of durability and overall survival long-term benefit. This is a key hallmark of TGS-beta inhibition and FICERA's clinical profile. Building on that, the next slide shows that the depth drives durability story extends beyond duration of response. It carries through to both progression-free survival and overall survival. Looking at progression-free survival, deep responders had a median PFS of 37 months, and we're 65% more likely to remain progression-free with a hazard ratio of 0.35. With respect to the analysis of overall survival, median overall survival and deep responders has not yet been reached, with deep responders, 63% more likely to remain alive, corresponding to a hedge ratio of 0.37 and far exceeding 3 years of overall survival. Taken together, the data reinforce that deep responses were strongly associated with better long-term efficacy outcomes including substantially prolonged duration of response, progression-free survival and overall survival when compared to a standard response. In addition, neutralizing TGF-beta-mediated immune exclusion provides a clear biological mechanism for the deep and durable responses observed. Now that we've walked through the data, it's worth grounding ourselves and what oncologists actually care about when making treatment decisions in that context is what underscores the clinical significance of everything we've just presented. When oncologists evaluate a new treatment, they want confidence in tumor shrinkage, long-term disease control and preserve quality of life. Specifically, clinicians report that complete response rate, depth of response and duration of response are key factors in what drives that confidence beyond overall survival. Reflecting the need for a therapy that has fundamentally altering the tumor microenvironment and driving deep durable responses. Bicara delivers on all 3 overall survival rates out of 3 years that more than double standard of care in HPV-negative patients, complete response rates as high as 30%. Deep responses in more than 2/3 of responders and a median duration of response of 21.7 months at the pivotal trial dose. Exactly the profile oncologists say would move them to adopt a new regimen. Everything we've shown today connects back to 1 mechanistic thread. FICERA TGF-beta-mediated tumor penetration is what drives deep responses that are durable, and that results in improved long-term outcomes. Our translational biomarker data established this foundation, Targeted TGF-beta inhibition in the tumor drives immune cell penetration and immune activation. That mechanism translates directly into deeper responses. At doses with greater TGF-beta inhibition, complete response rates and the proportion of deep responders both increased, culminating in 80% of responders achieving a deep response at the 1,500-milligram pivotal trial dose. Now with long-term follow-up across these 3 cohorts, today's focus is on durability and improved long-term outcomes. Across approximately 90 patients and with up to 3 years of follow-up, we see consistent efficacy improvements. a clear trend of improved duration of response, progression-free survival and overall survival at doses with greater TGF-beta inhibition, and deep responses translating into meaningfully better long-term outcomes across all 3 end points. The totality of this data reflects an efficacy and safety profile that has strengthened over time and with broader patient exposure and positions Bicera as a potentially best-in-class option in this disease. We also believe that these data strongly validate the FORTIFI-HN01 design, giving us conviction in both the ORR-based interim analysis as well as the confirmatory overall survival end point. I'll now turn it back over to Claire for closing remarks.

Thanks, Bill. Before I turn the call back to the operator, let me just close by reiterating the significance of what we're presenting this week at ASCO Three years ago, we began enrolling patients in the disease with a median overall survival of 7 to 9 months. Today, the data speaks for itself, and we believe makes a compelling case for FICERA's differentiated potentially best-in-class profile. We extend our sincere gratitude to the patients, families and investigators whose participation and partnerships are the foundation of this work and the hope it represents for the broader head and neck cancer community. We are excited about what these data mean for our pivotal study, for FORTIFI-HN01, and we look forward to continuing to update you on our progress. Thank you.

[Operator Instructions] Our first question comes from Tyler Van Buren with TD Cowen.

Thanks very much for the presentation. Just curious, why do you think you're seeing greater depth of response at 24 weeks or even similar depth, frankly, with the 2,000 milligram dose group compared to the 1,500 milligram dose group because even though the dose itself is higher, of course, the exposure over time is lower, given that it's so every 2 weeks instead of every 1 week with milligram dose. Could this be due to the pulsatile nature of higher TGF-beta inhibition? Or could the biology here be different than what we typically think about in oncology?

Thanks for the question, Tyler. So as we look at it and we continue to characterize the exposure response relationships of both components, the eGFR as well as the TGF-beta. I think it's one of the things that I think there's far more kind of known pharmacodynamic biology associated with eGFR and we continue to characterize with our various data sets, TGF-beta. I think it does begin to, I think, make us think is that there's probably some Cmax-related effect that you're getting with TGF-beta. You're absolutely right. From an exposure perspective, it comes in lower than the 1,500-milligram dose, but there are -- is a higher Cmax, obviously. And we continue to see dose responsiveness clearly up to 2,000 milligrams across the various dose groups.

Our next question comes from Eric Schmidt with Cantor.

Congrats on a really clear and consistent data set. I continue to encouraged by your biomarker data. And I'm just wondering if on an individual patient basis, you can correlate some of these [indiscernible] reductions with greater tumor control or depth of response and then maybe second, based on everything you've shown us today, how can you tie this back to or what's the learning in terms of the viability of the Q3 week maintenance dosing strategy that you intend to execute on. Is there some correlation to evidence of support for that dosing.

Thanks, Eric, for your questions. So I'll answer the first question first, which was around individual results of FospaD2. So we do have individual results from a number of paired biopsies. Unfortunately, the N is small since we weren't able to get too many biopsies from these patients, in many cases, especially in our rapid deep responses with complete responses were unable to get a second on-treatment biopsy. But from the data that we have, there does seem to be an early correlation that our deepest responders have the highest postomat inhibition, so again, tying back to the data we presented today showing that at the higher doses we are seeing more TGF-beta inhibition, higher depth of response, and it's that depth of response that's leading to outsized durability seen with increased median PFS, median DOR and median OS in the cases where the data has matured Q3 dosing, I pass that over to Ryan.

Yes. From your question around every 3 weeks, the dose, again, as a reminder that we're taking into the maintenance phase of that is 2,250 every 3 weeks. And we ultimately landed on that dose because it does replicate on an exposure basis, the 750 milligrams weekly data. So as you look at the update that we provided at ASCO, you see meaningful durability even in the 750-milligram dose, which gives us confidence as we go into that essentially from a pharmacokinetic perspective every 3 weeks. And in a lot of ways, I think it's important to note in that 750-milligram cohort that we presented, you're basically starting to 750-milligrams from the very beginning. With the approach that we are taking, where we were going to initiate with 1,500 milligrams weekly, where we're seeing rapid deep responses. By the time we transition to every 3 weeks, in many, many patients, those tumors have reduced to 80% reduction and then 1 in 5 patients, a complete response. So that data that we've seen with 1,500 milligrams accompanied with the data and durability that we're seeing at 750-milligram gives us a high degree of confidence that we're able to get rapid deep responses and then maintain them in the maintenance phase.

Our next question comes from Stephen Willey with Stifel.

And think the graphs on Slide 21 kind of summarized this quite nicely. Can you just remind us of the dosing schedule at which pembro is being administered in 4 to 5? And just given the potential Cmax-driven benefit of TGF-beta ambition, I was just discussed, wondering if you think there's any potential synergy or additivity to extract by coupling the higher maintenance dose that you're planning to use with the higher bolus of pembro that's administered on the Q6W schedule. I know that was the temper dosing schedule used in the 2,000 big cohort.

Great. Actually, I'll start and then I'll pass it over to Bill to speak to a little bit as well. Again, what we see is pembro can be dosed either every 3 or every 6 and the FORTIFY trial, we're dosing every 3 weeks. I think it's interesting, your question around the Pulsatile nature and the potentially Cmax benefit with -- the -- I think the -- as you get out there to those maintenance phase patients, and again, I think one of the things that's really important is by that point in time, we have dramatically reduced the overall tumor burden in these patients. So I do think that the higher pulse, I think we believe that you will be able to maintain not only maintain, but potentially even some of the tons who haven't been able to get to complete responses by the time you transition to the [indiscernible] we do believe with the data that we've seen across our various cohorts, including the 2000, that we may be able to, even in the maintenance phase, continue to drive deeper responses. I think it's notable you at this update across all 3 cohorts you've seen additional patients get to complete responses. And so we really like, again, the possibility of being able to do that with the regimen that we've determined and kind of the alternative schedule with an initiation and a maintenance phase. And I don't know, Bill, if you want to add anything incremental to that?

Yes. Thanks, Ryan. In terms of the alternative dosing study, as we've discussed in the past, there'll be a loading dose for 12 weeks of 1,500 milligrams followed by the maintenance phase. And the question regarding Cmax and synergy with pembrolizumab we've modeled as Ryan said exposure response that study states are achieved by the time we get to the Q3 dosing. So when we give 2250 milligram in that study along every 3 weeks along with pmab. We're maximizing the TGF beta in ambition and maximizing the exposure response characteristics to drive these deep and durable responses that are demonstrated in these data here?

Okay. That's helpful. And then just curious if we should be expecting to see another cut of this data. I mean, obviously, median OS hasn't been reached in a couple of the dose cohorts, and I know you're still tracking longer-term landmark OS. So is this another -- or will there be another cut of this that we should expect to see at some point going forward?

Yes. I think, Steve, from that perspective, we have continued to update when there's been meaningful changes. And I think, obviously, this is one of them. And so I think we will continue to track against the cohorts. All these patients remain in long-term follow-up. So I think that again, as data continues to mature and inform the story, I think well consistent with what we've done in the past. I think we'll make updates when they make sense and add to the story.

Our next question comes from Tazeen mad with Bank of America.

A couple of questions. You talked about the deep responses that you've observed so far. So I wanted to ask if you've been able to identify any predictors who could have such deep responses just based on the data you've collected so far. Second, you presented a lot of data already today. So should we expect to see any additional data at ASCO itself and then a third one, if you could, can you just talk about the timelines for the maintenance dose study and what level of data you think you'll be available at the time of approval there.

Thank you for your question, Tazeen. So the first question was related to predictors of response. And so as you know, we have selected it for HPV-negative patients who have high overexpression of both eGFR and TGF-beta. What we typically seen, which is related to Eric Schmidt question from Cantor is that patients with the highest degree of phospho SMA2 inhibition tend to be some of our deepest responders. And so with the higher baseline phosphosmat-2, which is a correlate for TGF-beta activity, we typically see those as our deepest responders. But in general, this is again highly overexpressed in HPV-negative patients, which is why we focused on this HPV-negative population. Your second question was, will there be additional data at ASCO. The presentation this morning was a combination of our 2 data posters presented by Dr. Deborah Wang from new CLA and Dr. John Kassar, which is a combination of the 2 posters that will be presented at ASCO. Then I think last but not least, you asked a question around the Q3W maintenance study. So as we highlighted on our Q1 earnings call, the intent is to begin those studies -- the design of that study in Q3 of this year and have the data in hand in terms of PFS by the time of our ultimate approval. Thank you for your questions.

Comes from Brad Canino with Guggenheim.

You gave a lot of information on tumor burden and extensive disease. I think that's on Slide 18. And can you speak to the importance of including a broad population across all 3 of your cohorts? And how that shapes your confidence in your Phase I signal as we get nearer and near your interim Phase III readout next year.

Thanks for the question, Brad. So we find it important to be able to demonstrate, again, the consistency of activity regardless of whether we have small tumors, big tumors, local, regional and local tumors. And so it really speaks again, the consistency across all of the various different subsets that we know are kind of out there in the community, and we've been able to demonstrate again that consistency. I think particularly from a target -- overall target size or tumor sizing is we've recognized in today's treatment paradigm that many physicians are choosing chemotherapy-based regimens in those patients where the tumor burden is higher. And so being able to demonstrate that you see good activity, you continue to see rapid responses in those patients regardless of even if they have a high tumor burden. We do think that we provide an opportunity to be able to provide an alternative to chemotherapy-based regimens where you see durable responses, rapid responses and I think 1 of the things that has been a shortcoming in those patients who received chemotherapy, you saw it in the KEYNOTE-48 study is that many of them has to come off because of tolerability. And with us being able to show great durability. We think that, that's an important element as we think about being able to treat across a range of patients, including those today who are getting chemotherapy-based regimens.

Our next question comes from Kelsey Goodwin with Piper Sandler.

Congrats on the update. So I think 2 questions from us. First, we still sometimes get questions about safety for TGF-beta traps. I guess, across these 91 patients, I think what do you think that you can say definitively now for FICERA versus some of the prior TGF-beta trap? And then secondly, as we see some changes across some of the key competitor trials. What do you hear in your channel checks in terms of FICERA's relative competitive positioning? And how has that changed, say, from this time last year.

Great. So I'll start with your second question and then ask Bill to elaborate on the safety profile related to TGF-beta. I think we definitely -- as we continue to develop the drug and make updates I think what we're consistently hearing both in the KOL community, we do as well as our research with community oncologists is I think the durability certainly stands out. And I think there continues to be confirmation, the difference between HPV positive and HPV negative disease, I think we continue to be validated amongst the KOL community and even as the data is emerging, and I think we're even -- we're seeing it with -- in other investigational agents, the profile stands out, the ability to show in a more difficult population extended durability. And I think the other thing that is standing apart is the depth that we believe squarely driving the durability and ultimately with long-term outcomes. And so as that data continues to mature, we believe our profile and the KOL community I think is supportive of that, that this is a profile that is standing apart really based upon the contribution that we think is being driven by the TGF-beta biology. And so with that, I'll ask Bill to speak and elaborate on the TGF-beta profile from a safety perspective.

Yes. Thank you. So with respect to the safety profile, what we're seeing is that the AE profile, TRE profile is consistent with what we'd expect from the mechanistic action of FICERA with skin toxicity being the most common with EGFR inhibition and then with TGF-beta, we're seeing some anemia and low-grade non-mucosal bleeds, with respect to anemia, it's important to contextualize that in this patient population, the HPV negative patients. Anemia is -- baseline anemia is more common related to their comorbidities and prior therapies and underlying disease state. With respect to TGF-beta, we're seeing some increase in anemia related to effect on red blood cell production, but this has been well managed with iron supplementation and general supportive measures. The overall safety profile though has been generally well managed. And as you've seen, there's been consistent and very low discontinuation rates related to TRAs and to less than 10% and less range. So overall, there's been a consistently generally well tolerated and manageable profile with low discontinuation rates.

And I think -- and also, what I'd add to that as well, again, with the design of this molecule, we designed it in such a way where the trap is the extracellular domain TGF-beta receptor II, and we did that purposefully in order to be able to dial out some of that historical both cardiomyopathy and some of the bleeding that was associated with TGF-beta. So I think what we're seeing is the profile continues to evolve is that by making that design choice very early in the construct of this molecule, I think we've been effective in being able to really begin to mitigate some of the stuff that was historically seen at TGF-beta.

Our next question comes from Judah Frommer with Morgan Stanley.

This is Park on for Judith. Just 1 from us. On the 1,500 mg group, are you guys seeing any differences in OS trending between CPS 119 and CPS greater than 20 patients.

Thank you for the question. I'll ask Bill. Again, in terms of -- at this point, I don't believe we've disclosed the difference between the 2 populations. And I'll ask Bill to elaborate if there's anything that we have yet seen there.

Yes, specifically related to the 1,500-milligram cohort we're seeing a generally consistent efficacy in patients with CPS low versus the CPS high, and as Ryan commented before, this is also consistent across other tumor characteristics, including patients with bulkier tumors and more poor prognostic characteristics.

Our next question comes from Reni Benjamin with Citizens Bank.

Congratulations on this data. As we think about the FORTIFY study and this data as it pertains to the FORTIFY study, how should we be thinking about other selection criteria that you might be employing so that we might not see a diminution in terms of response rates and activity given the larger patient population and the potential for heterogeneous disease.

Yes. I think what I would say is, again, the inclusion/exclusion criteria is in the FORTIFY trial is very consistent with what we've had in the Ib trial. And I think in terms of the way we thought about the population, again, we did so, recognizing that probably the best anchoring study historically was the KEYNOTE-48 trial, and as we think about being able to have a reproducible control outcome, I think that was important to us. So I'd say what you see in baseline characteristics of the data that we presented across these 3 cohorts, I would say that you could expect to see a consistent demographic profile. And again, that is very consistent with what we've seen in the KEYNOTE-48 trial.

Got it. And maybe just as a follow-up, as we think about the ORRs that we're seeing, -- it seems like there's a step down in the ORRs as we go up in dose. But then the CR rates and the depth of responses kind of go the other way, right, and we start seeing an improvement in those. Can you maybe just help me reconcile how that might be working?

Yes. I'd say it really is, again, consistent with what we have seen with the pharmacodynamics of TGF-beta. And I think similar to I think a question we received earlier around the -- is there a Cmax dynamic that's driving those deeper responses. I think the nice thing across these 3 data sets is it really has allowed us to characterize the contribution of TGF-beta. And I don't know, Claire, if you have anything else that you'd like to add to that. But again, I think we really attribute it to the TGF-beta across and the PD of the TGF-beta.

Yes, very much so. I think what we know is responses are predominantly driven by the EGFR arm. And so we've seen strong consistency across those very similar to other EGFR inhibitors but if you really see what the differentiating profile of FICERA, it's really predicated on the TGF-beta arm, where we've seen higher TGF-beta inhibition at both the 1,500-milligram weekly in the 2,000 milligram every 2-week dose. And consistent with that, those are the 2 tumor -- the 2 cohorts where we've seen not only improved depth but improved durability and ultimately, overall survival. So I think the goal of this data set was really to speak to, again, TGF-beta inhibition driving depth of response and ultimately, durability and overall survival benefit.

Our next question comes from Jit Murat with BTIG.

So we spoke a lot about drug exposure levels and its relationship with efficacy. But have you seen any trends on exposure levels as it relates to safety and tolerability, particularly as it relates to anemia and the bleeding events and ultimately, just your confidence around the safety profile for the maintenance 2250 dose.

Yes. Good question. And I think what I would point to is, again, data that we previously presented at the 2,000 milligrams, you did see a slight increase in Grade 3 anemia as those doses went higher. I think 2 things that I would say there is you don't see meaningful differences between 750 and 1,500 milligrams from a safety perspective, which, again, when we align with the FDA for project Optimis, the key thing that FDA is looking for is the risk benefit of the 2 doses. And it was clear in the data that we've demonstrated and agreed to by the FDA that the benefit associated with 1,500 milligrams with greater depth, greater durability ultimately outweighed any incremental tolerability profile at the 1,500-milligram picked up, given that it was so minimal. I think also it's key to look at those AEs that require discontinuation or dose holds. And again, as you compare between 750 and 1,500 milligrams, there was minimal differences while at the same time we saw a benefit in efficacy. In terms of what gives us our confidence as we go to 2,250 maintenance dose, and part of the thing that gives us that confidence is our exposure response modeling, recognizing that the 2,250 is stretched out to every 3 weeks. And from an overall exposure basis, it then, again, replicates a profile that's more comparable to 750. We have not seen anything from a Cmax-related tax perspective that gives us concern. So again, across the totality of the data that we have, and it's allowed us to do robust exposure response modeling. We've got a lot of confidence in the approach that we're taking.

Our next question comes from Boris Peaker with Jones Trading.

Great. I just want to follow up on your prior comments. Talking about discontinuation. I know the rate was relatively low, but are there any strategies that you can implement in the planned studies to reduce the discontinuation rate across the board?

Yes. I think it's certainly something that we have interrogated deeply from our Ib experience. I would say, generally, the discontinuations have been very low. There's been no consistent thing that has led to those discontinuations. So it's not like there's a specific area I think we have -- one of the things Bill spoke to the anemia, one of the things that we're doing proactively is you see a lot of baseline anemia in head and neck patients. We're looking at that closer as they come on to study in order to make sure that if a patient has come on at initial screening, and they're already running with a low hemoglobin that we'll be more proactive with oral iron to bring that hemoglobin up. That being said, anemia hasn't led the discontinuations. And so I think that while we continue to monitor the overall I think profile of these patients as they come on to therapy, I'd say that there's nothing in particular that we're seeing within the profile that you're able to kind of mitigate prospectively.

Great. My second question is you run the FORTIFY study as well as the loading and maintenance dose studies. Are some of those both trials going to be running at individual clinical sites. I'm just trying to understand if there could be potential competition between 2 studies for the same patients? And if so, how would those investigators kind of decide which way to randomize the patient and if that could somehow induce some bias in patient selection?

Yes. It's definitely something that we're very mindful of in terms of the overall operational plan of those 2 trials, recognizing that we're looking to rapidly enroll both I'd say that in many cases, we'll be looking at alternative sites in order to do that to mitigate, I think, that potential risk. I think that being said, the every 3-week trial also for patients where their proximity to the clinic is a little further. I think that is an option for them. But again, it's something that we're incredibly, I think, deliberate and intentional amount as we think about the operational plan for both trials and being able to maximize enrollment.

Our next question comes from Eva Forteo with Wells Fargo.

A very quick 1 from us. I forget, are there any plans for a potential subcutaneous formulation for FICERA?

Thanks for the question. And we absolutely are doing feasibility work around I think the initial focus here was for us to, again, be able to develop the every 3-week maintenance regimen, which I think meaningfully improves on the overall convenience and administration schedule. That being said, we are doing work as it relates to understanding the feasibility and our ability to potentially offer a subcutaneous formulation in the future.

That concludes today's question-and-answer session. I'd like to turn the call back to Claire Mazumdar for closing remarks.

Thank you all for listening in today, and we look forward to seeing many of you at ASCO. Thank you.

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