Bicara Therapeutics Inc Aktie

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. Please go ahead.

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 filings 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 statement made on this call represents 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 and mature clinical data set assembled for ficerafusp alfa or FICERA in first-line recurrent or metastatic HPV-negative head and neck cancer. These data span approximately 90 patients across 3 dose cohorts with up to 3 years of follow-up in 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 FICERA, a potentially first and best-in-class bifunctional EGFR-directed antibody combined with the TGF-beta ligand trap. FICERA combines tumor targeting with tumor modulation, where the EGFR arm localizes to the tumor, while the TGF-beta arm serves as the tumor modulator designed to deliver superior efficacy, improved safety and enhanced 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 or 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, but 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 standard of 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, drives resistance to checkpoint inhibitors such as pembrolizumab and limits the durability of any response. Standard EGFR antibodies don't address this. That's precisely why FICERA 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, FORTIFI-HN01, 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 a 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 have repeatedly demonstrated deep and durable responses consistent with our underlying mechanism of action to inhibit TGF-beta. 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 after 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 locoregional recurrence were enrolled in each of 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.

Hypothesized TGF-beta-related AEs, specifically mucosal bleeds, gingival 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 confirmed that FICERA achieved sustained TGF-beta neutralization in plasma across all 3 dose cohorts. Importantly, we saw intra-tumoral reduction in phospho-SMAD2, a pharmacodynamic marker for TGF-beta pathway inhibition across all 3 doses.

We also saw upregulation 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-beta inhibition enables immune cells to penetrate the tumor and drive meaningful immune activation at the site of disease. When comparing median depth of response and 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-beta 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 maintains therapeutic exposure while offering greater patient convenience. All 3 dose cohorts of 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 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, but 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 is meaningfully differentiated from other investigational combinations, which have not shown durability measures of 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-milligram 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 plus 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, a 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 week cohort is particularly noteworthy with a median PFS of 12.7 months, more than triple the PFS seen 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 thrilled 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 an 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 doubles 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, FICERA 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 to 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 and 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 achieved deeper responses experienced substantially more durable disease control with meaningfully longer duration of response and 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 TGF-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 were 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 in deep responders has not yet been reached with deep responders 63% more likely to remain alive, corresponding to a hazard ratio of 0.37 and far exceeding 3 years of overall survival.

Taken together, the data reinforced 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 in what oncologists actually care about when making treatment decisions. And 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 preserved quality of life.

Specifically, clinicians report that complete response rate, depth of response and duration of response are key factors in what drive that confidence beyond overall survival, reflecting the need for a therapy that is fundamentally altering the tumor microenvironment and driving deep durable responses. FICERA 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 one mechanistic thread. FICERA's TGF-beta mediated tumor penetration is what drives deep responses that are durable and that result 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 increase, 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 endpoints.

The totality of these data reflects an efficacy and safety profile that has strengthened over time and with broader patient exposure and positions FICERA 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 endpoint. 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 a 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.

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 dosed every 2 weeks instead of every 1 week with 1,500-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 what 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 be encouraged by your biomarker data. And I'm just wondering if on an individual patient basis, you can correlate some of these phospho-SMAD2 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 question. So I'll answer the first question first, which is around individual results of phospho-SMAD2. 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, we're 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 phospho-SMAD2 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 is mature. Q3 dosing, I'll pass that over to Ryan.

Yes. Eric, from your question around every 3 week, 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 replicates 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 at 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 at 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 in 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 milligrams 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.

I think the graphs on Slide 21 kind of summarize this quite nicely. Can you just remind us of the dosing schedule at which pembro is being administered in FORTIFI? And just given the potential Cmax-driven benefit of TGF-beta inhibition that 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 pembro dosing schedule used in the 2,000-milligram cohort.

Great. Actually, yes, I'll start, and then I'll pass over to Bill to speak to it a little bit as well. Again, what we see is pembro can be dosed either every 3 or every 6. And in the FORTIFI trial, we're dosing every 3 weeks. I think it's interesting, your question around the pulsatile nature and 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 continue to maintain -- not only maintain, but potentially even some of the patients who haven't been able to get to complete responses by the time you transition to the 2,250.

We do believe with the data that we've seen across our various cohorts, including the 2,000 milligrams that we may be able to, even in the maintenance phase, continue to drive deeper responses. I think it's notable with 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 in 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, an exposure response that steady states are achieved by the time we get to the Q3 dosing. So when we give 2,250 milligrams in that study along every 3 weeks along with pembrolizumab, we're maximizing the TGF-beta inhibition 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 we'll -- 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 Ahmad 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 will 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've typically seen, which is related to Eric Schmidt's question from Cantor, is that patients with the highest degree of phospho-SMAD2 inhibition tend to be some of our deepest responders. And so with the higher baseline phospho-SMAD2, 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? No, the presentation this morning was a combination of our 2 data posters presented by Dr. Deborah Wong from UCLA and Dr. John Kasmar, 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.

Next question comes from Brad Canino with Guggenheim.

You gave a lot of information on tumor burden and extent of disease. I think that's on Slide 18. 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 nearer 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 to, 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 size as we recognize 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 one of the things that has been a shortcoming in those patients who received chemotherapy, you saw it in the KEYNOTE-048 study is that many of them have 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 traps? 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 is 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 even we're seeing it with other investigational agents that 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 is squarely driving the durability and ultimately the 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, TRAE 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, HPV-negative patients, anemia -- 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 an 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 TRAEs in the 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 Kelsey, 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 of TGF-beta receptor 2. And we did that purposely 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 that 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 with TGF-beta.

Our next question comes from Judah Frommer with Morgan Stanley.

This is Parth on for Judah. Just one from us. On the 1,500-milligram group, are you guys seeing any differences in OS trending between CPS 1 to 19 and CPS greater than 20 patients?

Thank you for your 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 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 FORTIFI study and this data as it pertains to the FORTIFI 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 that, again, the inclusion/exclusion criteria that is in the FORTIFI 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-048 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 that 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-048 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 is it's really predicated on the TGF-beta arm, where we've seen higher TGF-beta inhibition at both the 1,500-milligram weekly and the 2,000-milligram every 2-week dose. And consistent with that, those are the 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. Thank you for your question.

Our next question comes from Jeet Mukherjee 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 2,250 dose.

Yes. Good question. And I think what I would point to is, again, data that we previously presented at the 2,000 milligrams, where 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 that you don't see meaningful differences between 750 milligrams and 1,500 milligrams from a safety perspective. which, again, when we aligned with the FDA, for Project Optimus, 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 is that the benefit associated with 1,500 milligrams with greater depth, greater durability ultimately outweighed any incremental tolerability profile that 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 milligrams 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 a 2,250 maintenance dose, again 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 milligrams. We have not seen anything from a Cmax-related tox perspective that gives us concern. So again, 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 comment. Talking about discontinuation, I know the rate was relatively low, but are there any strategies that you could 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 kind of 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're being more proactive with oral iron to bring that hemoglobin up.

That being said, anemia hasn't led to 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. And my second question, as you run the FORTIFI 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 a 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 about as we think about the operational plan for both trials and being able to maximize enrollment.

Our next question comes from Eva Fortea with Wells Fargo.

Very quick one 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 subcu. 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.

Good morning, everybody. Welcome back to the Bank of America Healthcare Conference. I'm Tazeen Ahmad, one of the senior biotech analysts here at the bank. It is my pleasure to have our next presenting company Bicara Therapeutics. Up here on stage with me is Ryan Cohlhepp from Bicara. Ryan, good morning. Thank you for making the trip over from Boston.

Thank you. Thank you for having us, and I appreciate the opportunity to meet with you here today.

So maybe for those who aren't as familiar with the Bicara story, can you just give us a quick overview of the company and your lead program, and then we can go into some questions from there.

Yes, absolutely. So Bicara Therapeutics, so we're a company focused on large molecules, so bifunctional antibodies focused in solid tumor oncology. Our lead program is ficerafusp alfa, which is an EGFR TGF-beta and we -- the company was founded in 2020. We're based in Boston, Massachusetts. And today, we're a development phase company and have about 100 employees. We've grown fairly rapidly over the last 2 to 3 years following going public in 2024. Our lead program, again, as I mentioned, our focus is on bifunctionals, where what we're looking to do is use tumor targeting to get things like TGF-beta to the tumor. Early on, when the asset was being developed, one of our views was that TGF-beta had a lot of promise, but we had seen very limited activity, particularly in the oncology setting with TGF-beta.

I think the most notable was the Merck KGaA GSK molecule bintrafusp alfa that ultimately had to be discontinued. And our view was that what the shortcoming was there, you weren't able to get adequate levels of TGF-beta to the tumor. And so we were using EGFR, cetuximab as our mechanism to get to the tumor, ultimately to deliver TGF-beta there. I think ultimately, we've now seen that has played out clinically with the data, which I'm sure we'll get into in more detail. But overall, kind of that's the concept and the focus that we have as a company.

Okay. So your leading indication is for head and neck cancer. How did that become your first optimized indication?

Yes. So as we evaluated, one of the things that we have done and continue to do is to evaluate those tumor types where there's both a role for EGFR and for TGF-beta. And there are a handful of tumors. I think a couple of the more obvious ones are head and neck cancer, colorectal cancer, there's a clear view for EGFR. It wasn't always clear whether there was a TGF-beta signature there. And early on, we -- one of the things we wanted to be able to characterize is the contribution of TGF-beta. With molecules like Erbitux, there was a clear view that you had activity in head and neck cancer. And in CRC, as we looked at that development landscape, it's likely one where we would have to go head-to-head against Erbitux given kind of where it is in the treatment paradigm.

And head and neck, we look there, the standard of care in the recurrent metastatic setting was pembro monotherapy or pembro plus chemo has a 19% response rate. There have also been investigator-sponsored studies, one by Dr. Tina Sacco at UCSD another by Christine Chung at Moffitt, who showed when you added pembro to cetuximab, you were able to increase response rates pretty significantly. So we looked at the standard of care, where the opportunity was. We also felt that it gave us an opportunity where based upon the IST data that the likelihood that we were going to be active was very high and it would give us the opportunity to understand what we were getting from TGF-beta before going into a tumor type like colorectal cancer, where we were going to have to go head-to-head against cetuximab.

I think we clearly have now been able to do that. We've seen in our data of particular interest is we're seeing deep responses. Our complete response rate in head and neck cancer, we have 21%, which, again, is kind of unprecedented in the head and neck space. So that really was ultimately in terms of where we thought we could develop the drug, where we thought we could be able to characterize the contribution of both EGFR and TGF-beta. We thought head and neck was a good opportunity.

Okay. So you talked about the targets that you've got for your bispecific. There's another asset that is now part of -- it's the Merus assets, peto, and it's been acquired and the acquirer Genmab has made some changes to the trial design. So maybe let's start with how do you think your molecule is differentiated from theirs? And maybe why do you think that they've decided to upsize that study, which is their pivotal study for frontline?

Yes. So I'll start with the differentiation. I think it really comes down to we all have EGFR as a component of the molecule. And another molecule that is also developing in that space is J&J's Ami, which is an EGFR/c-MET. The petosemtamab molecule, their secondary component is LGR5 and then with Ficera, it's TGF-beta. And we really think that it's that secondary component where you see differentiation clinically. And what we've seen in our data is more than 80% of our patients who respond will have a reduction of their tumor of 80% or greater. And so we're seeing really deep responses. We believe that depth of response is ultimately delivering durability. We presented at ASCO 2025 median duration of response of over 21 months, again, which is unprecedented in those investigator-sponsored studies that I had mentioned, you see with cetuximab plus pembro around a 13-month median duration of response. With some of the other investigational EGFRs, you're seeing similarly kind of in that teen range.

What really stands out with our molecule is the duration of response. We believe that ultimately is predictive and has translated into the median overall survival, which again is approaching 22 months. And so at the end of the day, we believe that the depth is driving durability. The durability is driving overall survival and where ultimately our molecule will separate and differentiate from an efficacy perspective. You pointed out the recent changes that we saw on clinicaltrials.gov in the petosemtamab LiGeR-1 trial. What we see there is an increase of the total in of about 200 patients. I think that trial is now 700 patients. And one of the key areas of difference between the way we designed our program and the way that program and that trial was designed is they included HPV-positive patients.

We made the decision to focus our trial exclusively on HPV negative based upon our own data as well as data from other EGFR monoclonal antibodies. You see historically, whether it be with cetuximab, Vectibix and panitumumab had done a study. There was an EGFR monoclonal that Genentech had been developing. In all of those cases with close to 1,000 patients' worth of data, you consistently see that with EGFR monoclonal antibodies, you see far better activity in HPV-negative patients than what you do in HPV-positive patients. You see the response rates more consistently kind of in the 30% range. Based upon that, we wanted to develop our molecule where we thought we were going to have the ability to see the most profound benefit, which is in HPV negative. Do we work in HPV positive? Yes.

Again, we had 11 patients in our Phase Ib experience. 3 of those 11 responded. 2 of our 3 responders were complete responses. So the drug is absolutely active there. We made the decision to do a biomarker selective population based on HPV negative. I think ultimately, we've not heard exactly what was behind the thinking in terms of why Genmab decided to increase that. I think what they have stated publicly is they're looking to do so to increase probability of success. I think to some degree, that is validating of our approach, again, where we thought the greatest benefit was going to be in the HPV-negative patients. And so it's likely that there was that recognition by Genmab as well.

Okay. So for clarification, head and neck cancer can be caused by HPV. So if you are HPV positive versus HPV negative for those that may not know the story, and what percent of the population is HPV negative based on your research?

Yes. If you look at the recurrent metastatic setting, about 85% is HPV negative. As you break down, there are multiple subtypes of head and neck cancer, 4 specifically. Three of those 4 are presumed to be HPV negative. The only one the testing is required is in the oropharyngeal subset. And in that case, that accounts for about 30% of the subtype and about 1/3 of oropharyngeal is HPV negative. So you've got, again, I think, 70% that is presumed to be negative of that last 30%. You have an incremental 15%, gets you to 85% that are HPV negative.

Okay. So as of right now, I don't think Genmab has made any statements about timing for the readout for Phase III. When it was part of Merus, I think the expectation was it would read out like at year-end of this year. So let's say that by adding more patients that might increase the time to read out for them. Just remind us of when you expect your pivotal study to read out and maybe just remind us also of the study design for that.

Yes. So we -- what we have guided to is that we will have top line data from our study middle of next year. And enrollment continues to be on track. The other thing we have guided to is that we will be substantially enrolled by the end of this year, which will enable that top line data cut middle of next year. The design of our trial is -- we initially actually started with 2 different doses of Ficera to satisfy Project Optimus by the FDA. Earlier this year, we were able to announce that we had met with the FDA and we're able to move forward with the 1,500-milligram dose, so the higher of the 2 doses and formally transitioned to the Phase III component of the trial.

We now, in the Phase III portion, we're randomizing 2:1 to Ficera 1,500 milligrams plus pembro versus pembro monotherapy with the first interim analysis is look at overall response rate with 6 months of durability. And so we'll do a data cut once we've had about 350 patients with 6 months of follow-up to assess the durability of those responses, and that's what will yield the top line data cut middle of next year.

Okay. What would you consider to be good data, competitive data?

Yes. Again, if you go back to benchmarking pembro monotherapy, Merck never broke out HPV positive versus HPV negative. There are multiple real-world data sets. Flatiron had done a study of about 600 patients. There, you see an HPV-negative pembro monotherapy doesn't do quite as well as the 19% that we see in the KEYNOTE-048 study. But I think a roughly doubling of response rate is clinically meaningful. Ultimately, at the end of the day, what matters is getting overall survival. And I think that's one of the things that if you look across even the KEYNOTE-048 study, there, when you added chemotherapy, what you saw is you were able to increase response rates. The response rate when you added chemotherapy went from 19% to 36%, but it didn't really have a meaningful increase in overall survival.

That overall survival went from 12.3 months to 13. And so while a doubling of response rate is clinically meaningful and based on feedback that we have from the FDA will be supportive of being able to get that accelerated approval. At the end of the day, being able to deliver a meaningful benefit in overall survival, again, which we think the early predictor of that is going to be the durability of those responses is what really is going to be the most important.

Okay. So in terms of the market opportunity for head and neck, I think people have been trying to back out KEYTRUDA sales and what proportion of it is head and neck, and that number seems to be increasing. I think the latest I've heard is that head and neck sales for KEYTRUDA are around somewhere between $3 billion and $4 billion. I don't know what you're hearing, but would love to hear the latest on any market data that you've enlisted market data research.

Yes. We've heard similar. We've heard anywhere from 5% to 10% of global KEYTRUDA sales are in head and neck. And I think it's interesting to think about that. What we know, particularly in head and neck is you don't have great response rates. Again, in the monotherapy setting, only 1 in 5 patients are responding and that duration tends to be relatively low. Pembro monotherapy has a good duration. But when you add chemotherapy, that duration goes down to about 7 months. So you think in a scenario where KEYTRUDA sales globally for head and neck are 3 to 4 and you've got a real opportunity based upon our Phase Ib data, we see the opportunity to both expand the responder population and to meaningfully expand the duration of therapy. So we really see the opportunity here. I envision probably by 2030, the eGFR bifunctional class in head and neck probably easily exceeds $5 billion as you think about the opportunity of adding these into the treatment and being able to both obviously expand the responders and the duration.

Okay. So given that it's seemingly becoming a more crowded market. So if you think about peto, if you think about Ficera, let's also talk about J&J and some recent data that was released from Inhibrx. How do you think about the sizing of the opportunity relative to the number of players that are trying to enter head and neck?

Yes. I think the interesting thing, I think we're -- J&J also is developing an HPV-negative population. And I would say that the trial approach they are taking is slightly different than what ourselves and Genmab are taking. Again, with what we've seen from J&J is they're developing in combination with chemotherapy. One of the things that we know in terms of the treatment decisions is those patients who today are getting chemotherapy often are patients with lower CPS scores, CPS 1 to 19, but also have bulky disease. What we hear consistently from oncologists is if you have a patient that has high tumor burden that they're looking to debulk that pretty quickly, that's today where they're using pembro plus chemo or they're using cetuximab plus chemo.

One of the things that we've been able to demonstrate is the consistency of our data regardless of CPS score. You see very consistent overall response rates regardless of whether it's CPS 1 to 19 or CPS 20 or greater. The other thing that we've been able to demonstrate, and we broke it out and we have begun to show it this way as recently as ASCO over the last year is the activity based on some of the target lesions. One of the things that early on, people were questioning based upon our complete response rate is where we see in CRs only in those patients with really small tumors. And what we've been able to demonstrate is even if you have a bulky disease, we're able to get rapid responses. And so I think even though the trial is designed with pembro monotherapy as the control arm, the data that we have demonstrated and we will continue to build on that data is the ability to also have activity in those patients today who are getting chemotherapy.

One of the things I had mentioned the lack of the response reading through to better overall survival. One of the reasons we believe that happened is about 30% of patients on the pembro chemo arm ultimately had to discontinue early because of adverse events associated with chemotherapy. With a regimen like Ficera plus pembro, we've got the ability to see those long durations, not add the toxicity of chemotherapy. So we really believe that we are positioned to be able to compete both in that chemo market as well as the pembro monotherapy market whether it be -- and I think that that's where we're able to kind of straddle both relative to some of the other EGFR bifunctionals.

Okay. And any thoughts on the IL40?

Yes. I think we saw data on Monday. That data came out at the same time we were doing our earnings call. So we were kind of multifaceted trying to look at that data at the same time. I think there, the data that they demonstrated is in the population of CPS20 or greater. I thought that for that mechanism, I think it was probably exceeded expectations for the mechanism. That being said, that response rate doesn't really stand up to what the other EGFR bifunctionals have been able to demonstrate ourselves included. And I think there are still some questions. I don't think we've yet seen detailed safety data.

And so I think that in terms of both the data as well as where they are in terms of overall development, I think they have publicly declared enrollment will finish that trial in 2029. So it puts them well behind where we are. I think it's -- I think it could be an option for some patients. But again, I think that so far, the data package doesn't look quite as competitive as some other agents.

Okay. I wanted to maybe touch on the safety profile of the drug. What's your view of the profile so far? I think earlier on, there was some concern that there might be a bleeding signal. But as you've collected more data on more patients, how doctors response been to the overall profile of the drug, specifically on safety? And what are your expectations of what the Phase III readout could show?

Yes. So on the tolerability side, you have the on-target EGFR acneform rash that you see very consistently with historical EGFRs and the other EGFR bifunctionals. I think one of the interesting things in our molecule, again, the mAb portion of it is cetuximab the molecular kind of composition, 80% of our overall molecule is cetuximab. And so you think about that at a 1,500-milligram dose, we're getting 1,250 milligrams of cetuximab on board, which is almost 3x what Erbitux was able to do, yet you're seeing a similar rash profile.

One of the things that was interesting about that is we've seen preclinically is the TGF-beta actually is playing a role around neutrophil trafficking that is mitigating some of that severity of rash, which allows us to get more EGFR on board. I think very, very consistent with what we expected. In fact, maybe even a little bit better than what we expected because we were given such a much higher dose of cetuximab. On the TGF-beta side, early approaches to TGF-beta, there were concerns, cardiac concerns that was focused on TGF-beta 2. In the design of our trap, we actually designed it in such a way to dial out some of that cardiomyopathy that was seen in earlier versions of TGF-betas.

I think there were perceived concerns around bleeding risk. What we've seen in our molecule is we see some nose bleeds, some gingival bleeding. The one thing to note is in head and neck cancer, there's a lot of disease-related bleeding. And we've been really pleased in those events where we do see some mucosal bleeding, it tends to be very transient grade 1 and those cases haven't required discontinuations or dose holds. So I think we've been able to dose -- and we now have dosed up to 2,400 milligrams as we continue to explore alternative doses for less frequent -- one of the things that we announced on our call on Monday is we have aligned with the FDA on a maintenance regimen where we will start with weekly therapy for 12 weeks, and then we will transition to 2,250 milligrams every 3 weeks, which gives the ability for patients to synchronize their dosing with pembro, which is every 3 or every 6 weeks.

And even at doses exceeding 2,000 milligrams, we still see a safety profile that is very tolerable, that keeps people on therapy. That's, I think, real key here. I think you go back to studies even like the lenvatinib plus pembro study where a lot of patients had to come off because of AEs. And at the end of the day, pembro monotherapy did better than pembro plus lenvatinib. And so in head and neck, we need to keep people on therapy, and we've been able to do that with our tolerability profile.

Okay. So in terms of the data readouts for '27, of course, is the pivotal. Have you guided to when next year?

Mid next year.

Middle of next year. Okay. And then between now and then, let's talk about -- you have a poster update, I believe, coming up at ASCO. Can you just remind us what you're going to show?

Yes. We're going to show we have 2 posters. One is focused on longer-term follow-up with all of our cohorts. The 3 main cohorts of patients we have are the 750-milligram cohort, the 1,500 milligram, which is the selected dose. And then we had a cohort of 2,000 milligrams every 2 weeks. What we've demonstrated last year at ASCO was the 1,500-milligram 2-year follow-up, and that's where we had a stable median overall survival, median duration of response. We now will have 3 years of follow-up in that patient population, you'll be able to further characterize the tail. And by comparison, pembro monotherapy in an HPV-negative population at 3 years, their survival is about 15% from a benchmarking perspective.

For other 2 cohorts, the data wasn't mature enough when we first presented it. So you haven't yet seen duration of response, PFS or overall survival. We will update the data with those durability endpoints at ASCO. And so that will be part of what you'll be able to see there is, again, we want to continue to characterize the clinical contribution of TGF-beta because we think that is so critical in our differentiation and ultimately, what's going to deliver better overall survival. And again, what you saw for response rates between 750 and 1,500 milligrams were similar response rates. And that makes a lot of sense because at 750, we have fully saturated EGFR and you think mechanistically what EGFR is going to deliver versus TGF-beta.

TGF-beta really doesn't overcome de novo resistance. It overcomes acquired resistance. So it will contribute to durability endpoints. And so what you would really expect is that you're going to see -- you saw similar response rates, you would expect to see better durability than what you would see with just an EGFR mAb, but probably not as good as 1,500 milligrams. But again, what that allows you to do is really begin to demonstrate the real benefit and the contribution of TGF-beta, and that's what those posters will really be able to demonstrate.

Okay. Any other updates at any other medical meeting this year planned?

We have the possibility -- we have -- we're accruing to CRC cohorts and the possibility of being able to show our first CRC data in the second half of this year at a medical meeting.

Okay. So the inevitable comp will be versus what peto had shown early-stage CRC data. I think it came in probably below expectations. So based on that, what level of confidence do you have that you'd be able to show higher quality efficacy?

Yes. The third-line population is a tough one. And again, I think peto was able to demonstrate 10%. Historically, with cetuximab retreatment, you see about 13%, which is small in a really difficult patient population. We know the drug is active with the EGFR component. As we look at that, in CRC, we're taking a fairly measured approach and not only do we want to ensure that we have a competitive profile within CRC, but we also know we have a lot of other opportunities with this molecule. We've shown activity -- monotherapy activity in cutaneous squamous cell. We've seen anal canal activity. We know that there is a huge opportunity in locally advanced. So for us, our internal bar not only is being competitive in CRC, but it has to be competitive with our other options as a company.

And so as we look at that data in the second half of this year, it really will be from the perspective of where we think we have the best opportunity to demonstrate a benefit for patients and the highest probability of success relative to the other opportunities that we have. And so I think we're looking forward to seeing that data. Again, we have 2 cohorts, both the monotherapy cohort and one in combination with pembro. That cohort may not be as obvious because you haven't really seen much activity of pembro there. But what we're looking for is, again, using -- with the TGF-beta mechanism and the hypothesis we have around being able to alter the immune environment, we want to see whether our molecule in combination with pembro actually is able to also do that in late-line CRC, the way it has in head and neck cancer.

Okay. And how many patients worth the data will that be?

Yes. We're expecting probably around 15 to 20 patients per cohort when we present it at a medical meeting.

Okay. So it's not going to be in a PR, it will be at a metical meeting?

It will be at a medical meeting.

Okay. As you think about the sizing of that opportunity, where do you think it could fit in CRC?

Yes. And again, I think for us from that perspective, third line, again, is not as huge of an opportunity. I think we also are seeing -- is there a signal there that would put us in a position where we would want to move into earlier lines more rapidly, which obviously is huge, but also competitive. And so as we think about, again, some of those other opportunities, a key for us not only is going to be response rates, but also is the durability of those responses in PFS, a 30% response rate with only a 2- to 3-month PFS probably isn't nearly as interesting as being able to go into locally advanced head and neck where you have the opportunity to have a meaningful benefit for a longer duration.

Okay. Maybe before we wrap up, I just wanted to get a sense of your balance sheet, cash needs and how far it could take you.

Yes. So we reported on Monday cash at the end of the quarter of $540 million. That gets us into 2029. So be able to fully execute on the pivotal trial, the randomized trial with every 3-week schedule as well as beginning to build out our commercial and medical affairs organization. We also announced on Monday the hiring of our Chief Commercial Officer, Chris Sarchi, who joined us last week. And so we're well funded, have the ability to execute on the trials that we have ongoing as well as to begin to plan and build for our commercial launch.

Okay. And then how big of a commercial organization do you think you would need? Do you have a sense for that?

Yes. Again, our base case expectation is we will launch first in the U.S. off the accelerated approval. I think that head and neck, as you look at it, definitely is an approachable for a company who will be launching for the first time. So I would fully expect that we would be, over time, adding an additional 100 to 150 people into the organization, inclusive of additional medical affairs and commercial team members.

Okay. And then last question for me is what are your thoughts on business development, bringing in external assets? Or do you feel like you have enough momentum on your internal efforts?

Yes. I think we're super excited about the opportunity with Ficera. I think there are a lot of opportunities there and frankly, more opportunities than the capital that we have. That being said, we're always looking as we think about building a sustainable company that will win and succeed in the future. We continue to look at opportunities that fit with what we're looking for. Again, I think large molecule solid tumor assets are something that we continue to explore and look out for to enhance what we already have with Ficera.

Okay. With that, we are out of time. So thanks very much, Ryan, for spending the last half hour with me on stage, and thanks, everybody, for joining.

Thank you.

Good day, and thank you for standing by. Welcome to the Bicara Therapeutics First Quarter 2026 Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your first speaker today, Rachel Frank, Vice President of Investor Relations and Corporate Communications. Please go ahead.

Thank you, and good morning, everyone. It's a pleasure to welcome you to Bicara Therapeutics First Quarter 2026 Earnings Call. Earlier this morning, we issued a press release highlighting results from the quarter and recent business progress. 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 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 filings 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 statement made on this call represents 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; Bill Schelman, Chief Medical Officer; Ryan Cohlhepp, President and Chief Operating Officer; and Ivan Hyep, Chief Financial Officer.

I'll now turn the call over to Claire.

Good morning, and thank you for joining us today. The first quarter of 2026 set a strong foundation for the year ahead. We made measurable progress on the strategy we outlined earlier this year with continued momentum behind our lead asset, ficerafusp alfa or ficera, which we believe is a potentially best and first-in-class bifunctional EGFR-directed antibody combined with the TGF-beta ligand trap for the treatment of HPV-negative first-line head and neck cancer.

Our priorities remain focused on executing a strategic development plan for ficera, preparing for commercial success by laying the foundation to capture a large and growing global market in head and neck cancer and expanding ficera's potential beyond our lead indication, while maintaining financial discipline.

To deliver on those priorities, we are building the team to match our ambitions as we transition from a clinical stage to a commercial stage organization. With that in mind, I want to share a few updates this morning.

After several years as our Chief Medical Officer, Dave Raben has transitioned to a Senior Executive Adviser role and Bill Schelman, previously Executive Vice President of Clinical Development, has stepped into the CMO role. Dave has been instrumental in shaping Bicara into the company it is today, guiding ficera into pivotal Phase III development and building the foundation of our clinical and medical organization. We are deeply grateful for his contributions and look forward to his continued partnership in his advisory capacity.

Bill is well positioned to build on that foundation. He joined us last fall as an experienced development and commercial stage leader and has quickly made an impact across our development programs.

And as we build toward commercial launch, we are thrilled to have brought on a proven leader to guide that work. Chris Sarchi joined last week as our Chief Commercial Officer, bringing extensive oncology, commercialization and leadership experience. Chris will continue building out the team with additional hires across market access and commercial operations in the months ahead.

In addition, we made a number of key updates in the first quarter. First, our continued execution has us on track to achieve substantial enrollment in FORTIFI-HN01 by the end of the year, positioning us for an interim analysis in mid-2027 for potential accelerated approval.

With that progress, our belief in ficera's potential to be both best and first-in-class in frontline recurrent and metastatic HPV-negative head and neck cancer has only strengthened. That conviction is grounded in ficera's differentiated mechanism, the depth and durability of response we have observed and our development approach.

Recent developments in the competitive landscape are reinforcing this view. While the market has at times viewed peer time lines as ahead of ours, that picture is changing, driven by our own continued progress as well as the significant upsizing of a peers pivotal trial. Together, these dynamics support our potential path to first-in-class. They also validate the strategic choice we made to develop ficera specifically for HPV-negative patients, where the science, the unmet need and the commercial opportunity align.

Second, and Bill will speak to this in more detail, based on discussions with the FDA, we plan to initiate a study that will evaluate ficera in combination with pembrolizumab as a loading and every 3-week maintenance dosing regimen. This is an advancement that we believe has the potential to expand optionality for patients and providers and enhances the long-term commercial profile of ficera.

Third, just last Friday, a peer-reviewed manuscript was published in the Journal of Clinical Oncology, detailing results from our Phase Ib expansion cohort, evaluating 1,500 milligrams of ficera weekly in combination with pembrolizumab in frontline recurrent metastatic head and neck cancer, data most recently presented at ASCO 2025. This publication is an important milestone that validates and adds to the growing body of scientific evidence supporting ficera's differentiated mechanism of action and clinical benefit. It also provides the broader oncology community with a peer-reviewed view of the data underpinning our pivotal program.

And lastly, with the completion of an oversubscribed public offering in February, built on an already strong cash position, we are well positioned to invest in the opportunities ahead of us.

As we look ahead to the next quarter and the remainder of the year, we're excited to share meaningful long-term follow-up data at ASCO in a few weeks. The data will further characterize ficera's safety profile, along with the depth and durability of response driven by TGF-beta inhibition. These data span all 3 clinical doses tested in expansion cohorts, including the dose we're advancing in our pivotal trial.

We are also continuing to enroll multiple Phase Ib expansion cohorts to identify early proof-of-concept signals and inform ficera's development strategy, both within head and neck cancer and across solid tumors.

With that, I'll turn it to Bill to walk through our recent clinical updates and what to expect from us at ASCO this year.

Thanks, Claire, and good morning, everyone. We have taken a deliberate and thoughtful approach to evaluating ficera in patient populations with high unmet need and with the strongest biological rationale. This has included development in head and neck cancer as well as other solid tumors, including metastatic colorectal cancer, cutaneous squamous cell carcinoma and anal cancer.

In that context, our recent disclosures have focused on clinical data from approximately 90 patients across 3 cohorts from our Phase Ib study evaluating ficera in combination with pembrolizumab in frontline recurrent or metastatic HPV-negative head and neck cancer. This patient population has particularly poor outcomes with limited treatment options and represents the vast majority of patients in this setting.

The 1,500-milligram weekly plus pembrolizumab cohort, which is the dose we are currently evaluating in the Phase III portion of the FORTIFI-HN01 pivotal trial was presented at ASCO last year and represents our most mature data set.

With 2 years of follow-up, deep and durable responses were observed with a median duration of response of 21.7 months and a median overall survival of 21.3 months, more than doubling the overall survival observed with the standard of care of pembrolizumab in HPV-negative patients.

The 750-milligram weekly plus pembrolizumab cohort supported the evaluation of the optimal biological dose of ficera in the Phase II portion of our ongoing FORTIFI trial and helped to inform selection of the 1,500-milligram weekly as the OBD that is currently being evaluated in the Phase III portion of the study.

The data from these cohorts also reinforces our confidence in the interim analysis of overall response rate as the foundation for pursuing accelerated approval.

The cohort evaluating 2,000 milligrams every other week plus pembrolizumab demonstrated that even at a less frequent dose, we see rapid and deep responses that are the hallmark of the ficera clinical profile. The data from this cohort also helped inform our alternative dosing regimen study.

Across all 3 Phase Ib cohorts, the depth and durability of response observed underscore the central role of TGF-beta inhibition in ficera's mechanism. By enabling tumor penetration, TGF-beta inhibition drives the kind of deep and durable responses that translate to long-term survival benefit.

Taken together, the data presented to date affirm that ficera has the potential to be a well-tolerated chemotherapy-free treatment option across the spectrum of disease burden, including in patients with large bulky tumors and low CPS scores, where rapid and deep responses are particularly critical.

As we look towards ASCO 2026, we will be presenting updated data across all 3 of these cohorts from the Phase Ib study. We will provide 3-year follow-up data from the 1,500-milligram cohort, which will allow us to characterize the long-term efficacy from this dose compared to the standard of care.

We will also share long-term endpoints from the 750-milligram weekly and the 2,000-milligram every other week data sets. These data will provide the most comprehensive look at ficera in frontline recurrent and metastatic HPV-negative head and neck cancer to date, including durability of outcomes not seen with other investigational agents targeting EGFR in this setting, a key differentiator and the signal of ficera's best-in-class potential. Additionally, the strength and consistency of these results across cohorts further derisk our pivotal FORTIFI-HN01 trial.

Another key aspect of our ASCO update is that we'll further characterize the role of TGF-beta in head and neck cancer. TGF-beta inhibition is the defining feature of ficera and what sets it apart from other EGFR-directed therapies.

Our translational data has shown consistent TGF-beta inhibition across all ficera doses, confirming the mechanism behind tumor penetration and immune activation with the strongest inhibition at the 1,500-milligram weekly dose and the 2,000-milligram every other week dose.

We'll also look to show how tumor penetration driven by TGF-beta inhibition translates into depth and durability of response that leads to long-term outcomes for patients.

Alongside the clinical story, we'll continue to build at ASCO, we're also focused on optimizing how ficera is delivered to patients. As previously mentioned, based on discussions with the FDA, we plan to initiate an alternative dosing study in the third quarter of this year. This study will enroll approximately 150 to 200 patients and will evaluate the efficacy of ficera on a 12-week loading phase followed by an every 3-week maintenance phase regimen.

All patients will receive 1,500 milligrams weekly of ficera plus pembrolizumab for 12 weeks and will then be randomized to either continue 1,500 milligrams weekly of ficera plus pembrolizumab or transition to 2,250 milligrams every 3 weeks plus pembrolizumab. The primary endpoint will evaluate progression-free survival.

In designing an alternative dosing regimen, our priority is to preserve ficera's potential best-in-class profile while creating practical options for patients and providers. Since we expect to seek accelerated approval for ficera with the 1,500-milligram weekly dose from the FORTIFI-HN01 study, running this randomized study in parallel will allow us to potentially have results from this study in time for a potential approval, creating a compelling path for early adoption of the streamline regimen.

Additionally, this addresses an important need for patients, providers and payers, specifically by providing treatment options that will reduce clinic burden, improve quality of life and support long-term adherence. And critically, this dosing strategy is shaping how we are thinking about life cycle management and ficera's opportunity beyond frontline recurrent or metastatic head and neck cancer.

With that, I'll turn it over to Ryan to discuss the potential market opportunity and what's ahead for the rest of the year.

Thank you, Bill. Turning to the broader opportunity, we have strong conviction in the differentiated profile ficera has shown across our clinical program compared to other investigational agents in head and neck and the development strategy we built around that profile designed to deliver against the full opportunity ahead. Head and neck cancer is a significant and fast-growing global market projected to reach more than $5 billion in global sales into the 2030s.

HPV-negative patients represent a large majority of patients in the frontline recurrent metastatic setting and HPV status is known at the time of diagnosis, which means that HPV testing is not a barrier to care. Across major markets, there are roughly 50,000 annually incident patients, including approximately 18,000 in the U.S. where we plan to launch initially.

The unmet need in this population for a therapy that drives deep, durable and clinically significant benefit while sparing chemotherapy and improving quality of life is what makes the rigor of our clinical data and the discipline of our development strategy matter.

It is also why we continue to invest in the medical and commercial infrastructure required to deliver ficera to patients. This includes the commercial leadership team we have been building with Chris now leading our commercial efforts, including the prelaunch evidence generation and field readiness work required for a successful oncology launch, and we look forward to having him on the road with us at ASCO and beyond.

While the frontline recurrent metastatic setting is our initial focus, the opportunity for ficera in head and neck cancer is much larger. Given our conviction in ficera's potential to be both first and best-in-class, we see clear space to own and lead a broader segment of the head and neck cancer landscape.

The locally advanced setting, in particular, represents another large market with clear biologic rationale for ficera and a meaningful opportunity for expansion.

As we think about that opportunity, we have initiated 2 investigator-initiated sponsored studies in the locally advanced setting and continue to enroll additional cohorts that will inform our expansion strategy. including a cohort of patients in frontline recurrent metastatic HPV-negative head and neck cancer with CPS less than or equal to 1 as well as a cohort of patients with frontline recurrent metastatic HPV-positive head and neck cancer with heavy history of smoking.

Beyond head and neck, we believe there is a strong biologic rationale to expand ficera's pipeline and the potential into solid tumor types with significant unmet need.

We have already shown proof of concept in indications such as cutaneous squamous cell carcinoma and anal canal cancer, reinforcing our conviction in ficera's broad applicability across TGF-beta-driven tumors.

Building on that foundation, we are currently enrolling patients in a Phase Ib expansion cohort evaluating ficera, both as a monotherapy and in combination with pembrolizumab in patients with third-line plus metastatic colorectal cancer.

TGF-beta is implicated in metastatic disease and resistance to current treatments, providing a biologic rationale for evaluating ficera in this setting. This is also a challenging setting. Patients are very sick, often progressing rapidly through prior lines of therapy. And with the treatment landscape in CRC continuing to evolve, we are taking a measured approach with a high bar for what would warrant further investment.

As the data mature across these cohorts, we will continue to make thoughtful decisions about where ficera can deliver the most differentiated value and how we allocate our resources accordingly.

With that, I'll turn it to Ivan to review the financials.

Thanks, Ryan. Earlier this morning, we reported detailed first quarter 2026 financial results in our press release, and I'll summarize a few highlights here.

Our total operating expenses for the first quarter of 2026 increased compared to our first quarter of 2025, driven by clinical operations and development expenses associated with our ongoing pivotal FORTIFI-HN01 study, including increased manufacturing and development costs.

We also saw an increase in personnel-related costs, including stock-based compensation as we have grown our workforce, primarily in support of clinical operations and development functions.

Consistent with the first quarter, we anticipate continued increases in operating expenses for 2026, reflecting increased investment in our clinical operations, particularly for the pivotal FORTIFI-HN01 study, with the interim analysis expected in mid-2027 and parallel study as well as an increase in SG&A, as we invest in early commercial and medical infrastructure to support the potential launch of ficera.

We ended the first quarter of 2026 with $539.8 million in cash, cash equivalents and marketable securities, bolstered by an oversubscribed public offering in February that generated $161.8 million net proceeds and meaningfully strengthened our balance sheet, which provides cash runway into the first half of 2029 and allows us to invest thoughtfully in areas we believe will deliver future clinical and commercial success.

With that, I'll now turn the call back over to the operator for questions. Operator?

[Operator Instructions] And our first question comes from Eric Schmidt of Cantor.

Maybe one in terms of what to expect at ASCO in a couple of weeks' time. Can you provide us with any benchmarks for 3-year outcomes data, landmark data in HPV-negative head and neck? And then you mentioned looking at the role of TGF-beta as well. Does that mean that we're going to see some correlations between PD and response rates?

Thank you for your question, Eric. So the question was relating to a preview of the ASCO 2026 data sets. So as we highlighted during the call, there are 2 separate abstracts that were accepted at behalf of ASCO. One is focused on long-term follow-up in terms of the 3 expansion cohorts in frontline recurrent and metastatic HPV-negative head and neck with the most mature data set being the 1,500-milligram one you were alluding to, which will have 3 years' worth of median follow-up. In that one, we really hope to speak to the so-called immunotherapy [ tail ] driven by the TGF-beta durability.

And so in there, if you look at prior precedents, pembrolizumab in all-comers delivers about a 20% to 25% 3-year overall survival, while it's believed to be about 15% to 20% in the HPV-negative subsets of real-world data sets.

The other abstract is focused on looking at depth and durability of response from the TGF-beta inhibition, and we'll continue to speak to what we believe is ficera's defining hallmark that TGF-beta inhibition is driving this depth and response that's ultimately leading to far superior durability than other investigational agents and leading to outsized overall survival benefit.

And our next question comes from Tyler Van Buren of TD Cowen.

Congrats on the progress. Just wanted to ask a quick follow-up before my question, if you don't mind. A follow-up on Eric's question related to the ASCO data. I guess it's clear that we'll have 3 years of follow-up with the 1,500 mg dose. But since investors are asking, it would be helpful if you could just clarify how much follow-up we should expect with the 2,000 and 750 dose cohorts. We can obviously guess, but just clarity there would be helpful.

And then I guess my main question is related to the alternate dosing regimen of the 1,500 mg induction with the 2,250 mg maintenance. Do you think it's possible that, that regimen could have improved durability than either 1,500 or 2,250 alone based upon exposure and the data that you've produced to date?

Thanks for your questions, Tyler. So I'll answer the first question first, which is a question around the other 2 cohorts being presented at ASCO, which are the 750-milligram weekly cohort as well as the 2,000-milligram every 2-week cohort. Both of those have approximately 12 to 18 months worth of median follow-up. And so we do plan to share longer-term follow-up data sets for both of those at ASCO in a few weeks.

And to help answer your question around durability of response in the maintenance setting, I'll pass that question over to Ryan.

Thanks, Tyler, for the question. In terms of the regimen, again, the overall approach that we are taking there, as you mentioned, is we're initiating with the 1,500 milligrams weekly and then transitioning to a maintenance phase of 2,250.

A couple of, I think, key tenets of that approach. One, as you recognize in the data that we presented thus far, we see deep rapid responses, which are enabled by the 1,500-milligram dose. And really being able to get a depth of response, more than 80% of our patients are getting depth of response of 80% or greater, which we really believe is contributing to that durability.

One of the things that the 2,250 every 3 weeks enables is an exposure profile that allows us to, I think, maintain that durability after we received -- or achieved very meaningful reductions in tumor reductions and keeping patients on from a tolerability perspective, I think being able to bring people into clinic every 3 weeks rather than every week while maintaining exposures that maintain that durable response. We absolutely believe that this regimen potentially enables both a more durable as well as a better -- a more tolerable profile.

And our next question comes from Stephen Willey of Stifel.

Maybe just some color around the use of PFS as a primary endpoint in the dose optimization trial, just given that this is obviously an event-driven endpoint, there's no control arm. And then is there a formal non-inferiority margin that you need to hit? I guess just any color you can provide around kind of this formal notion of comparability would be helpful.

Thanks for your question, Steve. So I'll actually answer the second part of your question first around non-inferiority. This is actually not designed as a noninferiority study. We got positive feedback from the FDA based off of our discussions based off of the sizing of the study, which we alluded to being approximately 150, 200 patients, it does not -- it would have required far more patients as a non-inferiority study.

The other focus, again, going back to Tyler's question, the other focus of looking at this dosing regimen is really, again, to ensure that we're maintaining the efficacy profile focused on depth and durability of response with the induction into maintenance dosing.

And so the focus of the PFS endpoint was really to look at that ensuring the durability is consistent between the 2 arms. And the FDA was comfortable with PFS being that endpoint for that reason.

And our next question comes from Kelsey Goodwin of Piper Sandler.

I think you alluded to it in the prepared remarks, but for your competitors' frontline trial where they increased target enrollment by about 200 patients, I just first wanted to confirm, is there any read-through to FORTIFI in its trial size? And then secondly, how do you think about the gap in timing now between ficera and [ Pido ].

Thank you for question, Kelsey. So just to highlight, we were alluding to the LiGeR-1 study, and you may have not seen on clinicaltrials.gov that the page is updated to reflect enrollment of 700 patients, up from the original 500 in an all-comers study. I think that's consistent with feedback we've been hearing from investigators that they were planning to add additional HPV-negative patients.

From what we have heard today that there was potentially an imbalance in terms of HPV-positive versus HPV-negative patients in that particular study given that -- there are no other HPV-positive studies in Phase III.

We haven't seen any read-through other than the fact that it continues to highlight what we've always highlighted that ficera has the potential to be both best and first-in-class. We've seen very strong execution of the FORTIFI-HN01 study, and those dynamics continue to speak to what we believe is a significant narrowing of the perception around ficera and FORTIFI being second to market. In fact, we continue to believe in our potential first in class.

And our next question comes from Brad Canino of Guggenheim.

It's nice to be on the call. At ASCO, maybe just to drill into one of the doses, the lower 750 mg, which wasn't selected for the Phase III. So how do you look at that as really being able to support the TGF-beta hypothesis given the exposure and coverage that it provides? And will that view only be in a subset of patients such as the responders?

And then just a quick second, given we're talking about the competitor trial and the upsize, where do you sit with expected timing of OS analysis for your Phase III study today?

Thanks, Brad, for your question, and welcome to the team. So to the first question around the 750-milligram dose, so that was, as you highlighted, a dose that we did not take forward in the pivotal Phase III study. However, we do see a significant TGF-beta inhibition. And we know that from an EGFR receptor occupancy, we are fully saturating the EGFR locus. So we've always thought of it as still superior than EGFR monoclonal antibody while showing slightly less TGF-beta inhibition.

What you will continue to see at ASCO is that even in this patient population, the hypothesis that TGF-beta inhibition is driving improved depth and durability will continue to speak to another strong data set that will reinforce the notion now in a total of 90 patients that we have strong depth and durability data that will speak to that overall survival benefit.

And your second question was related -- I apologize, timing of OS analysis. As we continue to guide to the interim analysis for potential accelerated approval is slated for mid-2027, which is a look at overall response rates with 6 months of durability and likely a look at qualitative overall survival at that time.

We do anticipate being focused on HPV-negative patients only that our event rates will happen more rapidly than those of our peers and that the OS endpoint will come again more rapidly than anticipated.

And our next question comes from Judah Frommer of Morgan Stanley.

Maybe just broadening out the competitor conversation a bit. We saw some data from an OX40 targeting asset this morning, but I believe in CPS greater than 20. So maybe can you just remind us of kind of the breakdown of the epidemiology by CPS score and kind of what the advantages of a broader targeting asset in ficera could be? And again, what time lines could look like versus this asset?

Thanks for your question, Judah. I do believe you're referring to an InhibRx presentation that actually I believe is happening at the same time as our call. So while we haven't had a chance to significantly look at the data set, I can speak at a high level to those results.

So as you alluded to, the data set from, I believe, a randomized Phase II is focused on CPS greater than or equal to 20. So these are considered the CPS high patients who typically do respond to pembro monotherapy.

What we do know is that ficera is being and the FORTIFI study is being looked at in the CPS greater than or equal to 1 as well, we have shown some strong results from our late-line patients in CPS 0 and are currently looking at an open-label CPS 0 cohort.

In the CPS 1 to 19 category, we see stronger response rates across all 3 of our cohorts between 50% to 70%, really speaking to the TGF-beta inhibition going after the more so-called immunosuppressive patients for the CPS low.

From an epidemiological standpoint, it's believed to be about 50-50 CPS 1 to 19 versus CPS 20 to greater and 15% of the frontline market being the CPS 0.

I think your other question was around just the competitive threat. What we believe we are hearing is that they are slating to start enrollment in the pivotal study later this year with full enrollment scheduled to be 2029. So significantly later than our interim analysis for potential accelerated approval coming mid-2027. So we do not see this as a competitive threat in terms of timing.

And our next question comes from Reni Benjamin of Citizens.

Congrats on the progress. As my question is mainly focused around the Phase Ib expansion cohorts and the early proof-of-concept signals. Can you just maybe provide more color on each of those expansion cohorts, kind of why we're going after CPS less than 1 and those patients with heavy smoking. And then same thing with the CRC, what is that high bar that you're hoping to achieve when those results come out in the second half?

Thank you for the question. So I'll start with the other cohorts. You mentioned CPS less than 1 and also the heavy smokers. So I think what we saw in dose escalation is we actually saw some pretty significant responses in those patients who had CPS 0. In fact, one patient in particular had a complete response there.

As you go back to kind of the fundamental biology of our molecule of EGFR and TGF-beta, there's a lot of biological support for the synergy associated with those 2 mechanisms being given together and also in combination with a PD-1. And so that was a biology that we wanted to probe and again, exploring a population.

As Claire had alluded to in the last response, in terms of an epidemiological perspective, about 15% of patients are CPS less than 1. So it's a meaningful population. And again, a biology that's supported by our molecule.

In the heavy smokers, I think it goes back to our view when we looked at our dose escalation data retrospectively, there was a responder population with an HPV positive. All of those patients who responded were heavy smokers. In that case, we saw people who had a history of smoking of 20 pack a year or greater who responded.

And again, of our 3 responders there, 2 out of the 3 of them were complete responses. So our view is that there's likely a component of smoking that's driving the biology there, even more so than the HPV positive infection. And again, an area that we wanted to probe as we think about those expansion opportunities within the head and neck population.

CRC, I think, honestly, it's an evolving target. We continue to look at the landscape. We've seen data sets out from other agents of recent. And I think the other thing not only is relative to the competitive landscape, but also our own internal.

We had mentioned activity in cutaneous anal canal. There's good opportunities for this molecule in the locally advanced setting of head and neck.

So as we evaluate the various opportunities, there are, I think, are ample opportunities to develop ficera across a range of different tumors and more broadly in head and neck cancer. And that really is the bar is, where we think we're going to have the most meaningful impact, and that's where we're going to end up investing our capital.

And can I just follow up with when we might see some of the data for -- we know when the CRC data is coming out, but maybe from these other cohorts, when might we see those data?

Again, we've not provided specific guidance on that. And again, we'll provide greater clarity in terms of timing for that in future updates.

And our next question comes from Jeet Mukherjee of BTIG.

Just looking ahead to your loading and maintenance regimen, just as you talk to your investigators, how do they think about a 12-week weekly regimen followed by once every 3 weeks versus just a pure once every 2-week regimen from [ Pido ] there? Is there any preference that they have generally between one or the other? Obviously, safety and efficacy being the primary point there. But just was curious if there's any preference there between the 2 regimens.

And then just coming back to ASCO, are we looking to have updated data be a part of the abstract? Or will they be reserved for the conference presentation?

So I'll take your first question there. As we have talked with investigators and the broader community, I think there's a real focus on that initial therapy and the rapidity and the depth of that initial therapy.

I think even if you look at the historical treatment paradigm, we continue to see a fair amount of chemotherapy used, and that is largely being driven by the desire to have very rapid responses.

And so in terms of that trade-off of being able to go to every 2 weeks at the outset versus being able to get rapid deep responses, the preference continues to be that rapid deep response, which the weekly regimen gives.

Again, I think as you think about the overall administration schedule transitioning to every 3 weeks at the 12-week mark, I think the view there is a willingness to get faster, better efficacy quick and then be able to go to a more convenient maintenance regimen over time.

And to your second question, Jeet, which I believe was about whether the abstracts -- whether the data presentation will have more mature data than the abstracts, that is correct. There will be more data provided during our presentation than what was provided in the abstracts. Thank you for your question.

And our next question comes from Boris Peaker of Jones Trading.

Just a follow-up on a prior question when we're talking about every 2-week dosing, every 3-week maintenance dosing. In addition to potentially satisfying FDA's Project Optimus requirements, how important do you see this dosing from the commercial perspective and kind of competitive perspective?

I'll answer your first question around Project Optimus and then pass it over to Ryan. So just to highlight for us, we have satisfied Project Optimus by choosing the 1,500-milligram dose weekly as opposed to the 750-milligram dose weekly within the FORTIFI-HN01 study.

So this is a separate parallel clinical study that is looking at moving this new alternative dosing regimen into a potential ultimate label.

To your second question around the commercial uptake, I'll pass it over to Ryan.

Yes. In terms of -- from a differentiation perspective, efficacy remains the key parameter for differentiation, consistent, I think, with most oncology molecules. Again, that's why we continue to initiate with 12 weeks of weekly therapy to maximize efficacy, deep durable, rapid responses.

And again, we think that, that will be the key that's going to drive differentiation and the initial share uptake between ourselves and competitor molecules.

Being able to then also maximize and optimize for schedule once you get out to that 12-week maintenance phase, we believe that we have -- we'll be creating a regimen that has the ability to not only compete but to differentiate and be best-in-class from an efficacy, tolerability and from a convenience perspective, really being able to fully optimize the profile across all 3 dimensions.

And our next question comes from Joe Catanzaro of Mizuho.

I actually had one as well on this maintenance trial that you've sort of, I think, touched on. But wondering if you could speak to the quantitative difference in exposure at steady state, if any, between 1,500 weekly and 2,250 every 3 weeks. It sounds like you need those longer-term efficacy metrics, but wondering if the argument can be made on sort of equivalent PK and safety between those 2 regimens.

Yes. I mean, again, from an overall exposure perspective, what we are looking to accomplish there, the 2,250, essentially, we're looking for exposures that are comparable to what you've seen at 750.

And again, why we look across the various data sets to really get, I think, the regimen that we have gotten to, we're looking at the strength of the data across all of our various cohorts.

So again, I mean, I think the key here is starting the 1,500 milligrams, getting that rapid deep response and then being able to maintain the exposure levels to maintain the durability of response.

Our next question comes from Richard Law of Goldman Sachs.

So based on that accelerated approval time line, I believe you mentioned in the past that only a small clinical team will be unblinded to review the interim Phase III results and management will still be blinded. So when will management team become unblinded? And when should we expect to see the data as well? And also, does it mean that the unblinded clinical team will file the BLA without management seeing what's in there initially when filed?

Richard, I think you're -- just to understand your question, the study is a blinded study. We have an interim for potential accelerated approval in mid-2027 that will be based on response rates with 6 months' worth of follow-up as well as qualitative overall survival.

Like any company, there will be -- the data cut will be done, the data lock will be done and then our team within Bicara will submit the BLA. There are no oddities to that process.

So there's no separate unblinding with a different team and then we're -- I thought that was the case before, if not.

No, there is an IDMC like in many cases that will allow us to submit and then we will move to the Bicara team.

I'm showing no further questions at this time. I'd like to turn it back to Claire Mazumdar for closing remarks.

Thank you for joining us today and for your continued support of Bicara. We're focused on the work ahead for the program and most importantly, for the patients we're working to serve. And we look forward to seeing many of you at ASCO in a couple of weeks.

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

Good day, and thank you for standing by. Welcome to the Bicara Therapeutics Fourth Quarter and Full Year 2025 Earnings Call. [Operator Instructions] Please be advised today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Rachel Frank. Please go ahead.

Thank you, and good morning, everyone. It's a pleasure to welcome you to Bicara Therapeutics Fourth Quarter and Full Year 2025 Earnings Call. Earlier this morning, we issued a press release highlighting results from the quarter and recent business progress. 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 filings 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 statement made on this call represents 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; Ryan Cohlhepp, President and Chief Operating Officer; and Ivan Hyep, Chief Financial Officer.

I'll now turn the call over to Claire.

Good morning, and welcome to Bicara Therapeutics Inaugural Quarterly Earnings Call. I'm Claire Mazumdar, Chief Executive Officer.

Today marks an important milestone for our company as we begin this tradition of regular communication with investors, analysts and stakeholders to provide transparent updates on our business progress and strategic direction via the quarterly earnings call process. We're implementing these quarterly calls as part of our commitment to maintain an open dialogue with the Street and ensuring you have consistent visibility into our execution against key milestones and strategic objectives.

Before I jump into our Q4 2025 highlights and recent progress, let me provide a brief background for those who are newer to our story. Bicara Therapeutics is a clinical stage biotech company pioneering bifunctional antibodies for targeted tumor modulation. Founded in 2020, we've built a global team of over 100 employees headquartered in Boston with a clear focus on advancing our lead asset, ficerafusp alfa or FICERA, a potentially first-in-class bifunctional EGFR-directed antibody combined with the TGF-beta ligand trap. Our innovative approach combines tumor targeting with tumor modulation, where one arm localizes to the tumor while the other serves as a modulator designed to deliver superior efficacy, improved safety and enhanced 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.

Over the past several months, there have been significant shifts in how the competitive landscape in frontline recurrent and metastatic head and neck cancer is evolving. Our recent clinical data and regulatory progress clearly position FICERA as a potential best and first-in-class asset with a differentiated clinical profile on both long-term outcomes and tolerability.

Looking back at the progress we've made since October 2025, I'm energized by the exceptional momentum we've built across our pipeline and operations. Over the past several months, we've achieved multiple critical inflection points that fundamentally strengthen our position as we advance FICERA toward a pivotal study interim analysis in the middle of next year.

First, FICERA received breakthrough therapy designation, or BTD, in combination with pembrolizumab for the first-line treatment of patients with metastatic or with unresectable HPV-negative recurrent head and neck squamous cell carcinoma. This designation from the FDA underscores the growing recognition of HPV-negative head and neck cancer as a distinct clinical indication within head and neck cancer, one with particularly poor outcomes, limited therapeutic options and that represents the vast majority of patients.

Second, we presented 2 additional Phase Ib clinical data sets across clinically active doses of FICERA that demonstrated consistent overall response rates, further validating FICERA's unique dual mechanism targeting both EGFR and TGF-beta and derisking the OR endpoint in our pivotal study interim analysis.

Third, building on this robust data set, we selected 1,500 milligrams as our optimal biological dose and have successfully moved into the Phase III portion of our pivotal FORTIFI-HN01 study, for which we expect an interim analysis in the middle of next year. This represents a major strategic advancement that brings us significantly closer to our goal of delivering a potential best and first-in-class treatment option for patients living with HPV-negative head and neck cancer.

Fourth, we recently announced plans to develop FICERA with a loading and every 3-week maintenance dose, a strategic commercial decision based upon updated clinical, translational and pharmacokinetic data that we believe will enable additional optionality for patients and providers choosing treatment with FICERA.

Lastly, to support this accelerated trajectory and pull forward investments in our early commercial and medical build, we successfully completed an oversubscribed public offering, strengthening our balance sheet and providing the capital foundation necessary to execute this next chapter of our business with confidence.

With that, I'll turn it to Ryan to provide a bit more detail on our recent clinical updates and business progress.

Thank you, Claire, and good morning, everyone. We've now reported clinical experience in approximately 90 patients across 3 Phase Ib cohorts evaluating FICERA in combination with pembrolizumab in frontline recurrent metastatic HPV-negative head and neck squamous cell carcinoma. Our 1,500-milligram every week data is the most mature with 2 years of follow-up and demonstrates deep durable responses that lead to median duration of response and median overall survival of 21.7 and 21.3 months, respectively, nearly tripling the median overall survival observed with the standard of care of pembrolizumab in HPV-negative patients.

Late last year and just last month, we presented 2 additional cohorts. In December of 2025 at ESMO Asia, we presented data from our 750-milligram every week cohort, which helped to ultimately inform 1,500 milligrams every week as the optimal biologic dose for our ongoing pivotal Phase III FORTIFI-HN01 trial. And just last month, at the Multidisciplinary Head and Neck Cancer Symposium, we presented data from a higher but less frequent dose of FICERA in combination with pembrolizumab, 2,000 milligrams every 2 weeks, from which we announced our plan to develop a less frequent loading and maintenance dosing option. Our aim is to gain alignment with the FDA on this approach and initiate that study in parallel to the pivotal study to allow to have data from that regimen in hand upon potential U.S. approval.

Clinically, tumor shrinkage is seen at all doses that trends deeper with higher exposure. The 1,500-milligram cohort showed deeper median depth of response versus 750 milligrams, and the exploratory 2,000-milligram every 2-week cohort produced consistently high proportions of deep responders with greater than 80% shrinkage and complete response rates. Our translational data shows consistent TGF-beta inhibition across all FICERA doses, confirming the mechanism that drives tumor penetration and immune activation. Importantly, inhibition is strongest with the 1,500-milligram weekly dose and less frequent 2,000-milligram regimen. We believe this TGF-beta-driven depth of response is the defining hallmark of FICERA and a clear differentiator versus EGFR-directed therapies, which do not target TGF-beta. This mechanism is especially meaningful in HPV-negative disease, a setting with poor outcomes and limited innovation where deeper, more durable responses are urgently needed for patients. We remain confident that this biology will continue to translate into clinically differentiated long-term outcomes for these patients.

Importantly, FICERA's deep responses are paired with sustained durability without any trade-off. The median duration of response approaches 22 months, more than 3x longer than the 6.7 months median duration of response reported with pembrolizumab plus chemotherapy. Our 2,000-milligram every 2-week cohort similarly delivered multiple deep responses persisting beyond 20 months, underscoring the consistency of benefit across dosing schedules. Crucially for patients, providers and payers, FICERA maintains this level of durability even with less frequent dosing. This positions FICERA favorably in a market moving toward treatment regimens that reduce clinic burden, improve quality of life and support long-term adherence. We believe this performance reflects FICERA's tumor-penetrating mechanism, enabling depth and durability that translate into meaningful long-term outcomes while supporting a more flexible patient-centric dosing paradigm.

We're often asked whether deep depth of response translates to long-term outcomes. As we first showed at ASCO last year, there is a clear distinction in duration of response, progression-free survival and overall survival among HPV-negative head and neck cancer patients who have had deep responses versus those that do not. This data is what drives our belief that deep responses that are the hallmark of FICERA's clinical profile drive outsized durability and long-term benefit. Importantly, other investigational agents also need to demonstrate the deep and durable responses to meaningfully improve long-term clinical outcomes.

As our recent financing highlights, we have strong conviction in FICERA's clinical data and its differentiated profile compared to other investigational agents in the head and neck space. And we are continuing to bolster our commercial and medical investment in preparation for a potential U.S. launch, including hiring of the Chief Commercial Officer this year. Head and neck cancer is a significant and fast-growing global market, projected to reach more than $5 billion in global sales in the 2030s. HPV-negative patients represent the heavy majority of patients in the frontline recurrent metastatic setting and HPV status is known by the time the disease recurs or metastasizes, which means the HPV testing will not be a barrier to care. There are roughly 50,000 annually incident patients across major markets, including approximately 18,000 in the U.S. where we plan our initial launch.

With FICERA, we have the potential to significantly expand an already significant HPV-negative head and neck cancer market. FICERA's clinical data show us that we further expand that market in 2 ways: first, by growing the number of patients who are responding to therapy as seen with the fact that FICERA provides a 2 to 3x greater overall response rate; and second, by growing the duration of response as seen by FICERA's two to threefold improvement over standard of care median duration of response. We are pioneering a new treatment paradigm for HPV-negative head and neck cancer with a tailored therapy engineered to overcome the unique biology of this disease and achieve deep, durable and clinically significant benefit while sparing the use of chemotherapy to further improve quality of life for patients.

With this knowledge in hand, we are eager to further invest in our prelaunch activities across commercial and medical, including additional evidence generation strategies that may further expand the market opportunity beyond that being studied in our pivotal trial. Recent competitive updates have only strengthened our conviction that FICERA may have the best chemo-sparing regimen that actually addresses both the EGFR and TGF-beta inhibition underlying biology of HPV-negative head and neck cancer to improve long-term outcomes for patients. We are preparing to launch in an environment where based upon evolving regulatory and clinical development commentary across our competitor set, we have the opportunity to set the tone for what the therapeutic bar looks like for significantly improving unmet medical need in this space.

As we head into the second quarter, we look forward to providing long-term follow-up data from across our Phase Ib studies of FICERA in combination with pembrolizumab in frontline recurrent metastatic HPV-negative head and neck cancer. The Phase Ib 1,500-milligram every week data presented at ASCO 2025 were mature with a median duration of response of 21.7 months and a median overall survival of 21.3 months. In this update, we are looking for a better understanding of that IO tail at extended duration of follow-up as well as the additional maturity on key endpoints from the 750 milligram every week and the 2,000-milligram every 2-week data sets. No other investigational agent targeting EGFR in the head and neck cancer space have shown durability of outcomes out this far, a key differentiating factor for FICERA that resonates deeply with clinicians.

With that, I'll turn it to Ivan to review the financials.

Thanks, Ryan. Earlier this morning, we reported detailed fourth quarter and full year 2025 financial results in our press release, and I'll summarize a few highlights here.

Our total operating expenses for 2025 increased compared to the fourth quarter and full year 2024, driven by clinical operations and development expenses, including increased manufacturing and process development costs associated with our ongoing pivotal FORTIFI-HN01 study. We also saw an increase in personnel-related costs, including stock-based compensation as we grew our workforce throughout the year, primarily in support of clinical operations and development functions.

We anticipate an increase in operating expenses for 2026, driven by increased investment in clinical operations, particularly for the pivotal FORTIFI-HN01 study, the interim analysis for which is expected in mid-'27 as well as an increase in SG&A and headcount expenditures as we invest in early commercial and medical infrastructure to support the potential launch of FICERA.

We entered 2026 with $414.8 million in cash, cash equivalents and marketable securities. In the first quarter, we raised an additional $161.8 million in net proceeds via an oversubscribed public offering, which further strengthens our balance sheet, and we maintain cash runway guidance into the first half of 2029. This additional capital will allow us to support a planned regulatory filing for FICERA, further invest and build in our medical and commercial infrastructure ahead of a potential U.S. approval and launch. Further accelerate the development of FICERA in head and neck cancer, including a less frequent dosing schedule, fund manufacturing costs for FICERA for ongoing and anticipated drug development efforts, fund early signal finding activities to support further indication expansion for FICERA and fund other general corporate purposes. Our existing cash as of year-end and this additional recent cash infusion puts us in a position to be able to drive smart growth for FICERA as we enter a period of disciplined but increased investment to drive future clinical and commercial success.

With that, I'll now turn the call back over to the operator for questions. Operator?

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

Can you provide more color on the patient demand and willingness to participate in pivotal FORTIFI study that you're seeing in both the U.S. and in ex U.S. sites? And as a follow-up or kind of related question, do you have a sense of how many patients you might need to enroll in a separate study of the less frequent dosing regimen to achieve registration?

Thank you for your question, Tyler. So there are two questions. One was around momentum around patient enrollment in the FORTIFI-HN01 study. And then the other was approximately how many patients do we plan to enroll in the parallel bridging study for the loading and maintenance dose? I'll answer the first one -- the second one first and speak to the fact that we are looking for regulatory alignment, and we'll provide far more clarity to the study in more detail once we have that regulatory alignment. But the approximate size is anywhere between 150 to 200 patients is our current estimate.

The first question was around enrollment of the FORTIFI study. What I can say is that we continue to build significant momentum in that study as we have both received breakthrough designation as well as moving from the Phase II to the Phase III portion and going now to the 2:1 randomization of 1,500 milligrams weekly, randomized 2:1 to pembro monotherapy. We've seen great momentum also ex U.S., in particular, in European sites, Asian Pacific sites as well as South America with a significant momentum in areas where we know that there's a high prevalence of smoking.

I will pass it over to Tanya to give additional details to the FORTIFI-HN01 momentum.

This is Tanya Green, Chief Development Officer. So yes, as Claire said, we're -- we have really strong momentum for the Phase III study in terms of enrollment. As is publicly available, we have 129 active sites right now. And this team remains highly focused in executing the study to achieve substantial enrollment by the end of this year, which will keep us on track to have our interim analysis by mid-2027.

Our next question comes from Eric Schmidt with Cantor Fitzgerald.

Congrats on all the recent progress. Questions on the colorectal cancer update that we might see in the second half of the year. Could you just give us a sense for the scope of that update in terms of patients dosing? And in particular, what type of benchmarks you think you'd hope to be able to provide in order to demonstrate proof of concept?

Eric, thank you for the question. In terms of our CRC update, as we've indicated, we look to have data in the second half of this year on those cohorts. In terms of the total number of patients that we plan to present, I think that's still somewhat variable based upon enrollment. But consistent with our previous updates, we're always looking for data sets probably no less than 20 patients per cohort. I think that certainly, even as recent, we've seen the treatment landscape evolve, and we're mindful of that with recent data that's been out. I'd say what we're -- the two cohorts that we are currently exploring and seeking signals in are third line. As you know, that's a highly challenging population. And again, we've got both a cohort in monotherapy as well as one in combination with pembrolizumab at the 1,500-milligram weekly dose.

So again, I think we continue to look at that data for signal-seeking purposes and determine whether there's a path forward in CRC, particularly as we look to see about the opportunity to move into earlier lines of therapy in colorectal cancer using those signals to determine whether there's something there to invest further.

Our next question comes from Stephen Willey with Stifel.

I guess with the understanding that you're going to be providing the kind of pooled expansion cohort data at ASCO in a few months. Just curious if the patients in the 750 mg once-weekly cohort were given the opportunity to up-titrate to the 1,500 mg dose, just given the, I guess, the relative deficiency in depth of response.

Great question, Steve. So what we'll be presenting at ASCO is likely an update from 3 separate cohorts. The 3-year follow-up -- median follow-up for the 1,500-milligram dose weekly. The 750-milligram weekly dose was about a 30-patient cohort with at least 18 months of follow-up and same for the 2,000-milligram every 2-week cohort, an additional 30 patients with about 18 months of follow-up. So in that particular cohort, to your question, the 750, we did not increase the dose afterwards. These were patients that were maintained at the 750-milligram dose throughout their course of treatment. And we will be providing an update to PFS and duration of response from those cohorts that will continue to speak to the depth and durability profile that we see across our cohorts.

If your question regarding the pivotal study in FORTIFI-HN01, I do believe that we were able to cross over the patients enrolled at this lower dose. And so they were -- if they remained on treatment, they did cross over to the 1,500-milligram dose in the pivotal study. Thank you for your question.

And then maybe just a quick follow-up. I know there's been kind of some background discussion about having interest in the pre-metastatic setting, whether it's neoadjuvant and adjuvant. And just wondering kind of where you are on that now? And does the pursuit of this new loading maintenance strategy and the need to generate maybe a couple of hundred patients worth of data change perhaps the plans to pursue [indiscernible] in the pre-metastatic...

No. I think to that question, we do believe that the locally advanced setting of head and neck has always been a large opportunity. And given the signal we've seen in the recurrent and metastatic setting, there is a strong biology to move into earlier lines of head and neck cancer. And we do believe it is also becoming a more competitive landscape as well. So we have begun initial signal-seeking studies in those areas and hope to provide updates as we move forward in more detail. But we do think it is a very important opportunity that could potentially triple the market opportunity compared to recurrent and metastatic setting.

Yes. Steve, I'd say that, in fact, our evolution of the dosing paradigm, I think, further supports and reinforces our ability to go into those earlier lines in head and neck cancer. And from an overall operational execution perspective, part of the key driver of our last financing was to be able to fund that alternative dosing schedule as well as continued investment in earlier areas of head and neck cancer.

Our next question comes from Judah Frommer with Morgan Stanley.

Maybe just can you help us with an update on how many centers you're in with FORTIFI-HN01, what overlaps are with petosemtamab trials and kind of what that does from a potential market share capture perspective for you, the likelihood based on investigator response for investigators at your centers to stick with FICERA in the case of an approval? And then just secondarily, maybe just help us with that cash runway guidance being maintained despite the raise, what was not contemplated in the previous guide that is in there now that will eat up some of the cash that was raised to maintain that guidance?

Sounds great. And so I'll pass over the first part of the question to Tanya Green, Chief Development Officer, to speak to the sites and the study and then to Ivan Hyep, our CFO for cash -- guidance.

Yes. Thanks for the question. So in terms of sites, we have 129 sites that are open globally. And in terms of the competitive overlap with the other studies, we do believe that there are some sites that overlap, but we have seen great momentum at all of our sites in terms of patients. So we don't see that being a consideration.

And Judah, thanks for the question. In terms of use of proceeds for this recent financing, we are heavily focused on the alternative dosing, prelaunch activities and investment in both commercial and regulatory. And so for us, we didn't feel that we needed to change guidance there as it allows us to kind of build up instead of just extending runway.

Our next question comes from Kelsey Goodwin with PSC.

Maybe again just on FORTIFI and the enrollment. How should we think about the ultimate split of enrollment across geographies? And is this similar to other trials in the setting? And then second, in terms of the bridging trial design, I guess, do you have a sense of when you might be able to provide more color for the Street?

Great, Kelsey, thank you for the question. In terms of geographical distribution on the trial, I'd say what we anticipated is it will be very similar to some of the recent trials, KEYNOTE-048 in particular, I think what we had anticipated and continue to see in our own enrollment is very consistent with some of those historical trials. In terms of the alternative dosing, again, as Claire mentioned, we intend to get regulatory input on that trial and do expect to be able to provide greater clarity later this year.

Our next question comes from Reni Benjamin of Citizens.

Congrats on the progress. Just sticking with FORTIFI, can you maybe just help quantify a little bit as to what you mean by substantial enrollment? And as we think about the number of patients required for the ORR interim versus kind of the final OS, can you give us a sense as to how that might look? And then just kind of related, since this would be used for accelerated approval, can you give us some thoughts on how you're thinking about more of a global filing as well for FICERA?

Great question. So to your question around substantial enrollment, that is really predicated on what the FDA is looking for at the time in terms of a seamless Phase II/III design. What the FDA wants to ensure is that we are close to fully enrolled in the total confirmatory study, so as not to introduce bias at the time of granting an accelerated approval. So substantial is a key objective for very meaningful enrollment to ensure we're not introducing additional bias into the confirmatory study.

To that question, we do believe that in the United States, with the FDA, we are on a path to potential accelerated approval predicated on a response rate endpoint from an interim analysis that will also look at durability of response as well as qualitative overall survival. The study will continue for full confirmatory approval on an overall survival endpoint. Today, we believe that ex U.S., a full overall survival endpoint is needed to predicate a global approval.

Our next question comes from Jeet Mukherjee with BTIG.

Great. Two for me. Could you speak to the rationale and reasons for confidence on the loading and once every 3-week maintenance strategy when it was a 2,000 mg once every 2-week regimen that showed a notable response and depth of response? And the second question was just related to the colorectal cancer update. Could you confirm if the patient enrollment criteria allows for liver mets?

Thanks for the question. So on the alternative dosing, we have gotten comfortable with our proposed strategy there. Looking at the compilation of all of our data sets. I think this is where really having the 750-milligram weekly, the 1,500 weekly and then the 2,000 every 2 weeks has given us the ability to do extensive exposure response modeling across those data sets. I think a couple of key notes in terms of the data. One of the things that we know when we look at the patients in our Ib data is that 1,500-milligram weekly dose, we're getting very rapid responses at 1.4 months that we're getting responses. The vast majority of patients will have achieved the response within 12 weeks. And at that same time, most of them will have hit their maximal depth of response by the 12-week time.

And so that gives us the confidence in why we want to initiate with a weekly dosing phase and then be able to transition to extend that interval out to every 3 weeks. Again, what we'll look to do is to match the pharmacokinetic profile from both an exposure as well as a C trough perspective to the 750-milligram weekly, which, again, we know, as you saw in that data set that we presented last year, you see really good response rates. You see really good activity even at the 750.

I think one of the things to remember here, if you recall our data, that depth of response, we're seeing more than 80% of our patients get an 80% or greater reduction in their tumor. So you think they're at that 12-week mark, you've got significantly less tumor in the patients at the 12-week mark, which gives us confidence in our ability to extend out that interval, maintain a very durable response and give the patients the ability to have a more convenient administration schedule.

For your CRC question, the inclusion criteria does allow for liver metastases. And in fact, the anal canal data that we have presented previously really shows our ability and FICERA's ability to resolve liver metastases in that population. So it is something that we think could be a unique differentiating perspective of our molecule, and so we did allow liver mets.

Our next question comes from Eva Fortea with Wells Fargo.

A quick one from us. We've seen now in the 3 different dose cohorts with FICERA plus pembro, a similar response rate or even higher in some cohorts with CPS 1-19 compared to CPS 20 or higher. And so is there anything about the biology that could explain this? And if this holds in the Phase III, could you comment on the potential implications from a commercial standpoint?

Great question, Eva. So to your question, it is known that, in particular, in HPV-negative head and neck cancer, there are both higher levels of EGFR and TGF-beta that makes these tumors typically more immunosuppressive or treatment-resistant than their HPV-positive counterparts. In particular, in fact, HPV-negative tumors tend to have a slight skewing for CPS low or the CPS 1 to 19. And in fact, it's in this patient population that pembro has worse response rates across the board. And so seeing very strong response rates in the CPS 1 to 19 really speaks to the underlying biology of being able to target both EGFR and TGF-beta, which is why we believe we're able to target these very immunosuppressive tumors.

In fact, we do think that it's always going to be a differentiating aspect for our molecule compared to other EGFR inhibitors that are currently being tested that have not seen the outsized impact in the CPS flow. And in fact, we do believe that especially given we are going after a chemo-sparing regimen, being able to go after these 1 to 19 will allow us to have a dominant share in what accounts for approximately 50% of the total head and neck market, but slightly skewed even higher in the HPV negative. In fact, to your question, you may remember that we also have a cohort open in the CPS 0 cohort that we plan to disclose at a later time point that also speaks to this underlying biology.

Our next question comes from Richard Law with Goldman Sachs.

This is [indiscernible] on for Rich. Just one from us. How are you thinking about when to unblind the study for the interim analysis for accelerated approval? Will it be based on an overall survival rate?

To your question, this is a fully double-blinded study. We will not be unblinding the study as it needs to continue for overall survival. At the time of our prespecified statistical analysis based off of the number of patients for overall response rates, durability and qualitative overall survival, the IDMC will look at that data. But as management, we will not be unblinded to the data. Thank you for your question.

And I'm not showing any further questions at this time. I'd like to turn the call back over to Claire.

Thanks, everyone, for joining us for our first quarterly earnings call and for your support of Bicara Therapeutics. There's never been a better time to be following our story, and we look forward to speaking with you all again soon. Thank you, and have a good day.

Well, ladies and gentlemen, this does conclude today's presentation. We thank you for your participation. You may now disconnect, and have a wonderful day.

Hello, everyone. I'm Etzer Darout, senior biotech analyst at Barclays. Happy to have Bicara Therapeutics with us for our next session. We have Ryan Cohlhepp, President and Chief Operating Officer. Ryan, maybe for those less familiar with the story, if you could just give us an overview of Bicara and progress that you've made in upcoming milestones.

Yes. Great. Thank you for the invitation and having us here at the conference. So Bicara Therapeutics is a company focused on bifunctional antibodies that are tumor targeting. And so our lead program is an exemplary of that. It's an EGFR TGF-beta again, where we're using EGFR to bring TGF-beta to the tumor microenvironment.

We founded the company in 2020, where we actually were able to license intellectual property from an organization, Biocon back in 2020 and have since over the last 4 or 5 years, continue to develop that. And we're now at a point where we've seen substantial activity with that molecule, which I'm sure we'll speak about a little bit later and have been able to embark upon a registrational trial in the recurrent metastatic head and neck setting. We initiated that trial early last year and are going to be in a position where we expect to have top line data in mid-2027 in the head and neck market.

Great. So you're looking at an HPV negative population in head and neck cancer. Historically, that's been a segment that's been sort of viewed as being immune excluded, right, where it's difficult to get drugs, effective drugs in that population. Maybe just talk about the EGFR, TGF-beta mechanism and how that's been able to really make and show clinical activity in that population of patients.

Yes, absolutely. And so as part of our rationale, again, when we design the molecule is, there's no synergy between EGFR and TGF-beta. You speak to the HPV-negative population, in particular. What we know of the negative population is that, a, there's higher levels of EGFR expression, but also higher levels of TGF-beta. And our rationale early on, again, in the development was there have been a number of historical approaches and where companies have tried to use TGF-beta in the cancer setting and have been unable to see activity there.

And really, our view there was you weren't able to see adequate levels of TGF-beta in the tumor microenvironment. So we're using EGFR to get there and to be able to get TGF-beta into the tumor. What we know is that TGF-beta, if you look at the biology of TGF-beta, what it does is it helps overcome acquired resistance mechanisms with EGFR. So there's this duality of effect as you think about EGFR and TGF-beta together. And that's why we paired the 2 together.

Not only to be able to get to the tumor, but we also know that there's kind of synergistic activity of the two and working together. And we've seen that. I think the first real signs of the contribution of TGF-beta was as we started to present data around our early signals of activity that we were seeing, we were seeing these really deep and durable responses. When we first presented our data in the head and neck population at ASCO 2023, at that point, we already had a number of patients with really deep responses and several patients with complete responses. If you look at in that HPV-negative population, the historical data for pembro, you typically only see at best about a 4% to 7% complete response rate.

We now, as the data has continued to mature, we're showing in the 1,500-milligram dose, which is the dose that we will carry forward into the pivotal trial is a 21% complete response rate. We have another 9% of patients who -- they weren't upgraded to complete responses, but they had 100% reduction in their primary tumor. So you're seeing that TGF-beta effect where you're seeing really, really deep responses.

I think the other notable thing here that stands out relative to other EGFR bifunctionals or EGFR monoclonals is the durability. What we know with pembro is in those patients, about one in five patients respond to pembro monotherapy. Those who do pretty well on it, they get about a 24-month duration of response. The issue is you're just not seeing many patients respond. What we were able to see is we have a confirmed response rate in that same population of 55%. So we have nearly tripled the responder population.

And what we showed was a 21.7 month median duration of response. And so what we had known all along is that, that responder population that would have responded to pembro monotherapy was still going to exist within our trials. But what about the next 30%, 35%, what's going to happen to their duration of response. What you've seen with cetuximab, what you've seen, I would say, even with petosemtamab is you actually see in that those additional responders EGFR-like duration.

And that's where, again, we think the TGF-beta has been able to distinguish itself and differentiate from the other mechanisms and really being able to drive not only depth but durability.

Great. And I guess one of the things we've seen with FICERA, as well is just the improved toxicity profile for FICERA versus sort of traditional or classic TGFR-beta. What do you owe that phenomenon to? Is it just the EGFR localization? Is it maybe a finer or more tuned TGF-beta?

I'd say, it's probably more of the latter, more fine-tuned. So what we did, the trap that we have in our molecule is the extracellular domain of TGF-beta receptor 2. So if we look at some of the older TGF-beta programs, you saw some cardiomyopathy there, which was attributed to TGF-beta 2. And by using the extracellular domain of 2, what we see is greater specificity for 1 and 3, which are also the cancer-associated forms of TGF-beta.

So again, I think we've been able to be a bit more targeted there, which I think it definitely has helped mitigate some of the historical TGF-beta tox that we've seen with other programs.

Got it. And for folks less familiar, can you give a sense of the proportion of patients that are HPV-negative head and neck versus HPV positive?

Yes. One of the important distinction, there are multiple subtypes of head and neck cancer. There are four main subtypes. The one subtype that is where you have a mix of positive and negative is the Oropharyngeal or OPSCC.

Overall, as you look at the totality of the various four subtypes, in the U.S., for example, the 80% of patients are HPV negative. It's actually a little bit higher as you go into Europe, even a touch higher as you get into the Asian countries where the incidence of smoking tends to be pretty high.

Again, one of the questions that we often get is, are we seeing an evolution in the epidemiology. We now have Gardasil, so you have HPV vaccinations, you see smoking rates beginning to decline. Actually, what we're seeing is those two phenomena are neutralizing each other. So you're seeing a pretty consistent proportion of the Fab and 80% negative, 20% positive.

Got it. You mentioned the 21-month OS that you've seen median OS, pembro monotherapy about 9 months, combination with chemo about 7 months. do you have a sense of how that sort of plays out in the real-world setting?

Are patients actually seeing the 9 months and the 7 months in the real world relative to what we observed in the clinical?

Yes. So actually, one of the things -- so Merck never disclosed the breakdown of positive versus negative for overall survival. If you look at the pooled population and CPS greater than 1, what you see with pembro monotherapy is around 12.

In the real-world data, there's been a pretty -- about a 600-patient real-world study that Flatiron published, there does show around 9 months. So you are seeing -- and what we were able to see in that data set is they actually broke out positives versus negative. So that 12.3%, it's really hard to understand what do you get from the positive versus negative.

What we know in the data, the real-world data that we've seen is you see a lower overall survival in HPV-negative patients and higher in the positive. What we also know is that many patients actually, if they're diagnosed, HPV-positive patients, if they're diagnosed in the locally advanced setting, many of those patients don't recur. So you start to also see the skewing towards the negative population as you get into recurrent metastatic disease. And again, they don't do as well if you're HPV negative.

Got it. And -- as far as the depth of response, which I think has been pretty unique and differentiated in the population, can you sort of relate that to what we would know or see from EGFR monotherapy in these populations?

Because there has always been a question, is this sort of EGFR plus? Or what's the contribution of TGF-beta for this population and maybe how the clinical studies, the trials, the data have answered those questions.

Yes. There's a couple of investigator-sponsored studies that really we use to help guide our thinking. One was cetuximab plus pembro. The other was cetuximab plus nivo. And in both of those cases, what you see there from a duration of response is around 13 months.

And so I would say purely, if you don't have that secondary component, you could expect to get about 13 months. I think even as you begin to look at some of the other EGFR bifunctionals, there's an ongoing question in terms of what does LGR5 or c-MET or TGF-beta deliver. And again, I think that what we see here is that of those three secondary components, thus far, the only one that really has been able to demonstrate the clinical benefit related to durability is TGF-beta.

And again, there's a lot of biological rationale for why that's happening. And again, you think back to the biology, we know that TGF-beta is helping to overcome the acquired resistance mechanism. So even as we started this program, what you anticipated was TGF-beta, if you're going to see a clinical contribution, it was going to be on those durability endpoints, duration of response, PFS, overall survival.

And that's exactly what we've seen. We've seen it not only at the 1,500-milligram dose, which is what we have in the pivotal trial, you see it at 750. You see it -- we presented data a couple of weeks ago of 2,000 milligrams every 2 weeks. So regardless of dose or schedule, you're seeing a real characterization of the pharmacodynamic benefit of TGF-beta.

And again, with our molecule, we fully saturate EGFR at 750. So as you look at doses beyond 750, it's we're able to isolate the benefit of EGFR versus TGF-beta, and you're seeing this really nice contribution in depth and durability from the TGF-beta component.

Great. And maybe a little bit more details about the Phase III, the ongoing Phase III and then also the endpoints that obviously you're going to be looking at for FICERA.

Yes. So we initiated a trial again in the first quarter of last year. We initiated it as a 3-arm trial at the beginning because we had not yet met the FDA's Project Optimus. They wanted us to do additional dose optimization work. So we had aligned with the FDA to look at two different doses of FICERA and then the control arm of pembro monotherapy.

We actually -- early this year, we aligned with the FDA and we're able to move forward with the 1,500-milligram dose. So we have now formally moved to the Phase III component of the trial with 1,500 milligrams being the chosen dose. The study is designed in such a way that it's got two primary endpoints. It's got overall response rate, and then we will continue to follow patients for OS.

One of the things that the FDA is they continue to look at innovative ways and trial design to facilitate and speed up earlier -- getting drugs into earlier lines of therapy is under Project Front Runner, we've got a design where instead of having to do a randomized Phase II and then do a confirmatory Phase III, we're doing it all in a single trial.

So we'll follow patients, probably roughly 350 patients will trigger the analysis for overall response rate. Those patients will continue to be followed. This trial will remain blinded, and they'll be followed all the way to the survival endpoint. And so the total trial size is around between 600 and 650 and we will get both an accelerated approval potentially off of ORR and then following a full approval on OS 1.5 years or so later than that.

Again, so it's a way for us to get out there earlier. What we also know the FDA not only will be looking at the accelerated approval, the ORR data, they will also look and are asking to have at least 6 months of follow-up on the majority of patients to make sure that a large proportion of your patients have maintained their response at 6 months and also expect that they will do their own sensitivity analysis around the trend of overall survival at that time.

Got it. And have you disclosed powering assumptions around overall survival?

We've not. Again, I think our view -- what was interesting KEYNOTE-048 trial, again at 12.3, a, we didn't know the proportion of negative versus positive. So we didn't have complete information to do sizing.

The other thing I think we -- that informed our view on how we size the trial is that there was data from the lenvatinib LEAP-010 trial, which is lenvatinib plus pembro. There -- in that trial, all of a sudden, we saw pembro monotherapy at 17.8. I think there are a lot of rationale to -- as you look at the inclusion/exclusion criteria, a number of reasons patients were excluded based upon toxicity from lenvatinib.

So we don't think that it's going to -- in our trial, we'll see 17.8. We also -- knowing that we are in a negative population only. What the data would suggest is the bounds there are probably anywhere from 8 to 18. And again, I think we looked at all the various data as we size the trial. That being said, the confirmatory endpoint for full approval will be in OS, we make sure that we size it in a way that, a, was not only clinically meaningful, but also we derisked the trial in terms of overall, it was worth an additional 100 patients or so to make sure that we had a high degree of confidence in our ability to meet the OS endpoint.

Got it. And any differences in sort of inclusion/exclusion criteria from sort of the Phase Ibs into the Phase III or just very similar?

Very, very similar. In fact, if you look at the patient demographics in our trial in our Phase Ib compared to KEYNOTE-048, very similar. We would expect the same thing as we have our pivotal trial.

Great. And for the 2,000 mg once every 2 weeks, how do you plan to leverage that profile? Is it maybe a maintenance post the 1,500? Is it completely sort of shift the market to 2,000 mg? Like how do you think about that?

Yes. So we -- I think looking at the totality of the data across our various cohorts, we now have close to 100 patients across three different cohorts, 750 milligrams weekly, 1,500 milligrams weekly and then 2,000 every 2.

So we've been able to do really robust exposure response modeling and to understand the contribution of the two different components of the drug, what's driving activity on the EGFR side versus the TGF-beta. Using all of that information, what we know is that we get very rapid deep responses at 1,500 milligrams weekly.

So our plan is to continue to initiate therapy with a loading phase of up to 12 weeks at 1,500 milligrams weekly. At that point, we know that the vast majority of patients will have not only responded but have hit their best response. And so you'll have significantly reduced the tumor size. That gives us the opportunity then to stretch the interval. And what we are looking to do is to match the PK profile of the 750-milligram weekly, both on an exposure as well as a C-trough basis.

We think not only does that will allow us to maintain a best-in-class efficacy profile with a very durable response. We think it actually has a benefit from a tolerability perspective because as you reduce the overall size of the tumor, again, you think back to, again, the rationale for this molecule. We're using EGFR to get TGF-beta the tumor as your TGF-beta tumor dramatically reduces, you need less drug.

And so we're going to -- with a very good understanding of the biology of our molecule as well as the disease, we think we have the ability to stretch that interval out to now sync up with pembro. And so you think across kind of the three dimensions of efficacy, safety and administration. This weekly loading phase into a every 3-week maintenance, we think optimizes across all three dimensions and gives us a best-in-class profile across all three areas.

So would that entail a new study, a bridging study?

It is, yes. One of the things that we -- on the heels of presenting the data at the head and neck meeting -- what we guide to is we will be doing another trial, which will run in parallel to our pivotal trial.

We anticipate doing a randomized trial. We still need to align with the FDA on the exact design of that trial. So we will disclose the full design. But we do anticipate that we'll be able to have data in hand from that trial to inform the way we are thinking strategically around pricing and other things at our first approval.

Got it. And the HPV testing, how routine is that in head and neck? And then also with the testing, how you plan to move that into sort of a commercial setting?

Yes. It's super routine. In fact, most guidelines, going back to the comment I made earlier, the vast majority of patients, probably more than 80% of patients are actually diagnosed in the locally advanced setting. It's during that initial diagnosis that they do HPV testing.

Historically, they've used p16 IHC. We are actually developing with a partner a PCR HPV test that we'll get a co-approval with. That being said, by the time they come in and they recur, the physician will already know their HPV status. So we've not seen it to be an impediment in enrollment at all.

We don't expect it to be a commercial impediment. We also from a payer perspective, what we know -- the feedback that we've gotten is actually that payers are comfortable using the IHC testing that they already have. And so there won't even be this element where they will need to get our PCR test in order to be able to be reimbursed.

Great. And how are you thinking about the commercial infrastructure and maybe the ongoing work in trying to build out a commercial infrastructure?

Yes. We -- about, I guess, 1.5 weeks ago or so, we raised an additional $172 million. The use of proceeds on that fund raise was to begin to build our commercial and medical affairs infrastructure.

As you look at head and neck, for a company who will be launching for the first time, head and neck is actually a pretty approachable tumor type. The prescriber universe is relatively concentrated. But you also have from an approval perspective, we will be approved first in the U.S. and then ex U.S. on overall survival. So it gives us our ability to build a commercial infrastructure to launch in the U.S.

We will maintain optionality as we think about whether we want to build our own infrastructure outside the U.S. or whether we'll partner. But we absolutely are going to build the organization and feel that we've got the capability and the know-how to be able to launch in the U.S.

Right. And you're looking at FICERA and opportunities beyond frontline head and neck cancers. If you could maybe talk about those opportunities in the remaining time that we have?

Yes. I think there are a lot of opportunities. I mean I think there are probably -- there are more ideas and opportunities than the capital available. You think about where EGFR expresses, where TGF-beta plays a role. I mean, we have cohorts open in colorectal cancer. We also have demonstrated activity, monotherapy activity in cutaneous and anal canal and even within head and neck, I think locally advanced is a really interesting opportunity.

One of the things that is known is radiation actually increases TGF-beta levels. So when you think about even there, we think that in that setting in patients who were radiated in the locally advanced setting that we are mechanistically differentiated to -- again, where TGF-beta kind of stand apart from the other EGFR bifunctionals.

Great. And I think for head and neck, the EGFR, TGF-beta story, I mean, I think it's pretty clear. Have you looked at sort of these other tumors in terms of the TGF-beta component and how those are expressed there to kind of get the...

Yes. And there's a fair amount of work that actually has been done. A researcher, Shannon Turley, who I believe is still at Genentech has done a lot around TGF-beta signatures.

And so we use that work and our own work to really guide the way we're thinking. One of the things that we don't want to just chase EGFR. What we know is that TGF-beta is a really important component of this molecule. And so we are looking for those tumor types where both EGFR and TGF-beta play a critical role.

Great. We're up on our time. Thank you, Ryan, for your time. Thank you for our listeners on the line, and we'll be back soon with our next session. Thank you.

Good day, and thank you for standing by. Welcome to the Bicara MHNCS Clinical Call Update. [Operator Instructions] Please be advised that today's call is being recorded.

I would now like to turn the call over to your speaker for today, Jenna Cohen, Chief Corporate Affairs Officer of Bicara Therapeutics. Please go ahead.

Thank you, and good morning, everyone. It's a pleasure to welcome you to Bicara Therapeutics' conference call. Yesterday, coinciding with the data presentation at the 2026 Multidisciplinary Head and Neck Cancer Symposium by Dr. Dan Zandberg of the UPMC Hillman Cancer Center, we issued a press release highlighting data from that presentation. 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 the statements made during the call today will include forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995 as amended. These forward-looking statements are based on our current expectations and assumptions, and actual results may differ materially from those indicated during this call as a result of various important factors, including those discussed in the Risk Factors section of our most recent quarterly report on Form 10-Q for the period ending September 30, 2025, which is on file with the Securities and Exchange Commission.

Any forward-looking statement made on this call represents our views only as of today, and except as required by law, we disclaim any obligation to update or revise any forward-looking statements.

Joining us on the call today are Claire Mazumdar, Chief Executive Officer; and Dr. Bill Schelman, Executive Vice President of Clinical Development at Bicara Therapeutics. Claire will review ficerafusp alfa or FICERA, the first and only EGFR TGF-beta bifunctional antibody that is being studied in the pivotal FORTIFI-HN01 trial in first-line recurrent metastatic HPV-negative head and neck squamous cell cancer, or HNSCC. Bill will review the preliminary safety and efficacy data from a less frequent dose of FICERA, 2,000 milligrams dosed every other week in combination with pembrolizumab presented yesterday at the conference. Together, Bill and Claire will outline our plan to explore a less frequent dosing regimen for FICERA.

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, Jenna. Good morning, everyone, and thank you for joining the call this morning. We are thrilled to be in Palm Springs this morning after announcing another significant milestone in our development program for FICERA yesterday during the Multidisciplinary Head and Neck Cancer Symposium plenary presentation. Not only have we further expanded the clinical experience observed with FICERA in frontline recurrent and metastatic head and neck squamous cell carcinoma to 90 total patients, where we collectively observed a generally well-tolerated safety profile and consistent efficacy with rapid and deep responses, but we now also have clinical data in hand, which supports further exploration of an alternative dosing regimen for FICERA. By exploring less frequent dosing, we hope to offer patients and clinicians optionality by maximizing convenience, particularly when dosed in combination with pembrolizumab. We believe we can achieve this while maintaining the rapid, deep and durable responses that are the differentiating hallmark to FICERA's clinical profile.

FICERA is the first and only bifunctional EGFR-directed antibody combined with the TGF-beta ligand trap designed to drive tumor penetration. One of the key challenges in the treatment of many solid tumors has been the inability of immune cells to penetrate the tumor and eliminate the cancer. FICERA is specifically designed to combat this challenge. The EGFR arm helps to localize TGF-beta inhibition to the tumor to break down barriers in the tumor microenvironment. In doing so, FICERA enables tumor penetration, specifically by reducing fibrosis, immunosuppression and T cell exclusion, and reverses TGF-beta-driven resistance mechanisms that are upregulated upon treatment with EGFR or checkpoint inhibitors. Taken together, these effects drive deep and durable responses that may lead to better outcomes and survival for patients.

Despite the advancement of immunotherapy, there remains a significant unmet medical need for improved treatment outcomes for patients with HPV-negative head and neck cancer. The current standard-of-care pembrolizumab provides response rates of only 19% as a single agent and 36% in combination with chemotherapy, but 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 standard of care.

Our data to date has demonstrated that FICERA can improve outcomes compared to standard-of-care pembrolizumab with or without chemotherapy. FICERA has shown a two to threefold improvement in response rates, complete response rate, duration of response and overall survival. This is a striking advance in the treatment of HPV-negative head and neck cancer, and we know of no other therapy that has demonstrated these results in such a difficult-to-treat tumor type.

Checkpoint inhibitor combination regimens, both approved and in development can deliver strong response rate but at the expense of durability, leading to little to no impact on overall survival benefit. The addition of FICERA to pembrolizumab maintains the strong immunotherapy-like durability of almost 22 months, more than triple the median duration of response of pembro plus chemotherapy at just 6.7 months, while also improving long-term clinical outcomes, including survival. This durability of response driven by the TGF-beta-targeting mechanism clearly distinguishes FICERA from other investigational agents in head and neck cancer.

As a reminder, our pivotal study, FORTIFI-HN01, began with the Phase II dose optimization portion to satisfy the Project Optimus requirements from the FDA. Patients were randomized to either receive 1,500 milligrams of FICERA weekly in combination with pembro, 750 milligrams of FICERA weekly in combination with pembro, or placebo plus pembro monotherapy. Just last month, we announced that we have reached alignment with the FDA that 1,500 milligrams of FICERA dosed weekly in combination with pembro is the go-forward dose for the Phase III FORTIFI-HN01 pivotal study. We have officially moved into the Phase III portion of the study and patients are being randomized in a 2:1 randomization to 1,500 milligrams of FICERA with pembro or to standard-of-care pembrolizumab.

Importantly, in this seamless design, enrollment never paused. The first patients treated with the 1,500-milligram dose will be included in both the ORR analysis for a potential accelerated approval and in the final overall survival analysis to support a full approval.

Bicara has built incredible momentum in just the first 2 months of this year. We initiated the Phase III portion of our pivotal study earlier than anticipated. And today, we can share more about our plan to explore less frequent dosing for FICERA to broaden patient and clinician optionality while maintaining the differentiated efficacy that is a hallmark of FICERA's clinical profile, driven by the underlying mechanism of action with TGF-beta inhibition.

With that, I'll hand the call over to Bill to review today's data.

Thanks, Claire. On behalf of my clinical and medical colleagues at Bicara, it's a pleasure to join you today to review the data that was shared by Dr. Dan Zandberg of UPMC at the 2026 MHNCS plenary session. I want to extend a heartfelt thank you to Dr. Zandberg and all other investigators and patients taking part in the Phase Ib and FORTIFI studies for their contributions to our program.

Today's presentation highlights preliminary data from our Phase Ib expansion cohort evaluating 2,000 milligrams of FICERA every other week in combination with pembrolizumab. This cohort enrolled frontline patients with HPV-negative recurrent or metastatic head and neck squamous cell carcinoma whose tumors had a CPS score of greater than or equal to 1. It's important to note that this exploratory cohort is evaluating both a higher dose of FICERA than is currently being used in the pivotal study and also a less frequent dosing regimen.

These patients present with a high disease burden and poor prognosis, making them fundamentally different from HPV-positive patients. As shown in the demographics and baseline characteristics, this cohort includes a significant proportion of patients with bulky tumors, many measuring 5 centimeters or greater, underscoring the aggressive nature of HPV-negative disease. This biology translates into markedly different clinical behavior. More than 80% of patients in this HPV-negative cohort had locoregional recurrence, either alone or with distant metastases, a hallmark of this disease.

Finally, the demographics and baseline characteristics in this cohort are consistent with our other first-line HPV-negative cohorts treated with FICERA at both 1,500 milligrams and 750 milligrams weekly as well as with prior registrational trials like KEYNOTE-048 and real-world clinical practice. This consistency reinforces the relevance and applicability of our data to the broader treatment landscape.

In terms of safety, similar with what has been previously reported, the combination of FICERA and pembrolizumab continues to demonstrate a well-tolerated safety profile. As we escalated to 2,000 milligrams, we have not seen any new adverse events and the severity of expected events has remained consistent with prior experience. As expected with this combination, the safety events fell into 2 main categories: EGFR-related events such as rash, which is consistent with what is typically observed with other approved EGFR antibodies like cetuximab, and potential TGF-beta-related events, including mild epistaxis and gingival bleeding, which when observed, resolved quickly without intervention. There was one Grade 4 event of an electrolyte imbalance, hypokalemia, that was possibly related to FICERA, which resolved with standard replacement therapy and did not require FICERA dose modification. There were no treatment-related deaths and discontinuation rates were low.

Overall, the safety profile of FICERA plus pembrolizumab in this cohort was manageable and generally consistent with FICERA's established profile at other doses administered weekly.

Preliminary efficacy data is shown here. 2,000 grams (sic) [ 2000 mg ] of FICERA every other week demonstrated consistently high response rates and importantly, rapid and deep responses. Notably, there was a 48% confirmed response rate and an 85% disease control rate in the 27 efficacy evaluable HPV-negative patients.

As we look at different patient subgroups, we continue to see robust and consistent responses across the CPS populations, including in the CPS 1 to 19 population as well as consistent clinical activity in patients with both low and high tumor burden. Even at less frequent dose, we see deep and rapid responses that are the hallmark of the FICERA clinical profile. 77% of responders achieved a deep response of greater than 80% tumor shrinkage, and we see a striking 26% complete response rate. The median time to response was rapid at 1.6 months.

We continue to believe that the strong depth of response ties back to FICERA's unique mechanism of action, whereby TGF-beta inhibition enables tumor penetration that is absolutely critical to driving durability and long-term survival.

We know that deep responses yield durable responses, and that's observed in this cohort as well, even when FICERA was dosed less frequently. The results on this slide are notable. While the overall data for this cohort are still maturing, as of the data cutoff, the vast majority of responders and in particular, the deep responders remained in response, including several beyond 20 months. When patients are driving benefit from a treatment, they stay on therapy. These data clearly show that even when FICERA is given at a higher dose, but less frequently, patients are staying on therapy longer than what has been observed with other pembrolizumab combination approaches, suggesting sustained efficacy with no trade-off on tolerability.

Now with a growing body of PK, translational and clinical data, including the 90 patients at varying doses and schedules, we have established a clear understanding of the exposure-response relationships of both the EGFR and TGF-beta components of FICERA. These insights have positioned us to identify a dosing schedule to optimize efficacy, safety and schedule.

I'll now hand the call back to Claire to talk more about our strategy here.

Thank you, Bill. Now that we've reviewed the clinical data from yesterday's preliminary at MHNCS, I'd like to outline some additional data that our team has been looking at in-house to inform our plan to explore an alternative dosing regimen, which includes a loading phase in every 3-week maintenance phase for FICERA alongside our pivotal study as well as what that plan is. Last December at ESMO Asia, we presented initial biomarker data showing a clear relationship between higher FICERA dose levels, increased TGF-beta inhibition in the tumor and deeper clinical responses. Today, we are sharing an updated analysis.

On the left, you see paired tumor biopsies from patients treated by FICERA plus pembro taken at baseline and at cycle 2 day 1. These samples directly measure intratumoral TGF-beta inhibition via phospho-SMAD2, the downstream biomarker of TGF-beta activity.

On the right, we show blood-based cytokine data measuring systemic immune activation across all 3 FICERA dosing regimens. Importantly, the trends are consistent. Higher but less frequent dosing continues to drive robust TGF-beta inhibition and increased immune activation. These results support advancing a less frequent dosing schedule for FICERA as we can maintain the TGF-beta inhibition that we believe underlies deeper and more durable responses while potentially improving patient convenience and compliance.

The biomarker data is important because it demonstrates that greater TGF-beta inhibition at higher doses of FICERA regardless of schedule, drives deeper tumor penetration. The paired biopsies shown here highlight the clear increase in T cell infiltration from baseline to cycle 2, day 1 with FICERA at 2,000 milligrams every other week. This is what meaningful tumor penetration looks like, and we know now that FICERA can achieve this both at weekly and less frequent dosing.

Next, we evaluated whether a less frequent dosing schedule of FICERA could still sustain TGF-beta inhibition in the tumor microenvironment, critical for the deep and durable responses that define FICERA's clinical profile. When comparing median depth of response and the proportion of deep responders at the same 24-week follow-up, the data are clear. The highest dose tested 2,000 milligrams delivered deep responses even when dosed less frequently than the pivotal 1,500-milligram regimen. These findings strengthen our conviction that robust TGF-beta inhibition drives the depth and durability seen to date and that a less frequent dosing regimen can achieve equal or greater clinical impact.

In summary, data presented to date tell us that higher but less frequent 2,000-milligram dose of FICERA delivers: one, a well-tolerated safety profile aligned with what we've consistently seen with FICERA plus pembro. Two, comparable or greater TGF-beta inhibition and cytokine activation, supporting durable immune engagement. And three, rapid and deep responses reflecting FICERA's mechanism of enhancing tumor penetration through TGF-beta inhibition. Taken together, these data give us a clear foundation for pursuing less frequent dosing.

Our priority is to maintain FICERA's potential best-in-class profile defined by depth and durability of response while creating practical dosing options for patients and providers. While our market research confirms that FICERA's differentiated efficacy will drive adoption, we believe it's important to create optionality for patients and clinicians. The totality of clinical and PK/PD data signals a straightforward path to offering additional dosing flexibility, especially given real-world use alongside pembrolizumab.

FICERA's bifunctional design using EGFR targeting to localize TGF-beta inhibition directly within the tumor microenvironment drives rapid tumor penetration and shrinkage. As tumor burden decreases, the level of TGF-beta inhibition required to maintain response also declines. This biology creates a natural opportunity to extend the dosing interval after the initial loading phase while preserving potency. By optimizing FICERA's relative dose intensity over time, we can better match treatment to the evolving needs of both the tumor and the patient.

We've now studied FICERA at 3 doses and across 2 dosing regimens. These data give us a robust coherent understanding of FICERA's kinetics and our additional pharmacokinetic and pharmacodynamic modeling further strengthens this picture. The findings show that TGF-beta inhibition drives rapid and deep responses within the first few cycles and that this inhibition remains sustained even with less frequent dosing. In other words, long-term weekly administration is not required to maintain the level of inhibition associated with deep durable responses.

Building on the biology and the totality of the data, we plan to develop FICERA with a dosing regimen that begins with the loading phase and transitions to an extended interval every 3-week maintenance schedule. This approach leverages FICERA's mechanism to maintain strong pathway engagement while reducing dosing frequency. We will provide further details on this loading maintenance regimen once we've achieved regulatory alignment on this approach and development strategy.

While we expect to initially seek accelerated approval for FICERA with the 1,500-milligram weekly regimen from FORTIFI-HN01, we believe that a parallel randomized study will allow us to have a loading and maintenance data available by the time of potential approval, creating a compelling path for earlier adoption of this streamlined regimen.

In summary, we are very pleased with the safety and efficacy observed at a higher and less frequent dose of FICERA at 2,000 milligrams every 2 weeks. We remain confident that the depth of response observed with FICERA reflects its differentiated mechanism. TGF-beta inhibition promotes effective tumor penetration, setting off a robust immune response that underlies the durability and long-term benefit we are seeing. That clinical differentiation can be maintained as we work to expand patient choice around dose regimen.

Before I turn over to the operator, I'd like to take a moment to thank everyone who is or has participated in our Phase Ib and FORTIFI studies for putting their hope and trust in FICERA and Bicara; our clinical trial investigators who have been thoughtful collaborators, particularly Dr. Dan Zandberg, who presented these data yesterday here in Palm Springs; and the passionate team of people at Bicara who are working relentlessly to bring FICERA to the world as quickly as possible.

And with that, we'll take some questions. Operator?

[Operator Instructions] The first question for today will be coming from Tyler Van Buren of TD Cowen.

Thank you very much for the very interesting data presentation. One of the more interesting statements in the release was the statement that preliminary efficacy data demonstrated enhanced durability when I first read the release. So curious to get your expanded thoughts on that and what you're seeing with the 2,000-milligram dose on durability as it relates to the 15-milligram (sic) [ 1,500 mg ] data and why that might be. Is this specifically referring to the depth of response at 24-week data and the percent of responders with deep responses that you kind of just showed towards the end?

And then just a second question, just on the topic of durability. I believe the Phase Ib/II OrigAMI study of YBREVANT FASPRO was announced yesterday and the median PFS was 7.7 months. So curious to get your thoughts on that data and the potential competitive implications for you guys.

Thank you for your question, Tyler. So alluding to the durability question for the 2,000 milligrams every 2 weeks, as you saw in the presentation, we also shared a swimmer plot that showed very strong durability in some of our early responders going out beyond 2 years in terms of duration of response. While our median duration of response is not yet mature and neither is our median PFS, we do believe it's trending quite strong on the scale of what we've seen at the 1,500-milligram dose. So really speaking to why the deep responses are leading to high duration of response and ultimately, overall survival.

To your second question around the data that was presented yesterday also here at the Head and Neck meeting from OrigAMI-4, so RYBREVANT or amivantamab showed in combination with pembro, a 7.7-month median PFS. What we've been able to demonstrate with the 1,500-milligram dose, if you may remember, at ASCO last year was a median PFS of just under 10 months, at 9.9 months. We also believe that the data from the 2,000 milligram every 2 weeks is trending quite strong and will also exceed what we've seen with amivantamab plus pembro yesterday. So we do believe, again, the differentiated profile of FICERA is really focused on these deep responses that are translating to durable responses, while the other EGFRs or EGFR bispecifics are really delivering a durability of a targeted therapy consistent with what we've seen across the board with cetuximab, petosemtamab and amivantamab.

And the next question is coming from the line of Eric Schmidt of Cantor.

Thanks also for really interesting and comprehensive update. Maybe first, Claire, some of the biomarkers that you're looking at here to guide dosing are systemic markers of inflammation, as you noted in your presentation. I guess we would hope that in some ways, what's happening in the tumor is even more potent in terms of TGF-beta inhibition. So can you talk about how you're looking to rely upon both intratumoral as well as systemic markers and what kind of weight you're putting on each of those aspects of information that you have? And then just a quick one, the one case of hypokalemia, is there a mechanistic rationale for that?

Thank you for your question, Eric. So I'll speak to the first question and then pass your safety question to Bill. So in terms of biomarker data, we're really looking at the totality of data. So we do have a number of intratumoral focuses, which is why we presented both the phospho-SMAD2 paired biopsy data, which shows across the doses that have been studied, a consistent TGF-beta inhibition.

As you know, of course, phospho-SMAD2 is measured by immunohistochemistry or IHC, which is a pretty sustained marker and doesn't give you the dynamic effects of what you're seeing if you look at TGF-beta inhibition via just systemic TGF-beta inhibition. And so those are also -- we've also seen those and those do seem to be consistent across even less frequent dosing regimens.

We've also been able to show T cell infiltration by immunohistochemistry and spatial transcriptomics that have really certified the fact that we're seeing tumor microenvironment remodeling even at the less frequent dosing. And it's a totality of, I would say, biomarker data as well as PK data that is reinforcing our thinking around loading and maintenance dose as well as clinical data.

And to your hypokalemia question, I'll pass it over to Bill.

Yes. Thank you, Eric. So with respect to hypokalemia, this is consistent with what has been seen with other EGFR inhibitors, including cetuximab. So with EGFR inhibitors, electrolyte imbalances, including hypokalemia are not unanticipated and it's fairly common. The management of this with standard replacement therapy also is very common.

The next question will be coming from the line of Stephen Willey of Stifel.

Maybe just a couple of housekeeping ones with respect to the data presentation itself. Do we know what the median duration of follow-up is on this cohort? And then do you happen to know if the incidence rate of just dose modifications, whether those are holds or reductions are any more significant with the Q2W dosing schedule relative to what you've seen at 1,500 mg? And then I just have a quick follow-up.

Thanks for your question, Steve. So this cohort was actually enrolled in 2 portions. We initially started this cohort about 2 years ago and then switched to enrolling the 750-milligram weekly cohort to satisfy Project Optimus. And so I believe the vast majority of patients were enrolled in the second part of the study to a total of 30 patients. So you have the first group of patients with over 2 years' worth of follow-up, which is why you saw the strong durability on those patients. The other patients have less than 12 months follow-up. And so we do hope to be able to provide a fulsome update once we've achieved median PFS, median DOR and the like.

And I believe your second question was focused -- will you repeat the second question?

It was just focused on whether or not you would seen a higher incidence rate of dose modifications with Q2W...?

No, we have not. So in terms of the AE profile, I would say it's quite consistent in terms of dose holds and dose modifications, very low in both cases and very similar to the 1,500-milligram weekly dose.

Okay. And then maybe just lastly, I know you need to reach some level of regulatory alignment on this loading and maintenance dosing strategy. But can you maybe just kind of provide a little bit of an overview in terms of when you expect to approach FDA, when you think you might have that guidance in hand in terms of what a parallel randomized study would need to look like? And any guess as to how many data points, how many patients you may need to have represented within that trial specifically?

Our intent is to have the fulsome data in hand by the time of our approval to be able to go to the FDA and allow flexibility for patients. So we do anticipate being able to get regulatory guidance in time to run the study. Again, this is -- this would be a parallel study in parallel to FORTIFI-HN01, much smaller and likely a randomized study looking at our weekly dosing randomized to the loading maintenance dose.

And our next question is coming from the line of Kelsey Goodwin of Piper Sandler.

Maybe just taking a step back from a competitive standpoint, I guess, how important do you think it is to have an additional dosing schedule in the first place in an eventual label? How competitive is QW versus Q2W versus Q3W in your opinion? And then, if I maybe just to follow up a bit on that last question, do you have a sense of when you might have regulatory alignment when you might be able to start the parallel study?

Thank you for your question, Kelsey. So as we mentioned in the call, we do -- our market research tells us that the differentiated profile in terms of depth of response and durability of response and the strong overall survival we've seen in our cohorts will really differentiate FICERA even in a weekly regimen. And so we do believe that a weekly regimen will lead to significant adoption. What we're really trying to do here with the loading maintenance dose is create optionality for investigators and patients as we think about what is the best clinical profile for this molecule.

And so it's really about, again, ensuring that we see these rapid deep responses in the loading phase and being able to create flexibility, especially in combination with pembrolizumab in the maintenance phase. And our intent right here from a regulatory standpoint is, again, not to get ahead of our regulatory conversations, and we'll provide an update when we have them.

Our next question is coming from the line of Judah Frommer of MS.

Can you just remind us how many centers you're in with the pivotal trial at this point? What overlap is between trials of peto or ami within those centers? I think you've said it's very low. And then just curious, from investigators, I guess, just given kind of depth of response and durability, does it seem like there is demand for a less frequent dosing schedule? Or is that more alignment with kind of the other clinical competitors out there?

Thank you for your question, Judah. So as of today, we've built significant momentum in FORTIFI-HN01, especially now that we're in the Phase III portion of the study. I believe we have 111 sites on clinicaltrials.gov with significant momentum building in Europe and outside of the United States as well. I would say there is, today, still minimal overlap in terms of sites between ourselves and the petosemtamab study, LiGeR-HN1. And the amivantamab study, which I believe is an OrigAMI study has just begun recruiting. But as you may be aware, again, this is a differentiated patient population. They are randomizing to pembro plus chemo. And we are not seeing significant overlap today from that standpoint.

To your question, we are here at the Head and Neck meeting here in Palm Springs and the feedback has been extremely positive on the data for FICERA even compared to the other EGFR inhibitors. I think what we're hearing is, again, that the differentiated profile, both in terms of depth of response, durability. But I think also importantly, safety really shows that FICERA is really the best-in-class. So one of the key feedbacks we've been hearing from investigators who have worked with all 3 molecules has been really the FICERA safety profile is also quite differentiated.

And so we do believe, again, that the weekly profile will not be an impediment to the best-in-class profile and being able to have the largest market share. But we do think from a life cycle perspective, being, again, able to create optionality and flexibility for our patients.

Bill, anything else you'd add in terms of the feedback we've been hearing?

Yes, Claire. Consistent with what Claire has been saying, we've been hearing feedback about the differentiated profile in terms of the rapidity, depth and durability of the responses. In terms of the dosing schedule, having a less frequent dosing regimen does allow flexibility and more convenience for patients. And so while not taking away from what we see on the weekly regimen, we are hearing that this provides optionality and flexibility for patients. This also inform the life cycle and other opportunities for FICERA.

Our question will be coming from the line of Reni Benjamin of Citizens Bank.

Congratulations on this data. Just to kind of flesh out a little bit more regarding the dosing regimen. Can you -- you said you plan on moving to a loading dose and a Q3 weekly maintenance. Can you talk a little bit more about like how you might be thinking about this? Are there going to be multiple loading doses and then a maintenance regimen? Is there the potential for a loading dose then going to a Q1 weekly and then a maintenance regimen? I'm a little bit kind of confused as to how this is going to look.

And just kind of related to it, is it -- is the next study going to be kind of a dedicated cohort to give you a good sense as to how it will move forward? Or does it go right into a potential registrational study? And I just have a quick safety follow-up after that.

Great question, Reni. So the loading and maintenance, the way we're currently thinking about it is, again, a loading dose at 1,500 milligrams weekly. So similar to the pivotal dose that we're taking into the Phase -- we've taken into the Phase III portion. So allow, again, for these rapid deep responses for a certain amount of cycles and then moving to a higher dose, but at every 3-week maintenance dose really to be able to create optionality. And the reason we chose Q3W is, again, in combination with pembro, it allows for same every 3-week visits.

And so the plan for, again, this study is to run a parallel study. We have looked at our molecule at a number of different doses. And so we do believe in the safety of this molecule. And so this would be, again, a randomized study that would allow to bridge to a potential data set in time for approval.

Got it. Great. And then just related to the safety aspect, we saw the Grade 3 anemia was a little bit higher in this cohort than prior doses. Can you maybe talk a little bit about that? Was it an early onset or not? Was it manageable largely with supportive care? Just any sort of color around that.

Yes. So anemia is a hypothesized TGF-beta-related event. What we have typically seen with our molecule is that anemia is a later-stage adverse event that tends to happen once patients have achieved longer-term follow-up with deep and durable responses. What we are seeing, again, at this higher dose is a slightly higher rate of anemia, which we believe is really predicated on the mechanism of action of this molecule in which by the time we've achieved deep and durable responses, there is less TGF-beta within the tumor microenvironment. And so there's more systemic TGF-beta inhibition.

One of the things that Bill can speak to is that typically our patients, especially head and neck HPV-negative patients with high tumor burdens do have high levels of baseline anemias. And so this is something...

Yes. Thanks, Claire. As Claire mentioned, these patients often come in with anemia as a result of their prior therapies and as a result of their tumors. So patients with head and neck cancer do have high baseline levels of anemia. We see a mild increase of the anemia. And to the point of management, these patients are well managed with standard supportive measures, iron supplementation. They don't require a high level of transfusions and usually require just dose holds and not other dose modifications. So it's fairly well managed with standard supportive measures.

Our question is coming from the line of Richard Law of Goldman Sachs.

This is [ Jane ]on for Rich. So my question is, so first, are you going to -- so first, what is the planned dosing regimen for the loading dose plus Q3W? And is the plan to commercialize the 3 dosing options, if approved, the 1,500 mg QW, 2,000 mg Q2W and then the loading plus the Q3W? And then are you going to conduct bridging studies in parallel with the first-line pivotal study? And what will be the design of the bridging studies required by FDA?

As I answered previously, we do, again, anticipate a loading dose of 1,500 milligrams weekly, moving them to a Q3W dose. We are anticipating regulatory feedback and do not want to get ahead of regulatory conversations, but we are predicating a study that would run in parallel to our pivotal study to be able to have the data in hand for -- in time for approval.

Claire, do you expect the efficacy and safety of this new loading plus Q3W dosing regimen to be different from the 1,500 mg QW dose regimen and why?

Again, we've seen consistency across the 1,500-milligram weekly as well as the 2,000-milligram every 2-week cohort. We do anticipate based off of the totality of PK/PD and clinical data, a strong efficacious profile that allows for rapid deep responses and durable responses that lead to outsized overall survival. Thank you for your question.

And our next question is coming from the line of Jeet Mukherjee of BTIG.

Two for me. Maybe just on the patient baseline features. It seems as though patients with locoregional-only disease was maybe a higher proportion as a part of this 2,000 mg cohort versus the 1,500 mg once weekly seen at ASCO. So if you could just elaborate, does this perhaps correspond to less aggressive disease? Or overall, how do you compare the 2 patient populations? And I have a follow-up.

Thank you for your question, Jeet. In fact, patients with locoregional disease only tend to do worse and so are far more sick and have higher radiation, highly fibrotic tumors. And interestingly, they respond typically less well to pembrolizumab. So again, the skewing to locoregional disease only just speaks to how difficult to treat these patients are and the fact that we're seeing such strong, deep and durable responses, again, speaks to being able to address the sickest patients in HPV-negative head and neck cancer.

Great. And as a follow-up, obviously, this 2,000 mg once every 2-week data looks quite compelling, but you've obviously articulated a plan to move forward with a loading plus once every 3-week maintenance strategy with a randomized study. I guess maybe my question there is, why not move forward with this 2,000 mg cohort in hand? You spoke to optionality. This certainly seems to provide that. So what really gives confidence on maybe trying a slightly different novel regimen here instead of going forward with 2,000 mg?

It's a great question. And again, I think it's the totality of clinical data as well as safety data wanting to optimize on both fronts, ensuring that we see these rapid deep responses, but we're also able to maintain those and creating a tolerability profile that's able to keep patients on for long term. And so being able to optimize across all 3 of these fronts really led us to a loading and maintenance dose.

And I would now like to turn the call back over to Claire Mazumdar, CEO, for closing remarks. Please go ahead.

Thank you all for joining this call today. We're thrilled to be here again in Palm Springs with the head and neck investigators, and thank you for your time. Thank you.

Thank you all for joining the conference call today. You may now disconnect.