Good day, and thank you for standing by. Welcome to the Bicara Therapeutics conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. In the interest of time, we ask that you please limit yourself to one question. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker, Jenna Cohen, Chief Corporate Affairs Officer at Bicara Therapeutics. Please go ahead.
Thank you, and good morning, everyone. It's a pleasure to welcome you to Bicara Therapeutics' conference call. Earlier today, following a data presentation at the ESMO Asia Congress 2025 by Dr. Deborah Wong of UCLA Medical Center, we issued a press release highlighting data from that presentation, as well as additional data that will be shared shortly on this corporate call. You can access the press release, as well as the slides that we'll be reviewing today, by going to the investor section of our company's website. Before we begin, please note that statements made during the call today will include forward-looking statements which are based on our current expectations and assumptions. These statements are subject to certain risks and uncertainties, and actual outcomes may differ materially. For additional information, please refer to our filings with the SEC.
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, Tanya Green, Chief Development Officer, and Ryan Cohlhepp, President and Chief Operating Officer. Claire will introduce ficerafusp alfa, or ficerafusp alfa, the first and only EGFR TGF-beta bifunctional antibody that is being studied in the pivotal FORTIFY-HN01 trial in first-line recurrent metastatic HPV-negative head and neck squamous cell cancer, or HNSCC. Tanya will review the preliminary safety and efficacy data from 750 milligrams of ficerafusp alfa, dosed weekly in combination with pembrolizumab, or Pembro.
Lastly, Ryan will provide additional context on the totality of Ficera data that we have in hand across both doses that confirm what we have always believed to be true: that greater TGF-beta inhibition drives deeper tumor responses that translate to more durable outcomes for patients. With that, I'll now turn the call over to Claire.
Thank you, Jenna. Good morning, everyone, and thank you for joining the call this morning. Today marks a significant milestone in the advancement of Ficera for the first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma, or HNSCC. We now have a robust open-label data set in hand for the 750 milligram dose that is currently being evaluated as part of FDA's Project Optimus in our pivotal FORTIFY-HN01 study. I want to take a few minutes before I hand the call over to Tanya to review today's data to talk about the promise of Ficera, the first and only EGFR TGF-beta bifunctional antibody that has recently been granted breakthrough therapy designation in combination with Pembro for the first-line treatment of patients with HPV-negative recurrent or metastatic HNSCC.
This important granting continues to support the recognition of HPV-negative HNSCC as a distinct clinical indication, which is consistent with the evolution of the treatment landscape and to which our development strategy is thoughtfully designed. One of the key challenges in the treatment of several solid tumors has been the inability of immune cells to penetrate the tumor and eliminate cancerous tissue. This is especially true in HPV-negative HNSCC, where, despite the approval of immune checkpoint inhibitors such as Pembro, outcomes remain poor, with only about a 19% overall response rate. Ficerafusp alfa was specifically designed to combat this challenge of inadequate tumor penetration by directly inhibiting TGF-beta at the tumor to break down these barriers in the tumor microenvironment.
In doing so, Ficera enables tumor penetration specifically by reducing fibrosis, immune suppression, and T-cell exclusion, and reverses TGF-beta-driven resistance mechanisms that are upregulated upon treatment with EGFR or checkpoint inhibitors such as Pembro. Taken together, these effects are designed to drive deep and durable responses and translate to better outcomes for patients. HNSCC is a debilitating disease with significant suffering, including pain, difficulty swallowing, and speech loss due to disfigurement caused by local recurrence or prior treatments. These challenges highlight the urgent need of therapies that not only significantly extend survival but also reduce toxicity and meaningfully improve quality of life for these patients. HNSCC is a sizable and growing market. In the U.S. alone, over 60,000 people are diagnosed each year with head and neck squamous cell carcinoma, including approximately 23,000 cases in the recurrent or metastatic setting.
The majority, roughly 80% of those people, have HPV-negative disease and tend to have significantly worse outcomes compared to those with HPV-positive disease. HPV-negative and HPV-positive head and neck cancers have distinct biology. HPV-negative disease is typically more aggressive, carries a higher mutational burden, and often has an immunosuppressive tumor microenvironment driven by high expression of both EGFR and TGF-beta. This may explain why HPV-negative patients typically respond poorly to therapies like Pembro and other anti-PD-1 inhibitors, and it's for these exact reasons that we believe HPV-negative disease is ideally suited for Ficera, a targeted agent designed to overcome these immunosuppressive barriers in the tumor to drive tumor penetration of immune cells and amplify the effects of immunotherapies like Pembro. Unfortunately, there remains a significant unmet need for improved treatment outcomes for patients with head and neck squamous cell carcinoma.
The current standard of care, Pembro, provides only a 19% overall response rate as a single agent, or if combined with chemotherapy, provides a 36% response rate, but median overall survival remains poor at only 12-13 months. Importantly, for people living with HPV-negative disease, real-world data consistently show worse survival outcomes as low as 7-9 months compared to the overall population when treated with standard of care. As a reminder, earlier this year, we presented data with two years of follow-up from our Phase 1b expansion cohort evaluating 1,500 milligrams of Ficera weekly. Those data demonstrated that 1,500 milligrams of Ficera in combination with Pembro nearly tripled the response rates in HPV-negative patients compared to historical and real-world data for Pembro alone.
While maintaining the strong immunotherapy-like durability of almost 22 months, more than tripled the median duration of response of Pembro plus chemo at just 6.7 months. Additionally, Ficera more than doubled the median overall survival in HPV-negative patients compared to the overall survival outcomes of Pembro alone or in combination with chemotherapy observed in real-world data sets. And we believe that Ficera's unique clinical benefit is driven specifically by design as the first and only EGFR TGF-beta bifunctional antibody targeting known drivers of disease. Ficera has already demonstrated great promise in the treatment of HPV-negative head and neck cancer. This case highlights the transformative potential of Ficera in combination with Pembro for patients with aggressive recurrent and metastatic squamous cell carcinoma.
A 66-year-old patient with recurrent oral cavity cancer had exhausted standard options after rapidly progressing following a second surgery with adjuvant chemoradiation and was eventually treated with 750 milligrams of ficerafusp alfa combined with Pembro. The results were remarkable. Within six weeks, the target lesion shrank by 55%, signaling a rapid and deep response. The response proved durable, with the patient remaining alive and still in response more than a year later as of the last follow-up in September 2025. This is not just a single success story. It's part of a growing body of evidence suggesting ficerafusp alfa could redefine outcomes for patients with advanced HPV-negative HNSCC.
Before we get into framing today's data, here's a brief overview of FORTIFY-HN01, our randomized double-blind placebo-controlled seamless Phase 2/3 clinical trial in front-line recurrent and metastatic HPV-negative head and neck patients with CPS, or combined positive score, that measures PD-L1 expression greater than or equal to 1. FORTIFY-HN01 begins with a dose optimization portion to satisfy the Project Optimus requirements from the FDA. Patients are randomized to either receive 1,500 mg of ficerafusp alfa weekly in combination with Pembro, 750 mg of ficerafusp alfa weekly in combination with Pembro, or control of Pembro monotherapy. Once the dose selection has been made, which we now expect in the Q1 of 2026, the unselected dose arm will be dropped, and the study will continue with a 2:1 randomization between the optimized ficerafusp alfa dose and the Pembro control arm. Importantly, in this seamless design, enrollment never pauses.
The first patients treated with selected optimal dose are included in both the ORR analysis for a potential accelerated approval and the final overall survival analysis to support a full approval. Lastly, before I pass it over to Tanya, I want to highlight that we now have open-label data in hand from two Phase 1b expansion cohorts for both doses that are being evaluated as part of the randomized dose optimization portion of the pivotal Fortify study. Long-term follow-up data from the 1,500 milligram cohort was presented this summer in an oral presentation at the 2025 ASCO Annual Meeting, and today's presentation at the 2025 ESMO Asia Meeting is the first disclosure of the preliminary safety and efficacy data for the 750 milligram cohort.
Both of these open-label data sets will inform the dose selection of Ficera and, importantly, will help provide adequate follow-up to assess longer-term safety and efficacy metrics between the two doses, including durability and overall survival. With that, I'll hand the call over to Tanya to review today's data.
Thanks, Claire. On behalf of my clinical and medical colleagues at Bicara, it's a pleasure joining you today to review the data that was shared by Dr. Deborah Wong of UCLA Medical Center at the ESMO Asia Congress. I want to extend a heartfelt thank you to Dr. Wong and all of our other investigators and patients taking part in the Fortify study and their contributions to our program. I am thrilled to have recently joined Bicara as Chief Development Officer to lead our development efforts. This is an incredible opportunity to work alongside such talented individuals and drive innovation that aligns with our mission. Today's presentation highlights data from our Phase 1b expansion cohort that targets one of the most challenging segments in head and neck cancer, HPV-negative disease.
This cohort enrolled front-line 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 one, who received 750 milligrams of Ficera weekly in combination with Pembro. 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 five centimeters or greater, underscoring the aggressive nature of HPV-negative disease. This biology translates into markedly different clinical behavior. Approximately 80% of this HPV-negative cohort demonstrates loco regional recurrence either alone or with distant metastases, a hallmark of this disease.
Finally, the demographics and baseline characteristics in our study align with other first-line HPV-negative cohorts treated with Ficera 1,500 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 to what has been previously reported, the combination of Ficera and Pembro continues to demonstrate a well-tolerated safety profile. As expected with this combination, adverse events were low grade, grade 1 or 2, well-tolerated, and fell into two main categories: EGFR-related events such as rash, consistent with what is typically observed with approved EGFR antibodies like cetuximab, and potential TGF-beta-related events, including mild epistaxis and gingival bleeding, which, when observed, resolved quickly and without intervention. Importantly, no treatment-related grade 4 or 5 adverse events were reported, and discontinuation rates have remained low.
Overall, the safety profile of Ficera plus Pembro is manageable and consistent with Ficera's established profile at other doses, including 1,500 milligrams weekly. Preliminary efficacy of 750 milligrams of Ficera plus Pembro is shown here and demonstrates consistently high response rates. Notably, there was a 57% confirmed response rate and an 83% disease control rate in the 30 efficacy evaluable HPV-negative patients. As we look at the different patient subgroups, we continue to see responses not just in the CPS greater than or equal to 20 population, but also in the CPS 1 to 19 population with a 73% response rate in this patient group. Similarly, we observe activity in patients with both low and high tumor burden measured by the sum of the target lesion diameters.
We are continuing to see strong depth of response, with almost 30% of responders achieving a deep response of greater than 80% tumor shrinkage, as well as a 10% complete response rate. Median time to response is rapid at 1.6 months, often the first year and we are also hearing patients often report rapid symptom regression within the first or second year. We continue to believe that this strong depth of response ties directly back to Ficera's unique mechanism of enabling tumor penetration that Claire outlined earlier and is absolutely critical to both durability and long-term survival. In summary, today's data continue to show that the combination of Ficera plus Pembro represents a promising new front-line treatment for HPV-negative, recurrent, or metastatic head and neck squamous cell carcinoma, which is supported by our recent Breakthrough Therapy Designation from the FDA.
The 750-milligram weekly dose of Ficera not only demonstrated a manageable safety profile, but also encouraging activity with a 57% response rate and several deep and rapid responses. This data set informs our dose selection in our pivotal Fortify study expected in the Q1 of 2026, and with that, I'll turn it to Ryan to expand on how we view this data in the context of Ficera's development.
Thank you, Tanya. I'll now spend the next few slides helping contextualize the impact of the data presented today on the Fortify study. So how do today's data fit into Ficera's development plan and the Fortify study? Well, first and foremost, today's data increases our confidence in the overall response rate interim analysis in Fortify. The similarly high response rates for both the 750 milligram cohort and 1,500 milligram cohort suggest strong efficacy of Ficera across multiple dose levels. We've now doubled our sample size to almost 60 patients with an additional 30 patients of prospectively defined HPV-negative disease, which tightens our confidence intervals around what we may expect to see with regards to overall response rates at our pivotal interim analysis.
With this total sample of 58 patients, we are now seeing an approximate 55% response rate, which is nearly triple that of what we might expect in our control arm based upon the 19% ORR for Pembro shown in KEYNOTE-048. Additionally, we believe this consistency in ORR across multiple doses in different trial cohorts in phase one reduces the likelihood that we'll see meaningful deterioration in ORR at the top line. Lastly, the strong activity across doses in both patient subsets of CPS 1 to 19 and CPS greater than 20, coupled with a consistently manageable safety profile, suggests a wide therapeutic index for this molecule and builds conviction in our FORTIFY study.
As we evaluate the two different doses of Ficera, one hypothesis we've had based upon our understanding of the molecule's pharmacodynamics data is that at doses above 750 milligrams, we're saturating the EGFR receptor, but we see increased TGF-beta inhibition in the tumor at higher doses. Shown here in the figure on the left is a biomarker analysis from paired tumor biopsies of patients treated with Ficera plus Pembro at baseline and at cycle 2, day 1, to assess the levels of TGF-beta inhibition directly within the tumor. Importantly, we observed downregulation of phospho-SMAD2, which is the direct downstream biomarker of TGF-beta inhibition, at doses of 750 milligrams and 1,500 milligrams of Ficera plus Pembro.
Additionally, despite the limited number of available samples, we observed a trend towards a greater reduction in phospho-SMAD2 at 1,500 milligrams versus 750 milligrams, supporting the notion of greater reductions in TGF-beta inhibition at higher doses. Furthermore, shown on the right, when evaluating key pro-inflammatory cytokines in the blood, we see increased markers of immune activation at 1,500 milligrams versus 750 milligrams, which again suggests that higher doses of Ficera are showing signs of an increased TGF-beta inhibition that's driving the immune activity. The pharmacodynamic data is significant given Ficera's mechanism of action, in which we believe that TGF-beta inhibition directly within the tumor microenvironment is what is driving the tumor penetration that results in deep and durable response.
Indeed, when we look at the clinical data to compare both the median depth of response and proportion of patients achieving a deep response at an equivalent time point of follow-up of 24 weeks, we observe deeper responses at the 1,500 milligram dose versus 750 milligrams, which we believe is an initial surrogate of what we may expect for durability. Ultimately, these data build confidence in our understanding of how TGF beta inhibition is contributing to the impressive depth and durability observed to date with Ficera and continue to establish the 1,500 milligram dose as a very high bar to beat based upon both the levels of TGF beta inhibition in the tumor, as well as the depth and durability observed in the clinical data thus far.
To summarize the key takeaways, today's 750 milligram data bolster our conviction in the transformative potential of Ficera for patients living with HPV-negative head and neck cancer. In our view, de-risk our ongoing pivotal FORTIFY in several key ways. First, we're seeing consistently high response rates across multiple dose levels, including both 750 milligrams and 1,500 milligrams weekly, which increase our confidence in the overall response rate interim analysis. Second, we're observing a similar safety profile at both doses that remains well-tolerated with manageable adverse events. Third, as highlighted, the biomarker data we've collected suggests a dose-dependent response in TGF-beta inhibition, which we believe is driving greater depth of response and durability with the 1,500 milligram dose.
Finally, with this open-label data from the 750 milligram cohort now in hand, we're one step closer in our advancement towards our dose selection in the Fortify trial, which, based upon our current enrollment and advancement of the trial, is expected in the Q1 of 2026. Before I turn it over to the operator, I'd like to take a moment to thank the people living with HPV-negative head and neck squamous cell cancer, as well as their caregivers, who are participating in the Fortify study, putting their hope and trust in Ficera and Bicara, our esteemed clinical trial investigators who are dedicating their time and energy to participate in this study, particularly Dr. Deborah Wong, who presented these data earlier today in Singapore, and the passionate team of people at Bicara, who are working relentlessly to bring Ficera to the world as quickly as possible.
With that, we're open to taking questions. Operator, can you please open the line?
Thank you, sir. As a reminder to ask a question, you will need to press star 11 on your telephone. To withdraw your question, please press star 11 again. In the interest of time, we ask that you please limit yourselves to one question. Please stand by while we compile the Q&A roster. And I show our first question comes from the line of Alexa Deemer from Cantor Fitzgerald. Please go ahead.
Awesome. Thank you. So this is Alexa on for Eric Schmidt, and congrats on an awesome data update. So based upon the data that was presented today, is there any reason to even consider the 750 mg dose any further? And if so, how many more patients or what data are you still waiting for to make the final dose selection decision? Thank you.
Thanks for your question, Alexa. I will be passing this question over to Ryan to answer your question.
Thanks, Alexa. So in terms of the 750, again, as we go back to the design of the pivotal trial, we had committed to the FDA around 10 to 20 patients per dose group. We now have the data sufficient to engage with the FDA, and we'll be doing that, which is why we have now tightened the guidance to the Q1 of next year.
Thank you. And now our next question in the queue comes from the line of Kelsey Goodwin from Piper Sandler. Please go ahead.
Hey, good morning, and thanks for taking my question. Congrats on this update. Regarding the depth of response of 750 versus 1,500, maybe just walk us through what gives you confidence that this finding and the clear delta that we see will hold up with longer follow-up? In other words, I guess, how much better could 750 get as you follow the patients longer? That's it for me. Thank you.
Thank you for this question, Kelsey. So just to reiterate the question, it was focused on the depth of response comparing the 750 milligram dose versus the 1,500. So we really attribute that to the totality of data that we have today. As you saw between the 750 and the 1,500 milligram dose, we do see a large difference in depth of response as measured by deep responses as well as our complete response rate. What we were able to show on this call as well is associated biomarker data between the two doses, importantly at the same time points, that really showed the follow-up in terms of time points that we are seeing much higher TGF-beta inhibition in the tumor at the 1,500 milligram dose.
It's really that inhibition of TGF-beta that we hypothesize is driving the depth of response and that will translate to durability and overall survival.
The other thing I would add to Claire's response is, and that's why we showed the 24-week landmark with both doses. Over time at the 1,500 milligrams, again, as we have continued to update that data, we absolutely did see deepening over time. But if you look at the kinetics of that response at the 1,500 milligrams, by the 24-week time mark, we had seen most of the deepening. And so again, that's why we felt it was an appropriate landmark to do the comparison of the two doses at 24 weeks. So we do expect that that will hold up in terms of kind of the comparison between 750 and 1,500.
Thank you. And now our next question comes from the line of Tyler Van Buren from TD Cowen. Please go ahead.
Hey, guys. Good morning. Thanks so much for the presentation. As we think about the dose selection next quarter, is there a metric that the FDA is most focused on when discussing dose selection? Is it tumor reduction and depth of response, or is it more duration of response and progression-free survival? And what's your confidence that this differential depth of response is going to translate to DOR and PFS?
Thank you for your question, Tyler. So a question around what is the data set that will really help inform and align with the FDA around dose selection? And so, Tyler, what I would point you to is really, again, a key focus of us being granted breakthrough designation was the additional data in terms of our durability and median overall survival that we presented at the two-year landmark at the 1,500 milligram dose, in addition to the safety and ORR responses we've seen across both doses. So we do really think of it as the totality of the data, but with the depth and durability of response really driving the dose selection. Today, what we've been able to show in addition to that is a very consistent safety profile across both doses.
I think in this situation, if we had seen a differentiated safety profile, it might have pointed us in a different direction. But today, the totality of the data points to the higher dose.
Thank you. And our next question comes from the line of David Nierengarten from Wedbush Securities. Please go ahead.
Hey, just a quick question. If you could remind us if there was any difference in discontinuation rates between the lower and higher dose, just speaking to the point about safety and tolerability made earlier? Thanks.
Thanks for your question, David, so between the two doses, we do see a pretty consistent discontinuation rate. I believe, if I'm not mistaken, it was about 14% at the higher dose with two years' worth of follow-up, and today, we disclosed it was 750 milligram dose, which is with lower follow-up is a 10% discontinuation rate, so very consistent between the two.
Thank you. And I show our next question comes from the line of Eva Privitera from Wells Fargo. Please go ahead.
Good morning. Congrats on the progress, and thanks for taking our question. A quick one from us, just remaining within the tolerability topic. You discussed a dose response highlighting biomarkers on the TGF-beta side of the mechanism. So I was wondering, could you provide a bit more color on the TGF-beta-associated adverse events and how they compare between the two doses? Thanks. Happy to. So the question is focused on safety events relating to both the TGF-beta arms of the molecule. So maybe just to reiterate how we think about a dose response to your question around dose response, what we do know is at the 750-milligram dose, we do believe we are fully saturating the EGFR locus. The reason we explored both of these two doses was on the differentiated tumor target engagement on the TGF-beta side.
What we see today, again, is a consistent tolerability profile across both doses with no severe adverse events related to TGF-beta in either dose.
Yeah. I think the other thing that one of the hypothesized TGF-beta-related AEs is anemia. And actually, to that point, I think that's the one area, as you compare the two different doses, we do see higher rates of anemia at the 1,500 milligrams, which is consistent, again, with greater TGF-beta inhibition and what we would have expected. So you absolutely see a dose responsiveness, both in terms of the efficacy side as well as the safety as it relates to anemia. As we focus on anemia, though, again, the key there is that we don't see any discontinuations from anemia, and it's been manageable predominantly with oral iron. And so again, I think it's really, as we look at those two, despite seeing a higher grade of anemia, again, it's very manageable with the 1,500 milligram dose.
Thank you. Our next question comes from the line of Stephen Willey from Stifel. Please go ahead.
Hey, good morning. This is Josh on for Steve. Thanks for taking our question, and congrats on the data. If I could just quickly squeeze in two, how are you thinking about providing updates regarding the progress of the FORTIFY-HN01 trial? And then is there anything you can maybe qualitatively say about the comparison and the median duration of follow-up between the two data sets?
Happy to. Thank you for your question, Josh, on behalf of Steve. So just to speak to the clinical trial, we continue to build strong momentum in enrollment, and we'll be providing updated guidance in the new year around the pivotal study. To your second question around duration of follow-up for both of those, what we've guided to is the data presented today was really early preliminary safety and efficacy of the 750 milligram dose with less than one year's worth of follow-up. What we presented at ASCO this summer in an oral presentation for the 1,500 milligram dose was two years' worth of follow-up at a median. Thank you.
Thank you. And I show our last question in the queue comes from the line from Dania Bilkadi from Jones. Please go ahead.
Hi. I'm calling in for Sean Kim. Congratulations on the data, and thank you for taking our question. Could you explain the lower response rate observed in patients with CPS higher than 20? Thank you.
Great. And so for this question, I will pass it over to Tanya, our Chief Development Officer.
Thanks, Claire. So the difference in CPS distribution is unlikely to material impact efficacy interpretation given the small sample sizes that we had in the data update. Importantly, the responses that have been observed across the CPS scores, that really underscores the TGF beta inhibition delivering benefit regardless of CPS status.
Thank you.
Thank you. I'm showing no further questions in the queue at this time. I'd like to turn the conference back to Claire Mazumdar, CEO, for closing remarks.
Thank you very much for your call today and your questions. We look forward to further updates in the new year. Thank you.
Thank you. This concludes today's presentation. Thank you all for attending. You may now all disconnect.