Chung of Moffitt Cancer Center, we issued a press release highlighting updated data demonstrating deep and durable responses with ficerafusp alfa, plus pembrolizumab in patients with HPV-negative head and neck cancer. 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 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 statements made on this call represent 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 to walk through the data update are Claire Mazumdar, Chief Executive Officer; David Raben, Chief Medical Officer; and Ryan Colleran, President and Chief Operating Officer. With that, I'll now turn the call over to Claire.
Good afternoon, everyone, and thank you for joining our call. We are incredibly excited to have the opportunity to review our updated data with you today. We're at a propitious moment in the treatment of head and neck cancer, one that brings real hope and potential new treatment options to patients who have long faced limited outcomes. 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 includes HPV-negative head and neck cancer, where there often remains a fibrotic and immune-excluded tumor microenvironment, or TME, that prevents the full potential of immunotherapy, evidenced by low response rates of only 19% with pembrolizumab, the current standard of care.
As we think back to the original development of this molecule by Bicara, our EGFR TGF-β bifunctional antibody was specifically designed to inhibit TGF-β directly at the tumor and break down these barriers by modulating the TME. Ultimately, it is this mechanism that enables the penetration of cytotoxic immune cells that drives deep and durable responses in patients. A picture is worth a thousand words, and shown here is an image of tumor tissue from one of our HPV-negative patients treated with ficerafusp alfa plus pembro. On the left is the tumor at baseline, which illustrates a dense barrier of cancer fibroblasts in yellow that surround the tumor and prevent the immune cells, shown in purple, from penetrating.
On the right, after just three weeks of treatment with ficerafusp alfa plus pembro, you can see the significant remodeling of the TME and penetration of immune cells into the tumor, which ultimately resulted in a very deep 84% partial response for this patient. As we think about the mechanism of action of this drug and its initial design, the premise has always been to leverage an EGFR antibody to selectively target TGF-β inhibition at the tumor. As a cancer biologist by training, we've sought to fully characterize the contribution of TGF-β inhibition it is having and deepen our understanding of the mechanism at play. Now, with more data from patients treated with ficerafusp alfa, we believe the picture is becoming increasingly clear.
alfa is fundamentally different than other antibodies or bispecifics that act at the surface of tumors and instead is uniquely positioned as a molecule that is solving this critical challenge of tumor penetration. Specifically, ficerafusp alfa's inhibition of TGF-β modulates the TME and enables tumor penetration by reducing fibrosis, immunosuppression, and T-cell exclusion. Furthermore, it reverses resistance mechanisms that are upregulated upon treatment with EGFR or checkpoint inhibitors. Taken together, these effects are designed to drive complete tumor responses and translate to more durable outcomes for patients. The mechanistic insights I've shared are supported by findings from paired tumor biopsies from patients treated with ficerafusp alfa plus pembrolizumab, which were presented at the AACR earlier this year. First, we see downregulation of phospho-SMAD, which is the direct downstream biomarker for TGF-β inhibition. Importantly, this TGF-β inhibition is accompanied by a corresponding increase in CD8-positive T-cells to the tumor.
While this data comes from HPV-negative head and neck patients from our combo studies, we've published similar findings with ficerafusp alfa as monotherapy as well. Secondly, on the right are spatial transcriptomics data from these tissues, which illustrate not just inhibition of both EGFR and TGF-β pathways, but show hallmarks of immune cell activation. Lastly, we see downregulation of epithelial to mesenchymal transition, or EMT pathways, that drive resistance to EGFR treatment, which is critical for maintaining durable responses to EGFR-based therapies. Building on this mechanistic data, the next question is, how does this translate to clinical outcomes for patients? Shown here is an HPV-negative head and neck cancer patient with local regional recurrence resulting in a very bulky tumor. This patient was treated with a ficerafusp alfa combination and had a very rapid and complete resolution of their tumor and continues to be in a complete response.
Importantly, following treatment, the patient reported immediate symptom relief, discontinued pain medication, and returned to eating well, a rare outcome for these difficult-to-treat patients. I'd now like to hand it over to our Chief Medical Officer, Dr. David Raben, who's dedicated his 35+ year career to the treatment of head and neck, and will walk you through an overview of HPV-negative recurrent and metastatic head and neck, as well as our updated phase IB clinical data.
Thanks, Claire. On behalf of the investigators, patients, and their caregivers, it's a privilege to be here today. I'll start with a brief overview of head and neck cancer, specifically a focus around HPV-negative head and neck cancer. It's a disease I've spent much of my career studying through both clinical care and translational research. I'm also pleased to share our phase IB clinical updates with two-year follow-up data that reflects our continued commitment to turning science into real progress for patients. Unfortunately, head and neck cancer remains a common and challenging disease with significant unmet medical needs. Globally, more than 700,000 cases of head and neck cancer are reported, and this number continues to grow. 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, where median overall survival is around 12 months, and the five-year survival is just 13%. Beyond the statistics, patients with this disease often endure significant suffering, from pain, difficulty swallowing, and speech loss to disfigurement caused by local recurrences or prior treatment. These challenges highlight the urgent need for therapies that not only significantly extend survival but also reduce toxicity and meaningfully improve quality of life. Head and neck cancer is broadly divided into two distinct subsets: HPV- positive, which is driven by the human papillomavirus infection and typically arises in the oropharynx, and HPV- negative, which is more often associated with environmental risk factors like heavy tobacco and alcohol use.
Importantly, HPV-negative disease accounts for the majority, around 80%, of patients in the recurrent and metastatic setting in the U.S., and these patients tend to have a significantly worse outcome compared to those with HPV positive disease. Today, treatment decisions in head and neck are increasingly personalized, evolving based upon the HPV status and often guided by what's known as the CPS score, a biomarker used to assess PD-L1 expression in both tumors and immune cells. Pembrolizumab is recommended for patients with a CPS score greater than or equal to 1, with other treatment options limited to chemotherapy and EGFR antibodies such as cetuximab. Still, these treatments only help a small portion of patients. There remains a real need to develop more effective options that benefit more people and lead to longer-lasting results.
At Bicara, we recognize HPV-negative and HPV-positive head and neck cancers as different diseases, each with unique biology consistent with how the field has evolved over the last five years. HPV-negative disease is more aggressive. It carries a higher mutational burden and often has an immune-suppressive tumor microenvironment driven by EGFR and TGF-β. As a result, HPV-negative patients typically respond poorly to therapies like anti-PD-1 inhibitors. This underscores the urgent need for more effective therapies. We believe HPV-negative disease is ideally suited for ficerafusp alfa, a dual-pathway agent designed to overcome resistance and amplify immune responses where current options fall short. Unfortunately, in sharp contrast to HPV-positive cancer, outcomes for HPV-negative patients are especially poor. The real-world data consistently shows worse survival compared to the overall head and neck cancer population when treated with standard of care pembrolizumab, with or without chemotherapy.
While median overall survival for all patients is around 12 months, it drops to just 9 months for HPV-negative patients, with only 20%-25% surviving at two years. Even with the addition of cetuximab to checkpoint inhibitors, median overall survival still remains at roughly 10 months in HPV-negative patients. Now, let's move to our exciting clinical updates shared earlier today by Dr. Chung at the 2025 ASCO Annual Meeting. Today's presentation highlights data from our phase IB expansion cohort focused on HPV-negative frontline recurrent and metastatic head and neck cancer patients who received 1,500 mg of ficerafusp alfa weekly in combination with pembrolizumab. The patient demographics and baseline characteristics are shown here and demonstrate an HPV-negative head and neck cancer population with a high burden of disease, and this is consistent with both real-world practice and prior registrational trials like KEYNOTE-048.
Specifically, the site of recurrence in 77% of cases included local regional failure, which is a hallmark of HPV-negative recurrence. 47% of patients presented with bulky disease at baseline, with the sum of the target lesion diameters in excess of 5 cm and, in many cases, 7 cm. Furthermore, there was a balance of tumor CPS scores 1-19 versus CPS greater than 20. Both through my discussions with investigators and my own clinical experience, it's clear to me that this is not a group preselected to respond well to pembrolizumab therapy. These HPV-negative patients have bulky local regional recurrences with low CPS scores, and they're unlikely to survive past 12 months if they don't respond to or progress on treatment. Consistent with what we've previously reported, the combination of ficerafusp alfa and pembrolizumab continues to demonstrate a manageable safety profile. Adverse events fall into two primary categories.
The first are EGFR-related events, such as rash, consistent with what's been seen with the approved EGFR monoclonal antibody cetuximab, and the second are potential TGF-β-related adverse events, including grade 1 epistaxis and gingival bleeding, which resolve quickly without intervention, typically within a week of presentation. Importantly, the safety data suggests ficerafusp alfa is a generally well-tolerated molecule. Illustrated here on slide 14 is the best overall response amongst the efficacy evaluable HPV-negative patients as of a March 2025 data snapshot, which highlights a 54% confirmed response rate and an 89% disease control rate. Importantly, we have continued to see several of our responses deepen since our last clinical update and are now observing that 80% of our responders are achieving what we characterize as a deep response of at least 80% tumor shrinkage.
We believe this magnitude of depth seen in these deep responses ties directly back to ficerafusp alfa's mechanism of enabling tumor penetration that Claire outlined earlier, and it's absolutely critical to the durability and the outcomes that I'll highlight here shortly. We're seeing an extremely high proportion of our responses achieve this level of tumor reduction, including an increase to our complete response rate now at 21%. Finally, ficerafusp alfa and pembrolizumab exhibit clinical activity across the various patient subgroups that I highlighted previously, including in patients with high tumor burden. Progression-free survival of this cohort has been reported previously, but to recap, ficerafusp alfa plus pembrolizumab demonstrates a median progression-free survival of just under 10 months. This more than triples the three-month progression-free survival observed with pembrolizumab alone in an HPV all-tumor population in KEYNOTE-048. The 6 and 12-month PFS rates are 64% and 48%.
On slide 16, continuing on durability, after two years of follow-up on all patients, the final median duration of response has been reached at 21.7 months. Several patients still remain in response beyond 22 months, and the duration of response rates are 79% at 6 months, 65% at 12 months, and 57% at 18 months. Finally, the overall survival analysis demonstrates a 21.3-month median overall survival in these HPV-negative patients. With 24 months follow-up on all patients' post-data snapshot for this analysis, the two-year overall survival rate remains at 46%. We view this as a very strong achievement, especially in relation to the 20%-25% two-year OS rates typically seen in this patient population, and believe that the durability observed thus far is translating into improved long-term survival.
In summary, we believe ficerafusp alfa and pembrolizumab represents an exciting, potentially new frontline option for HPV-negative patients that demonstrates a manageable safety profile, a 54% response rate with 80% of responders achieving a deep response, over 80% tumor shrinkage, a near 10-month PFS, strong durability with a median DOR of 21.7 months, and finally, prolonged overall survival with a median overall survival of 21.3 months and a 46% two-year overall survival rate. More than any single data metric at a single point in time, the totality and consistency of ficerafusp alfa's efficacy profile across all metrics, including not just response rates, but depth of response, progression-free survival, durability of response, and overall survival, continues to speak to the exciting potential of this combination for HPV-negative patients. I will now pass it back to Claire.
Thanks, Dave. Earlier, I walked through how ficerafusp alfa was designed to drive depth and durability, and now we're seeing this translate into the clinical data itself. As Dave highlighted, ficerafusp alfa plus pembrolizumab showed a median duration of response, or median DOR, of 21.7 months in an HPV-negative population, and this slide helps contextualize ficerafusp alfa's durability amongst other recurrent and metastatic head and neck treatments. In KEYNOTE-048, pembrolizumab alone had a modest 19% overall response rate but delivered a 23.4-month median DOR, reflecting the hallmark durability, or so-called long tail, of immunotherapy responders. By contrast, combinations like pembrolizumab plus chemo have raised response rates, but at the expense of durability, with a median DOR falling to just 6.7 months. With ficerafusp alfa, we are seeing a different story.
By targeting immune exclusion in the TME, we believe ficerafusp alfa synergizes with checkpoint inhibitors to enable immune cell penetration that is driving a 22-month immunotherapy-like DOR, similar to what was shown with pembrolizumab. The phenomenon of trading off durability for higher response rates with combination regimens in head and neck cancer presents a major unmet need. More specifically, there remains a gap for an agent that not only improves the response rates but does so while simultaneously maintaining the strong durability observed with immunotherapy, or said differently, a molecule that can enable an immunotherapy-like durable response in patients that are otherwise resistant to immunotherapy. This is where ficerafusp fits in as a potential addition to the treatment paradigm that can not only increase response rates but also drive durable benefits.
alfa is nearly tripling the population of HPV-negative responders, and yet we are still seeing a pembrolizumab-like duration of response of almost two years. Shifting from durability to depth of response, we're again seeing how ficerafusp alfa's design to drive deep responses is translating into the clinical data. Responses with ficerafusp alfa plus pembrolizumab have continued to improve over time, and an analysis of the more recent data cut amongst HPV-negative responders illustrates that the median depth of response is 100% tumor shrinkage. This exemplifies how ficerafusp alfa is not just killing cells on the surface of the tumor but instead remodeling the tumor microenvironment to enable the immune cell penetration that drives complete tumor responses. As Dave noted, a staggering 80% of responders have achieved a deep response of at least 80% tumor shrinkage.
As we look across our data, this level of depth appears to be a key driver of both the durability and improved survival outcomes we've seen in patients. To this end, we believe that one of the most important insights emerging from our data set is the clear relationship between depth of response, durability, and long-term survival outcomes. Internal analysis of our phase IB data to date shows that patients who are able to achieve a deep response of at least 80% tumor shrinkage or more experience markedly better duration of response, progression-free survival, and overall survival compared to those with less tumor reduction or none at all. While this data is preliminary, the sizable gap between the curves illustrates how the durability and survival benefit observed with ficerafusp alfa and pembrolizumab is being driven by these deep responses.
With that, I'd now like to pass it over to our President and Chief Operating Officer, Ryan, who will take you through our FORTIFI-HN01 pivotal study.
Thank you, Claire. 2025 has been off to an exciting start for Bicara. In February, we dosed our first patients in our ongoing registrational trial, FORTIFI-HN01 , and continue to build great momentum. The slide shows the study design of FORTIFI, which is a randomized, double-blind, placebo-controlled phase II/III trial in frontline recurrent and metastatic head and neck cancer patients with CPS greater than or equal to 1. As mentioned, the trial focuses solely on HPV-negative patients and is designed to compare ficerafusp alfa plus pembrolizumab versus a control arm of pembrolizumab plus placebo.
Shown in the schema, the trial begins with a dose optimization portion in which patients will be randomized 1:1:1 to either receive 1,500 mg of ficerafusp alfa in combo with pembrolizumab, 750 mg of ficerafusp alfa weekly in combination with pembrolizumab, or a control of pembrolizumab plus placebo, and is designed as such to satisfy Project Optimus requirements from the FDA. Once the ficerafusp alfa-containing dose regimen has been selected, 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 pembrolizumab control arm. Importantly, in this seamless phase II/III design, enrollment never pauses. The first patients treated with the selected dose are included in both the response rate analysis for a potential accelerated approval and the final overall survival analysis to support a full approval.
This development strategy in the frontline head and neck setting was carefully designed to successfully demonstrate an improvement in overall survival and improve the study's probability of success. Unfortunately, many advanced clinical programs in head and neck cancer have shown promising initial results improving response rates or early landmark analyses that have failed to translate to improvements in overall survival in a phase III study. With this in mind, there are several features of the FORTIFI trial that have been designed alongside the top head and neck cancer investigators who participated in and learned from recent registrational trials in this setting, including KEYNOTE-48 and LEAP-10.
This includes an adequately sized phase III study of 650 patients to show a significant and clinically meaningful difference in survival, a double-blind trial that is intended to mitigate any imbalances in subsequent second-line therapy and minimize patient dropout in the control arm of the study, and finally, a focus on a targeted patient population of HPV-negative patients that we believe are the most likely to benefit from ficerafusp alfa plus pembrolizumab. Focusing on HPV-negative patients is a key part of our development strategy. Historically, registrational trials have grouped HPV-positive and HPV-negative patients together, despite their distinct biology and treatment response. At Bicara, we listen to the leaders in the field to follow the science and what the data are telling us by treating these two as distinct diseases, and we are excited to be at the forefront of this evolution in the treatment landscape.
In our phase IB study, we saw response rates greater than 50% across HPV types, nearly tripling standard-of-care response rates. However, we retrospectively analyzed the data to better understand which patients were driving benefit on ficerafusp alfa and which patients were not. Despite seeing activity, including two complete responses, it was quite clear that HPV-positive patients were not deriving as much of a benefit from ficerafusp alfa itself, consistent with historical published data sets showing EGFR antibodies have minimal activity in this group. As a company, we follow the data, and we have intentionally tailored our development approach to the HPV-negative population, which represents the vast majority of recurrent and metastatic patients. I'll now hand it back to Claire for some concluding remarks.
We at Bicara are excited by the clinical data emerging to date and the promise that tumor-penetrating therapies can bring to the treatment of solid tumors. Using head and neck cancer as an example, next-generation treatments evolved from chemotherapy to include EGFR antibody therapies such as cetuximab to immunotherapy checkpoint inhibitors. We view a tumor-penetrating therapy like ficerafusp alfa as the potential next major advance that can deliver clinical benefit to the large population of patients not responding to treatment. There are several other solid tumors that remain challenged by inadequate tumor penetration, where this next generation of treatment can drive deep and durable responses and enable long-term survival benefits.
In conclusion, ficerafusp alfa plus pembrolizumab is a promising potential frontline regimen that is currently being evaluated in our ongoing phase II/III FORTIFI-HN01 s tudy, which we believe will support a potential accelerated approval in HPV-negative recurrent and metastatic head and neck, a large commercial opportunity with significant unmet need. We're fortunate to have a strong financial foundation to be able to execute on our goal of realizing the full potential of ficerafusp alfa in head and neck and beyond. Thank you all for your time. I will now turn it over to the operator for any questions.
Thank you. As a reminder to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. We ask that you please limit yourself to one question. One moment for our first question.
Our first question is going to come from the line of Eric Schmidt with Cantor. Your line is open. Please go ahead.
Thanks for taking my question and congrats on some very impressive data. Maybe one around your phase III trial design and decision to follow the data and go with an HPV-negative selected cohort. What do you hope to gain in terms of either trial execution or statistical powering or outcome by choosing that HPV-negative subtype? Thanks.
Thank you for your question, Eric. I'll pass it over to Ryan to speak to our FORTIFI-HN01 design.
Yeah, Eric, thanks for the question. In terms of selecting the HPV-negative population, as we had indicated, again, I think you see the HPV-negative patients obviously are responding much better historically to EGFR monoclonal antibodies. We've also seen it with our own data. As we think about the effect, I think, across multiple endpoints, both the response rate endpoint as well as overall survival. In Christine's presentation earlier today, in her own data, there you're seeing a median OS in the HPV-negative population at 10 months. With the data that we showed with our own data today and knowing where we've seen historical controls, we think the selection of the HPV-negative population gives us the ability to show a profound difference in effect on multiple endpoints and particularly overall survival.
Thank you. One moment as we move on to our next question. Our next question is going to come from the line of Stephen Willey with Stifel. Your line is open. Please go ahead. Stephen, your line might be on mute.
Apologies. Thanks for the question. Congrats on the data update, and thank you for providing these additional data details in the slide deck here today. I was just curious just to kind of follow on to the phase III design question. I know that you're kind of targeting the interim response rate analysis occurring in and around 400 patients. I'm just kind of curious as to where is that number based relative to the FDA feedback that you've received thus far? I know that there seems to be maybe some suggestion that others have made that a smaller number based upon something like the breakwater trial could be sufficient for the purpose of an interim. I just have a really quick follow-up.
Thanks for your question, Steve. To your point, we are planning to do our interim analysis at about 400 patients, and that is really focused on three different factors, the first of which is looking at response rates with at least six months' worth of durability. The key reason for doing it at that time really is based off of project front-runner feedback. In many ways, we're overpowered for just a response rate analysis at that time, but the FDA in our discussions with them are looking for us to be almost fully enrolled in the study at the time of granting an accelerated approval. You had an additional follow-up?
Yeah. So I guess just on the enrollment side, I think as of clintrials.gov, as of a relatively recent update, you have about 25 sites that are up now and recruiting. Can you just remind us what the target trial site number is and how should we just be thinking about the cadence of these additional sites being brought online over the coming months? Thanks.
Happy to pass it over to Ryan.
Yes, Steve. In terms of our overall target number of sites, we are expecting somewhere between 150-200 sites globally for the trial. We're making great momentum both in terms of enrollment as well as the site activations, and you'll continue to see that number ratchet up very aggressively in the coming months as you would expect.
Great. Thanks for taking the questions, guys.
Thank you. One moment as we move on to our next question. Our next question comes from the line of Tyler Van Buren with TD Cowen. Your line is open. Please go ahead.
Great. Thanks very much. Congrats on the presentation and the impressive mature survival data. Can you spend a bit more time elaborating on the patient baseline characteristics? Specifically, how does the target lesion size, the percentage of distant metastatic disease patients, and the percent of CPS-low patients compare to historical trials? I guess most importantly, what impact can these patient metrics have on outcomes such as overall survival?
Thanks for your question, Tyler. To our knowledge, we haven't seen many studies break out tumor burden by lesion sizes, but with respect to CPS scores and distant metastatic disease, what we've seen is they have actually major impacts on overall survival in prior trials. For example, if you look at the lenvatinib plus pembro study, the LEAP-010 study, 59% of patients had distant metastatic disease only, and there was a very high proportion, almost 30% of patients with a CPS greater than 50, which we believe was actually a major driver of the outsized 18-month median OS compared to pembrolizumab control. In contrast, if you look at our own study, only 23% of our patients were distant mets only, and we had a balance of CPS low versus high. That's actually very consistent with KEYNOTE-048 as well, which reported a 12-month median OS.
Thank you.
Thank you. Thank you. One moment as we move on to our next question. Our next question is going to come from the line of Judah Frommer with Morgan Stanley. Your line is open. Please go ahead.
Yeah, thanks for taking the question and congrats on the update here. Just curious, as you kind of receive feedback at a conference, and obviously there's competitor data there as well, just how you're thinking about if this data set is kind of repeatable in the pivotal trial, how you would compete in a commercial setting in the HPV-negative population, and more specifically, how a companion diagnostic would factor into the commercial setting for you guys? I had a quick follow-up. Thanks.
Great. I think if we look at the totality of our data, especially with two-year long-term follow-up in terms of both median overall survival and median DOR, we're quite excited about what we showed earlier today with a 21-month median DOR and a 21-month median OS. I think it really speaks, especially if you look at historical benchmarks in HPV-negative disease, to more than doubling what we've typically seen with pembrolizumab monotherapy, but also importantly, the other investigator-initiated studies looking at PD-1s plus cetuximab. To us, it really speaks to the underlying depth and durability and the underlying mechanism of action of our molecule.
Now, I think to your question, Judah, about a companion diagnostic, the field is really moving to consider this, and this is what we highlighted in our presentation, to view HPV-positive and HPV-negative disease as two distinct diseases with different outcomes and likely different treatments. In collaboration with the FDA, we've worked with CDRH to develop a companion diagnostic. This is something that's typically done at diagnosis, and we really see no commercial impact to being able to select the best populations for our molecule like Bicara.
Okay. That's helpful. And then just jumping to the safety side, I think it was on slide 13, you have a bullet noting no treatment-related deaths, but there were, I think, three patients that fell out of the intended treat population, and I think in HPV-negative, you had 28 of 30 being efficacy evaluable. So can you just remind us of those three patients that didn't make it to first baseline scan, what the circumstances were around those, and then the case of the grade 4 case of pericarditis? Did that resolve? Anything you can comment on there? Thanks.
Yeah, happy to highlight. You are correct. In our initial intent to treat, we had 30 HPV-negative patients, of which 28 were efficacy evaluable. Both of those patients withdrew consent prior to first scan, and I believe both were treated with only up to two doses of ficerafusp alfa plus pembro. To your second question, was the grade 4 pericarditis? That was one of our only grade 4 event in this HPV-negative population, and that was actually attributed to the pembrolizumab part of the combination.
Okay. Thanks.
Thank you. One moment for our next question. Our next question is going to come from the line of Rich Law with GS . Your line is open. Please go ahead.
Hey, guys. Congrats on the results. A couple of questions for me. The first question is, in Seckles' pembrolizumab plus cetuximab, it showed around 18 months of OS in HPV-negative patients, and your competitor with initial about 79% OS rate at one year for the overall population compared to Pfizer's 61% in HPV-negative. How do you compare Pfizer's results across these two data sets, and what are the caveats that you have when comparing? I have a couple of follow-ups.
Maybe to answer your question first on the cetuximab plus PD-1 data sets, as earlier disclosed from Dr. Christine Chung, in the pembro plus cetux studies when actually separated by HPV status, HPV-negative patients with a CPS score greater than or equal to 1 showed a median 10.6-month overall survival. Dr. Sacco has not disclosed the separation of median OS by HPV status, and that was in an all-comer population. To your second question around 12-month landmark OS, what we know is from other historical trials, one-year landmark overall survival can be completely misinterpreted and confounded by baseline characteristics and subsequent therapy. We have demonstrated, I think, the totality of our data. We have seen a very strong depth and durability of response, which correlates far more to two-year overall survival than one-year overall survival, offering greater statistical stability with longer-term follow-up.
We believe the durability Bicara has demonstrated to date is the key driver of the median overall survival we're seeing, evidenced by our median DOR of 21.7 months and 21.3 months OS, respectively. I think what's important of that is also that it's regardless of CPS score.
Okay. Great. Just a couple of follow-ups. The results for CPS greater than 20 and less than 20 seem to contradict conventional wisdom where we saw in the pembrolizumab studies. Do you think this is an artifact of a small data set that is not yet reliable to make sense of this trend, or is there something more meaningful related to the mechanism for Bicara? The final question is that can you discuss what it means by, I think you guys mentioned that 80% of responders had greater than 80% tumor shrinkage, but why are they not counted with the ORR? Thanks.
First, to speak to your initial question, sorry, I apologize. On the 80% questions, they are counted in our ORR. We have an overall response rate of 54% and a complete response rate of 21% in the HPV-negative population. What we're highlighting here is that the vast majority of those responses are an 80% depth or greater. Those count, we're just highlighting the totality of the responses being 80% of those are 80% or greater. In your question to you, the CPS 1-19 versus CPS greater than 20, what I think we're seeing is really consistency across both of these subsets. It does really speak to the underlying mechanism of action with our molecule in TGF-β, which is known to go after far more immunosuppressive tumor and microenvironments.
We always expected to see deep and durable responses even in the CPS low, which is why we are also enrolling in a CPS-0 cohort, having seen prior responses in this patient population as well who do not respond to pembro.
Very helpful. Thank you. Congrats again.
Thank you. Our next question is going to come from the line of Eva Fortea with Wells Fargo. Your line is open. Please go ahead.
Hi, it's Eva. Congrats on the progress, and thanks for taking our question. A quick one from us. Can you provide a bit more color on these unconfirmed responses and whether there's a chance to see them confirmed in future updates? Thanks.
Thank you for your question. As we've mentioned previously in our last ASCO presentation and at ESMO 2023 as well, those three patients will not confirm. They withdrew consent prior to confirmatory scan.
Thank you. This is going to conclude today's question and answer session. Ladies and gentlemen, this is also going to conclude today's conference call. Thank you for participating, and you may now disconnect. Everyone, have a great day. Good day, and thank you for standing by.
Welcome to the Bicara Therapeutics ASCO Data Conference Call. At this time, all participants will be in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you'll need to press star one one on your telephone. You will then hear an automated message advising you your hand is raised. To withdraw your question, please press star one one again.
Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Rachel Frank, Head of Investor Relations. Please go ahead.
Thank you, and good afternoon, everyone. It's a pleasure to welcome you to Bicara Therapeutics' conference call. Earlier today, following a data presentation at the 2025 ASCO annual meeting by Dr. Christine Chung of Moffitt Cancer Center, we issued a press release highlighting updated data demonstrating deep and durable responses with ficerafusp alfa plus pembrolizumab in patients with HPV-negative head and neck cancer. 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 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 statements made on this call represent 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 to walk through the data update are Claire Mazumdar, Chief Executive Officer; David Raben, Chief Medical Officer; and Ryan Colleran, President and Chief Operating Officer. With that, I'll now turn the call over to Claire.
Good afternoon, everyone, and thank you for joining our call. We are incredibly excited to have the opportunity to review our updated data with you today.
We're at a propitious moment in the treatment of head and neck cancer, one that brings real hope and potential new treatment options to patients who have long faced limited outcomes. 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 includes HPV-negative head and neck cancer, where there often remains a fibrotic and immune-excluded tumor microenvironment, or TME, that prevents the full potential of immunotherapy, evidenced by low response rates of only 19% with pembrolizumab, the current standard of care. As we think back to the original development of this molecule, ficerafusp alfa, our EGFR/TGF-β bifunctional antibody was specifically designed to inhibit TGF-β directly at the tumor and break down these barriers by modulating the TME.
Ultimately, it is this mechanism that enables the penetration of cytotoxic immune cells that drives deep and durable responses in patients. A picture is worth a thousand words, and shown here is an image of tumor tissue from one of our HPV-negative patients treated with ficerafusp alfa plus pembro. On the left is the tumor at baseline, which illustrates a dense barrier of cancer fibroblasts in yellow that surround the tumor and prevent the immune cells, shown in purple, from penetrating. On the right, after just three weeks of treatment with ficerafusp alfa plus pembro, you can see the significant remodeling of the TME and penetration of immune cells into the tumor, which ultimately resulted in a very deep 84% partial response for this patient.
As we think about the mechanism of action of this drug and its initial design, the premise has always been to leverage an EGFR antibody to selectively target TGF-β inhibition at the tumor. As a cancer biologist by training, we've sought to fully characterize the contribution TGF-β inhibition is having and deepen our understanding of the mechanism at play. Now, with more data from patients treated with ficerafusp alfa, we believe the picture is becoming increasingly clear. Ficerafusp is fundamentally different than other antibodies or bispecifics that act at the surface of tumors and instead is uniquely positioned as a molecule that is solving this critical challenge of tumor penetration. Specifically, ficerafusp alfa's inhibition of TGF-β modulates the TME and enables tumor penetration by reducing fibrosis, immunosuppression, and T-cell exclusion. Furthermore, it reverses resistance mechanisms that are upregulated upon treatment with EGFR or checkpoint inhibitors.
Taken together, these effects are designed to drive complete tumor responses and translate to more durable outcomes for patients. The mechanistic insights I've shared are supported by findings from paired tumor biopsies from patients treated with ficerafusp alfa plus pembro, which were presented at AACR earlier this year. First, we see downregulation of phospho-SMAD2, which is the direct downstream biomarker for TGF-β inhibition. Importantly, this TGF-β inhibition is accompanied by a corresponding increase in CD8-positive T-cells to the tumor. While this data comes from HPV-negative head and neck patients from our combo studies, we've published similar findings with ficerafusp alfa as monotherapy as well. Secondly, on the right are spatial transcriptomics data from these tissues, which illustrate not just inhibition of both EGFR and TGF-β pathways, but show hallmarks of immune cell activation.
Lastly, we see downregulation of epithelial to mesenchymal transition, or EMT pathways, that drive resistance to EGFR treatment, which is critical for maintaining durable responses to EGFR-based therapies. Building on this mechanistic data, the next question is, how does this translate to clinical outcomes for patients? Shown here is an HPV-negative head and neck cancer patient with local regional recurrence resulting in a very bulky tumor. This patient was treated with a ficerafusp alfa combination and had a very rapid and complete resolution of their tumor and continues to be in a complete response. Importantly, following treatment, the patient reported immediate symptom relief, discontinued pain medication, and returned to eating well, a rare outcome for these difficult-to-treat patients. I'd now like to hand it over to our Chief Medical Officer, Dr.
Dave Raben, who's dedicated his 35+ year career to the treatment of head and neck, and will walk you through an overview of HPV-negative recurrent and metastatic head and neck, as well as our updated phase I B clinical data.
Thanks, Claire. On behalf of the investigators, patients, and their caregivers, it's a privilege to be here today. I'll start with a brief overview of head and neck cancer, specifically a focus around HPV-negative head and neck cancer. It's a disease I've spent much of my career studying through both clinical care and translational research. I'm also pleased to share our phase I B clinical updates with two-year follow-up data that reflects our continued commitment to turning science into real progress for patients. Unfortunately, head and neck cancer remains a common and challenging disease with significant unmet medical needs.
Globally, more than 700,000 cases of head and neck cancer are reported, and this number continues to grow. 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, where median overall survival is around 12 months, and the five-year survival is just 13%. Beyond the statistics, patients with this disease often endure significant suffering, from pain, difficulty swallowing, and speech loss to disfigurement caused by local recurrences or prior treatment. These challenges highlight the urgent need for therapies that not only significantly extend survival but also reduce toxicity and meaningfully improve quality of life.
Head and neck cancer is broadly divided into two distinct subsets: HPV-p ositive, which is driven by the human papillomavirus infection and typically arises in the oropharynx, and HPV- negative, which is more often associated with environmental risk factors like heavy tobacco and alcohol use. Importantly, HPV-negative disease accounts for the majority, around 80%, of patients in the recurrent and metastatic setting in the U.S., and these patients tend to have a significantly worse outcome compared to those with HPV- positive disease. Today, treatment decisions in head and neck are increasingly personalized, evolving based upon the HPV status, and often guided by what's known as the CPS score, a biomarker used to assess PD-L1 expression in both tumors and immune cells. Pembrolizumab is recommended for patients with a CPS score greater than or equal to one, with other treatment options limited to chemotherapy and EGFR antibodies such as cetuximab.
Still, these treatments only help a small portion of patients. There remains a real need to develop more effective options that benefit more people and lead to longer-lasting results. At Bicara, we recognize HPV-negative and HPV-positive head and neck cancers as different diseases, each with unique biology consistent with how the field has evolved over the last five years. HPV-negative disease is more aggressive. It carries a higher mutational burden and often has an immune-suppressive tumor microenvironment driven by EGFR and TGF-β. As a result, HPV-negative patients typically respond poorly to therapies like anti-PD-1 inhibitors. This underscores the urgent need for more effective therapy. We believe HPV-negative disease is ideally suited for ficerafusp alfa, a dual-pathway agent designed to overcome resistance and amplify immune responses where current options fall short. Unfortunately, in sharp contrast to HPV-positive cancer, outcomes for HPV-negative patients are especially poor.
The real-world data consistently shows worse survival compared to the overall head and neck cancer population when treated with standard of care pembrolizumab, with or without chemotherapy. While median overall survival for all patients is around 12 months, it drops to just 9 months for HPV-negative patients, with only 20%-25% surviving at two years. Even with the addition of cetuximab to checkpoint inhibitors, median overall survival still remains at roughly 10 months in HPV-negative patients. Now, let's move to our exciting clinical update shared earlier today by Dr. Chung at the 2025 ASCO Annual Meeting. Today's presentation highlights data from our phase IB expansion cohort focused on HPV-negative frontline recurrent and metastatic head and neck cancer patients who received 1,500 mg of ficerafusp alfa weekly in combination with pembrolizumab.
The patient demographics and baseline characteristics are shown here and demonstrate an HPV-negative head and neck cancer population with a high burden of disease, and this is consistent with both real-world practice and prior registrational trials like KEYNOTE- 048. Specifically, the site of recurrence in 77% of cases included local regional failure, which is a hallmark of HPV-negative recurrence. 47% of patients presented with bulky disease at baseline, with the sum of the target lesion diameters in excess of 5 cm and, in many cases, 7 cm. Furthermore, there was a balance of tumor CPS scores 1-19 versus CPS greater than 20. Both through my discussions with investigators and my own clinical experience, it's clear to me that this is not a group preselected to respond well to pembrolizumab therapy.
These HPV-negative patients have bulky local regional recurrences with low CPS scores, and they're unlikely to survive past 12 months if they don't respond to or progress on treatment. Consistent with what we've previously reported, the combination of ficerafusp and pembrolizumab continues to demonstrate a manageable safety profile. Adverse events fall into two primary categories. The first are EGFR-related events, such as rash, consistent with what's been seen with the approved EGFR monoclonal antibody cetuximab, and the second are potential TGF-β-related adverse events, including grade 1 epistaxis and gingival bleeding, which resolve quickly without intervention, typically within a week of presentation. Importantly, the safety data suggests ficerafusp alfa is a generally well-tolerated molecule. Illustrated here on slide 14 is the best overall response amongst the efficacy evaluable HPV-negative patients as of a March 2025 data snapshot, which highlights a 54% confirmed response rate and an 89% disease control rate.
Importantly, we have continued to see several of our responses deepen since our last clinical update and are now observing that 80% of our responders are achieving what we characterize as a deep response of at least 80% tumor shrinkage. We believe this magnitude of depth seen in these deep responses ties directly back to ficerafusp alfa's mechanism of enabling tumor penetration that Claire outlined earlier, and it is absolutely critical to the durability and the outcomes that I will highlight here shortly. We are seeing an extremely high proportion of our responses achieve this level of tumor reduction, including an increase to our complete response rate now at 21%. Finally, ficerafusp alfa and pembro exhibit clinical activity across the various patient subgroups that I highlighted previously, including in patients with high tumor burden.
Progression-free survival of this cohort has been reported previously, but to recap, ficerafusp plus pembrolizumab demonstrates a median progression-free survival of just under 10 months. This more than triples the 3-month progression-free survival observed with pembrolizumab alone in an HPV all-comer population in KEYNOTE- 048. The 6 and 12-month PFS rates are 64% and 48%. On slide 16, continuing on durability, after two years of follow-up on all patients, the final median duration of response has been reached at 21.7 months. Several patients still remain in response beyond 22 months, and the duration of response rates are 79% at 6 months, 65% at 12 months, and 57% at 18 months. Finally, the overall survival analysis demonstrates a 21.3-month median overall survival in these HPV-negative patients. With 24-month follow-up on all patients post-data snapshot for this analysis, the two-year overall survival rate remains at 46%.
We view this as a very strong achievement, especially in relation to the 20%-25% two-year OS rates typically seen in this patient population, and believe that the durability observed thus far is translating into improved long-term survival. In summary, we believe ficerafusp alfa and pembrolizumab represents an exciting, potentially new frontline option for HPV-negative patients that demonstrates a manageable safety profile, a 54% response rate with 80% of responders achieving a deep response over 80% tumor shrinkage, a near 10-month PFS, strong durability with a median DOR of 21.7 months, and finally, prolonged overall survival with a median overall survival of 21.3 months and a 46% two-year overall survival rate.
More than any single data metric at a single point in time, the totality and consistency of ficerafusp alfa's efficacy profile across all metrics, including not just response rates, but depth of response, progression-free survival, durability of response, and overall survival, continues to speak to the exciting potential of this combination for HPV-negative patients. I will now pass it back to Claire.
Thanks, Dave. Earlier, I walked through how ficerafusp alfa was designed to drive depth and durability, and now we're seeing this translate into the clinical data itself. As Dave highlighted, ficerafusp alfa plus pembrolizumab showed a median duration of response, or median DOR, of 21.7 months in an HPV-negative population, and this slide helps contextualize ficerafusp alfa's durability amongst other recurrent and metastatic head and neck treatments.
In KEYNOTE 048, pembrolizumab alone had a modest 19% overall response rate but delivered a 23.4-month median DOR, reflecting the hallmark durability, or so-called long tail, of immunotherapy responders. By contrast, combinations like pembrolizumab plus chemo have raised response rates but at the expense of durability, with the median DOR falling to just 6.7 months. With ficera, we are seeing a different story. By targeting immune exclusion in the TME, we believe Fisarra synergizes with checkpoint inhibitors to enable immune cell penetration that is driving a 22-month immunotherapy-like DOR, similar to what was shown with pembro. The phenomenon of trading off durability for higher response rates with combination regimens in head and neck cancer presents a major unmet need.
More specifically, there remains a gap for an agent that not only improves response rates but does so while simultaneously maintaining the strong durability observed with immunotherapy, or said differently, a molecule that can enable an immunotherapy-like durable response in patients that are otherwise resistant to immunotherapy. This is where ficerafusp alfa fits in as a potential addition to the treatment paradigm that can not only increase response rates but also drive durable benefits. Ficera is nearly tripling the population of HPV-negative responders, and yet we are still seeing a pembrolizumab-like duration of response of almost two years. Shifting from durability to depth of response, we're again seeing how ficera is designed to drive deep responses is translating into the clinical data.
Responses with ficera plus pembro have continued to improve over time, and an analysis of the more recent data cut amongst HPV-negative responders illustrates that the median depth of response is 100% tumor shrinkage. This exemplifies how ficerafusp alfa is not just killing cells on the surface of the tumor but instead remodeling the tumor microenvironment to enable the immune cell penetration that drives complete tumor responses. As Dave noted, a staggering 80% of responders have achieved a deep response of at least 80% tumor shrinkage. As we look across our data, this level of depth appears to be a key driver of both the durability and improved survival outcomes we have seen in patients. To this end, we believe that one of the most important insights emerging from our dataset is the clear relationship between depth of response, durability, and long-term survival outcomes.
Internal analysis of our phase IB data to date shows that patients who are able to achieve a deep response of at least 80% tumor shrinkage or more experience markedly better duration of response, progression-free survival, and overall survival compared to those with less tumor reduction or none at all. While this data is preliminary, the sizable gap between the curves illustrates how the durability and survival benefit observed with ficera and pembro is being driven by these deep responses. With that, I'd now like to pass it over to our President and Chief Operating Officer, Ryan, who will take you through our FORTIFI-HN01 pivotal study.
Thank you, Claire. 2025 has been off to an exciting start for Bicara. In February, we dosed our first patients in our ongoing registrational trial, FORTIFI-HN01, and continue to build great momentum.
The slide shows the study design of FORTIFI, which is a randomized, double-blind, placebo-controlled phase II/III trial in frontline recurrent and metastatic head and neck cancer patients with CPS greater than or equal to 1. As mentioned, the trial focuses solely on HPV-negative patients and is designed to compare ficerafusp alfa plus pembrolizumab versus a control arm of pembrolizumab plus placebo. Shown in the schema, the trial begins with a dose optimization portion in which patients will be randomized 1:1:1 to either receive 1,500 mg of ficerafusp alfa in combo with pembrolizumab, 750 mg of ficerafusp alfa weekly in combination with pembrolizumab, or a control of pembrolizumab plus placebo, and is designed as such to satisfy Project Optimus requirements from the FDA.
Once the ficera-containing dose regimen has been selected, the unselected dose arm will be dropped, and the study will continue with a 2:1 randomization between the optimized ficera dose and the pembro control arm. Importantly, in this seamless phase II/III design, enrollment never pauses. The first patients treated with the selected dose are included in both the response rate analysis for a potential accelerated approval and the final overall survival analysis to support a full approval. This development strategy in the frontline head and neck setting was carefully designed to successfully demonstrate an improvement in overall survival and improve the study's probability of success. Unfortunately, many advanced clinical programs in head and neck cancer have shown promising initial results improving response rates or early landmark analyses that have failed to translate to improvements in overall survival in a phase III study.
With this in mind, there are several features of the FORTIFI trial that have been designed alongside the top head and neck cancer investigators who participated in and learned from recent registrational trials in this setting, including KEYNOTE- 48 and LEAP-10. This includes an adequately sized phase III study of 650 patients to show a significant and clinically meaningful difference in survival, a double-blind trial that is intended to mitigate any imbalances in subsequent second-line therapy and minimize patient dropout in the control arm of the study, and finally, a focus on a targeted patient population of HPV-negative patients that we believe are the most likely to benefit from ficerafusp alfa plus pembrolizumab. Focusing on HPV-negative patients is a key part of our development strategy. Historically, registrational trials have grouped HPV-positive and HPV-negative patients together, despite their distinct biology and treatment response.
At Bicara, we listen to the leaders in the field to follow the science and what the data are telling us by treating these two as distinct diseases, and we are excited to be at the forefront of this evolution in the treatment landscape. In our phase Ib study, we saw response rates greater than 50% across HPV types, nearly tripling standard-of-care response rates. However, we retrospectively analyzed the data to better understand which patients were deriving benefit on ficerafusp alfa and which patients were not. Despite seeing activity, including two complete responses, it was quite clear that HPV-positive patients were not deriving as much of a benefit from ficerafusp alfa itself, consistent with historical published datasets showing EGFR antibodies have minimal activity in this group.
As a company, we follow the data, and we have intentionally tailored our development approach to the HPV-negative population, which represents the vast majority of recurrent and metastatic patients. I'll now hand it back to Claire for some concluding remarks.
We at Bicara are excited by the clinical data emerging to date and the promise that tumor-penetrating therapies can bring to the treatment of solid tumors. Using head and neck cancer as an example, next-generation treatments evolved from chemotherapy to include EGFR antibody therapies such as cetuximab to immunotherapy checkpoint inhibitors. We view a tumor-penetrating therapy like ficera as the potential next major advance that can deliver clinical benefit to the large population of patients not responding to treatment. There are several other solid tumors that remain challenged by inadequate tumor penetration, where this next generation of treatment can drive deep and durable responses and enable long-term survival benefits.
In conclusion, ficerafusp alfa plus pembrolizumab is a promising potential frontline regimen that is currently being evaluated in our ongoing phase II/III FORTIFI- HN01 study, which we believe will support a potential accelerated approval in HPV-negative recurrent and metastatic head and neck, a large commercial opportunity with significant unmet need. We're fortunate to have a strong financial foundation to be able to execute on our goal of realizing the full potential of ficerafusp alfa in head and neck and beyond. Thank you all for your time. I will now turn it over to the operator for any questions.
Thank you. As a reminder to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. We ask that you please limit yourself to one question. One moment for our first question.
Our first question is going to come from the line of Eric Schmidt with Cantor. Your line is open. Please go ahead.
Thanks for taking my question and congrats on some very impressive data. Maybe one around your phase III trial design and decision to follow the data and go with an HPV-negative selected cohort. What do you hope to gain in terms of either trial execution or statistical powering or outcome by choosing that HPV-negative subtype? Thanks.
Thank you for your question, Eric. I'll pass it over to Ryan to speak to our FORTIFI-HN01 design.
Yeah, Eric, thanks for the question. In terms of selecting the HPV-negative population, as we had indicated, again, I think you see the HPV-negative patients obviously are responding much better historically to EGFR monoclonal antibodies. We've also seen it with our own data.
As we think about the effect, I think, across multiple endpoints, both the response rate endpoint as well as overall survival. Again, in Christine's presentation earlier today, in her own data, there you're seeing a median OS in the HPV-negative population at 10 months. With the data that we showed with our own data today and knowing where we've seen historical controls, we think the selection of the HPV-negative population gives us the ability to show a profound difference in effect on multiple endpoints and particularly overall survival.
Thank you. One moment as we move on to our next question. Our next question is going to come from the line of Stephen Willey with Stifel. Your line is open. Please go ahead. Stephen, your line might be on mute.
Apologies. Thanks for the question.
Congrats on the data update, and thank you for providing these additional data details in the slide deck here today. I was just curious just to kind of follow on to the phase III design question. I know that you're kind of targeting the interim response rate analysis occurring in and around 400 patients. I was just kind of curious as to where is that number based relative to the FDA feedback that you've received thus far? I know that there seems to be maybe some suggestion that others have made that a smaller number based upon something like the Breakwater trial could be sufficient for the purpose of an interim. I just have a really quick follow-up.
Thanks for your question, Steve.
To your point, we are planning to do our interim analysis at about 400 patients, and that is really focused on three different factors, the first of which is looking at response rates with at least six months' worth of durability. The key reason for doing it at that time really is based off of project front-runner feedback. In many ways, we're overpowered for just a response rate analysis at that time, but the FDA in our discussions with them are looking for us to be almost fully enrolled in the study at the time of granting an accelerated approval. You had an additional follow-up?
Yeah. I guess just on the enrollment side, I think as of clintrials.gov, as of a relatively recent update, you have about 25 sites that are up now and recruiting.
Can you just remind us what the target trial site number is and how should we just be thinking about the cadence of these additional sites being brought online over the coming months? Thanks.
Happy to pass it over to Ryan.
Yes, Steve. In terms of our overall target number of sites, we are expecting somewhere between 150-200 sites globally for the trial. We're making great momentum both in terms of enrollment as well as the site activations, and you'll continue to see that number ratchet up very aggressively in the coming months as you would expect.
Great. Thanks for taking the questions, guys.
Thank you. One moment as we move on to our next question. Our next question comes from the line of Tyler Van Buren with TD Cowen. Your line is open. Please go ahead.
Great. Thanks very much.
Congrats on the presentation and the impressive mature survival data. Can you spend a bit more time elaborating on the patient baseline characteristics? Specifically, how does the target lesion size, the percentage of distant metastatic disease patients, and the percent of CPS-low patients compare to historical trials? I guess most importantly, what impact can these patient metrics have on outcomes such as overall survival?
Thanks for your question, Tyler. To our knowledge, we haven't seen many studies break out tumor burden by lesion sizes, but with respect to CPS scores and distant metastatic disease, what we've seen is they have actually major impacts on overall survival in prior trials.
For example, if you look at the lenvatinib plus pembro study, the LEAP-010 study, 59% of patients had distant metastatic disease only, and there was a very high proportion, almost 30% of patients with a CPS greater than 50, which we believe was actually a major driver of the outsized 18-month median OS compared to pembrolizumab control. In contrast, if you look at our own study, only 23% of our patients were distant mets only, and we had a balance of CPS low versus high. That's actually very consistent with KEYNOTE- 048 as well, which reported a 12-month median OS.
T hank you. And one moment as we move on to our next question. Our next question is going to come from the line of Judah Frommer with Morgan Stanley. Your line is open. Please go ahead.
Yeah, thanks for taking the question and congrats on the update here. Just curious, as you kind of receive feedback at a conference, and obviously there's competitor data there as well, just how you're thinking about if this dataset is kind of repeatable in the pivotal trial, how you would compete in the commercial setting in the HPV-negative population, and more specifically, how a companion diagnostic would factor into the commercial setting for you guys? I had a quick follow-up. Thanks.
Great. I think if we look at the totality of our data, especially with two-year long-term follow-up in terms of both median overall survival and median DOR, we're quite excited about what we showed earlier today with a 21-month median DOR and a 21-month median OS.
I think it really speaks, especially if you look at historical benchmarks in HPV-negative disease, of more than doubling what we've typically seen with pembrolizumab therapy, but also importantly, the other investigator-initiated studies looking at PD1s plus cetuximab. To us, it really speaks to the underlying depth and durability and the underlying mechanism of action of our molecule. Now, I think to your question, Judah, about a companion diagnostic, the field is really moving to consider this, and this is what we highlighted in our presentation, to view HPV-positive and HPV-negative disease as two distinct diseases with different outcomes and likely different treatments. In collaboration with the FDA, we've worked with CDRH to develop the companion diagnostic. This is something that's typically done at diagnosis, and we really see no commercial impact to being able to select the best population for a molecule like ficerafusp alfa.
Okay. That's helpful. Just jumping to the safety side, I think it was on slide 13, you have a bullet noting no treatment-related deaths, but there were, I think, three patients that fell out of the intended treatment population, and I think in HPV-negative, you had 28 of 30 being efficacy evaluable. Can you just remind us of those three patients that didn't make it to first baseline scan, what the circumstances were around those, and then the case of the grade 4 case of pericarditis, did that resolve? Anything you can comment on there? Thanks.
Yeah, happy to highlight. You are correct. In our initial intent to treat, we had 30 HPV-negative patients, of which 28 were efficacy evaluable. Both of those patients withdrew consent prior to first scan, and I believe both were treated with only up to two doses of ficerafusp alfa plus pembrolizumab.
To your second question, was the grade 4 pericarditis? That was one of our only grade 4 events in this HPV-negative population, and that was actually attributed to the pembrolizumab part of the combination.
Okay. Thanks.
Thank you. One moment for our next question. Our next question is going to come from the line of Rich Law with GS . Your line is open. Please go ahead.
Hey, guys. Congrats on the result. A couple of questions for me. The first question is, in SECO's pembrolizumab plus cetuximab, it showed around 18 months of OS in HPV-negative patients. Your competitor within the show about 79% OS rate at one year for the overall population compared to Pfizer's 61% in HPV-negative. How do you compare Pfizer's results across these two datasets, and what are the caveats that you have when comparing? I have a couple of follow-ups.
Maybe to answer your question first on the rituximab plus PD-1 datasets, as earlier disclosed from Dr. Christine Chung, in the pembro plus cetux studies, when actually separated by HPV status, HPV-negative patients with a CPS score greater than or equal to 1 showed a median 10.6-month overall survival. Dr. Sacco has not disclosed the separation of median OS by HPV status, and that was in an all-comer population. To your second question around 12-month landmark OS, what we know is from other historical trials, one-year landmark overall survival can be completely misinterpreted and confounded by baseline characteristics and subsequent therapy. We've demonstrated, I think, the totality of our data. We've seen a very strong depth and durability of response, which correlates far more to two-year overall survival than one-year overall survival, offering greater statistical stability with longer-term follow-up.
We believe the durability Bicara has demonstrated to date is the key driver of the median overall survival we're seeing, evidenced by our median DOR of 21.7 months and 21.3 months OS, respectively. I think what's important with that is also that it's regardless of CPS score.
Okay. Great. Just a couple of follow-ups. The results for CPS greater than 1,120 seem to contradict convention with what we saw in the pembrolizumab studies. Do you think this is an artifact of a small dataset that is not yet reliable to make sense of this trend, or is there something more meaningful related to the mechanism for Bicara? The final question is that can you discuss what it means by, I think you guys mentioned that 80% of responders had greater than 80% tumor shrinkage, but why are they not counted with the ORR? Thanks.
First, to speak to your initial question, sorry, I apologize. On the 80% questions, they are counted in our ORR. We have an overall response rate of 54% and a complete response rate of 21% in the HPV-negative population. What we are highlighting here is that the vast majority of those responses are an 80% depth or greater. Those count, we are just highlighting the totality of the responses being 80% of those are 80% or greater. In your question to the CPS 1-19 versus CPS greater than 20, what I think we are seeing is really consistency across both of these subsets. It does really speak to the underlying mechanism of action with our molecule in TGF-β, which is known to go after far more immunosuppressive tumor and microenvironments.
We always expected to see deep and durable responses even in the CPS low, which is why we are also enrolling in a CPS zero cohort, having seen prior responses in this patient population as well who do not respond to pembrolizumab.
Very helpful. Thank you. Congrats again.
Thank you. Our next question is going to come from the line of Eva Fortea with Wells Fargo. Your line is open. Please go ahead.
Hi, it is Eva. Congrats on the progress, and thanks for taking our question. A quick one from us. Can you provide a bit more color on these unconfirmed responses and whether there is a chance to see them confirmed in future updates? Thanks.
Thank you for your question. As we have mentioned previously in our last ASCO presentation and at ESMO 2023 as well, those three patients will not confirm. They withdrew consent prior to confirmatory scan.
Thank you. This is going to conclude today's question and answer session. Ladies and gentlemen, this is also going to conclude today's conference call. Thank you for participating, and you may now disconnect. Everyone, have a great rest.