Good day, and thank you for standing by. Welcome to the Bicara Therapeutics ASCO 2026 corporate 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'll need to press star one one on your telephone. You will then hear an automated message advising 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'd now like to turn the conference over to Rachel Frank, Vice President of Investor Relations and Corporate Communications. Please go ahead.
Thank you. Good morning, everyone. It's a pleasure to welcome you to Bicara Therapeutics Investor Conference Call to discuss an update that we will be presenting at the 2026 American Society of Clinical Oncology annual meeting. You can access the press release, as well as the slides that we'll be reviewing today, by going to the investor section of our company website. Before we begin, please note that this call will include forward-looking statements under the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995.
Please refer to our most recent SEC filings for important risk factors that could cause our actual performance and results to materially differ from those expressed or implied in these forward-looking statements. Any forward-looking statement made on this call represents our views only as of today, and we disclaim any obligation to update any forward-looking statements. Joining us on the call today are Claire Mazumdar, Chief Executive Officer, and Bill Schelman, Chief Medical Officer. Ryan Cohlhepp, President and Chief Operating Officer, and Tanya Green, Chief Development Officer, are also on the line and will join us for Q&A. I'll now turn the call over to Claire.
Thank you, Rachel, and good morning, everyone. Today, we're pleased to share new data from two posters being presented at ASCO 2026 that collectively represent the most comprehensive and mature clinical data set assembled for Ficerafusp Alfa , or Ficera, in first-line recurrent or metastatic HPV-negative head and neck cancer. These data span approximately 90 patients across three dose cohorts, with up to three years of follow-up at our 1,500 mg weekly pivotal dose, the longest follow-up presented of any investigational agent in the HPV-negative head and neck cancer space. Before we jump in, a quick reminder on the mechanistic differentiation of Ficera, a potentially first and best-in-class bifunctional EGFR-directed antibody combined with a TGF-beta ligand trap.
Ficera combines tumor targeting with tumor modulation, where the EGFR arm localizes to the tumor, while the TGF-beta arm serves as the tumor modulator, designed to deliver superior efficacy, improve safety, and enhance durability directly at the tumor site. Ficera specifically addresses a key challenge in solid tumor treatment by enabling immune cell penetration into tumors, reducing fibrosis and immunosuppression, while reversing TGF-beta-driven resistance mechanisms. Ultimately designed to drive the deep, durable responses that may translate into better outcomes and survival for patients. For patients with recurrent or metastatic head and neck cancer, there remains a significant unmet need for improved treatment outcomes. The current standard of care, pembrolizumab, provides response rates of only 19% as a single agent and 36% in combination with chemotherapy, but median overall survival remains poor at only 12-13 months.
Importantly, for people living with HPV-negative disease, real-world data consistently show worse survival outcomes, as low as seven to nine months compared to the overall population when treated with standard of care. The biology tells us why. These tumors overexpress both EGFR and TGF-beta. TGF-beta creates a hostile fibrotic tumor microenvironment that excludes immune cells, drives resistance to checkpoint inhibitors such as pembrolizumab, and limits the durability of any response.
Standard EGFR antibodies don't address this. That's precisely why Ficera was designed the way it was. The opportunity ahead is significant. Head and neck cancer is a fast-growing global market projected to exceed $5 billion in sales in 2030 and growing, with roughly 50,000 annually incident patients across major markets, including 18,000 patients in the United States alone. Today, we are presenting long-term data across three dose expansion cohorts from our phase I-B study.
The 1,500 mg weekly dose, which is currently being evaluated in our pivotal phase III study, FORTIFY-HN01, represents our most mature clinical data set. The additional dose cohorts of 750 mg weekly and 2,000 mg every other week were evaluated as part of a broader dose optimization effort to support dose selection and explore alternative dosing strategies. Importantly, what we'll show today is that results across all the cohorts have repeatedly demonstrated deep and durable responses consistent with our underlying mechanism of action to inhibit TGF-beta. Taken together, today's data further differentiates Bicara's clinical profile. I would like to highlight three key points.
At a median follow-up of three years, 1,500 mg weekly of Ficera plus pembrolizumab doubled overall survival versus standard of care, demonstrating a 31% overall survival versus pembrolizumab monotherapy, which demonstrated approximately 15% overall survival at nearly three years in a real-world study of HPV-negative patients. Across all doses of Ficera, there were no new safety signals observed up to three years of follow-up, and Ficera continues to demonstrate a generally well-tolerated safety profile.
Three, TGF-beta inhibition translates to unprecedented depth of response, which yields clinically differentiated long-term outcomes, including duration of response, progression-free survival, and overall survival. Collectively, these data provide further confidence in the differentiated clinical profile of Ficera, driven by the TGF-beta mechanism, and continue to de-risk our pivotal study. I'll now turn the call over to our Chief Medical Officer, Bill Schelman, who will walk us through the data.
Thanks, Claire. Before I review the efficacy and biomarker data, I want to draw your attention to the patient demographics and baseline characteristics. In line with what has been previously presented, baseline characteristics are consistent with those seen in HPV-negative head and neck cancer. Notably, patients with large bulky tumors with low CPS and local regional recurrence were enrolled in each of these cohorts.
As of the data cutoff, March 31st, 2026, the safety profile of Ficera continues to be generally well-tolerated and consistent across all three dose cohorts, with no new safety signals. A profile we are pleased to see maintained as the data set matures and patients have extended treatment exposure. Hypothesized TGF-beta related AEs, specifically mucosal bleeds, gingival bleeds, and epistaxis, remain generally low grade. There has been no meaningful increase in treatment discontinuation due to treatment-related AEs, even with longer follow-up.
The combination of Ficera with pembrolizumab demonstrated a favorable benefit-risk profile. Updated biomarker analyses confirm that Ficera achieves sustained TGF-beta neutralization in plasma across all three dose cohorts. Importantly, we saw intra-tumoral reduction in phospho-Smad2, a pharmacodynamic marker for TGF-beta pathway inhibition across all three doses.
We also saw upregulation of CD8-positive T cell infiltration in paired biopsies, reaching statistical significance in the 1,500 mg weekly and 2,000 mg every other week dose groups, confirming that TGF-beta inhibition enables immune cells to penetrate the tumor and drive meaningful immune activation at the site of disease. When comparing median depth of response and the proportion of deep responders at the same 24-week follow-up, the data are clear. The deeper responses are observed at doses of Ficera that show greater TGF-beta inhibition and tumor penetration. These data are also important for three reasons. First, they confirm target engagement.
Second, they provide mechanistic foundation for the depth of clinical responses observed in the cohorts. Third, they strengthen the confidence in our pivotal trial and provide the rationale for our loading and maintenance strategy, which maintains therapeutic exposure while offering greater patient convenience. All three dose cohorts of Ficera demonstrated high and consistent overall response rates.
Critically, the depth of response is more pronounced at higher doses, and the complete response rates underscore that finding. Since prior presentations of the 750 mg, 1,500 mg, and 2,000 mg cohorts, complete response rates in each of these cohorts have increased. In the 1,500 mg weekly cohort, the dose being evaluated in our phase III study, 80% of responders achieved a deep response, defined as response of greater than 80% tumor reduction. Similarly, 77% of patients in the 2,000 mg every other week cohort had deep responses.
Taken together, these data demonstrate that greater TGF-beta inhibition at higher doses drives not just responses, but responses of meaningful and durable depth. To put our data in further context, we continue to believe that the TGF-beta arm of Ficera is what drives depth of response that translates into durability. By targeting immune exclusion in the tumor microenvironment, we believe Ficera synergizes with immunotherapy to enable immune cell penetration that is driving a 22-month immunotherapy-like median duration of response, similar to what was shown with pembrolizumab, but with higher response rates and greater overall survival. Beyond standard of care, Ficera is meaningfully differentiated from other investigational combinations, which have not shown durability measures out this long. The median duration of response for the 1,500 mg cohort was mature at our two-year update last year, a striking 21.7 months.
New data show that while the 750 mg and 2,000 mg cohorts are still maturing, median duration of response has already surpassed approximately 17 and 13 months respectively, meaningfully exceeding what has been observed with pembrolizumab plus cetuximab and other investigational combination. This speaks to the mechanism of action of TGF-beta inhibition. When looking at progression-free survival, all three dosing cohorts demonstrated clinically meaningful disease control.
As a reminder, a median PFS of 3.2 months was shown with pembrolizumab in HPV all comers. At all three doses, Ficera improved upon PFS over standard of care from 6.9 months at 750 mg, 9.9 months at 1,500 mg, and 12.7 months at 2,000 mg. The 2,000 mg every other week cohort is particularly noteworthy, with a median PFS of 12.7 months, more than triple the PFS seen with pembrolizumab, which supports further development of our loading and maintenance dosing regimen.
This also shows that greater TGF-beta neutralization is associated with enhanced progression-free survival. Turning to overall survival, the mature data in the 1,500 mg weekly cohort showed a median overall survival of 21.3 months. Today, we are thrilled to present updated data confirming that Bicara drives a meaningful overall survival tail with a striking 31% three-year overall survival rate.
By comparison, pembrolizumab demonstrated an approximately 20%-25% overall survival rate in the HPV all-comer population and a 15% overall survival rate in the HPV-negative population. Bicara doubles the overall survival rate in HPV-negative patients at three years versus standard of care. While the 750 mg and 2,000 mg cohorts are still maturing, early trajectories suggest that median overall survival is trending towards the median overall survival we are seeing with the 1,500 mg weekly dose. As a reminder, our 2,000 mg cohort enrolled in a bimodal pattern.
In the initial 15 efficacy-evaluable patients, with a median follow-up of 27 months, median overall survival has not yet matured but has already surpassed 23.6 months. The remaining 12 efficacy-evaluable patients have a median follow-up of 11.7 months, and we anticipate this group to have consistent efficacy as the data mature. Ficera demonstrated rapid responses and high overall response rates across all doses, regardless of CPS score, tumor burden, and occurrence of distant metastases. The breadth of activity across CPS scores is particularly noteworthy. In patients with CPS 1-19, where pembrolizumab monotherapy yields only a 15% response rate, Ficera continues to drive strong responses. This is a result of TGF-beta inhibition, which reverses the fibrotic immune-excluded microenvironment that limits checkpoint activity in this population.
This is an area where no other investigational EGFR has shown comparable results, underscoring the potential for Ficera in combination with pembrolizumab to be a chemotherapy-free treatment option. I'll now turn to data from our second poster, which examines how depth of response translates into meaningful durability and survival benefit. To do this, we combined the three cohorts and separated patients into deep responders, those achieving tumor shrinkage of greater than 80%, and responders with tumor shrinkage between 30%-80%. This slide examines duration of response by depth of tumor shrinkage. What stands out is the clear separation between these two groups. Patients who achieve deeper responses experience substantially more durable disease control with meaningfully longer duration of response and a consistently more favorable clinical course across outcomes.
In practical terms, deep responders are significantly more likely to maintain their response over time compared to those with more modest tumor shrinkage. This reinforces that depth of response is a strong predictor of durability and overall survival long-term benefit. This is a key hallmark of TGF-beta inhibition in Ficera's clinical profile. Building on that, the next slide shows that the depth drives durability story extends beyond duration of response. It carries through to both progression-free survival and overall survival. Looking at progression-free survival, deep responders had a median PFS of 37 months and were 65% more likely to remain progression free with a hazard ratio of 0.35%.
With respect to the analysis of overall survival, median overall survival in deep responders has not yet been reached, with deep responders 63% more likely to remain alive, corresponding to a hazard ratio of 0.37%, and far exceeding three years of overall survival. Taken together, the data reinforce that deep responses were strongly associated with better long-term efficacy outcomes, including substantially prolonged duration of response, progression-free survival, and overall survival when compared to a standard response.
In addition, neutralizing TGF-beta mediated immune exclusion provides a clear biological mechanism for the deep and durable responses observed. Now that we've walked through the data, it's worth grounding ourselves in what oncologists actually care about when making treatment decisions, and that context is what underscores the clinical significance of everything we've just presented. When oncologists evaluate a new treatment, they want confidence in tumor shrinkage, long-term disease control, and preserved quality of life.
Specifically, clinicians report that complete response rate, depth of response, and duration of response are key factors in what drive that confidence beyond overall survival, reflecting the need for a therapy that is fundamentally altering the tumor microenvironment and driving deep, durable responses. Ficera delivers on all three. Overall survival rates out at three years that more than double standard of care in HPV-negative patients.
Complete response rates as high as 30%. Deep responses in more than two-thirds of responders, and a median duration of response of 21.7 months at the pivotal trial dose. Exactly the profile oncologists say would move them to adopt a new regimen. Everything we've shown today connects back to one mechanistic thread. Ficera's TGF-beta mediated tumor penetration is what drives deep responses that are durable and that result in improved long-term outcomes. Our translational biomarker data established this foundation.
Targeted TGF-beta inhibition in the tumor drives immune cell penetration and immune activation. That mechanism translates directly into deeper responses. At doses with greater TGF-beta inhibition, complete response rates and the proportion of deep responders both increased, culminating in 80% of responders achieving a deep response at the 1,500 mg pivotal trial dose. Now, with long-term follow-up across these three cohorts, today's focus is on durability and improved long-term outcomes.
Across approximately 90 patients and with up to three years of follow-up, we see consistent efficacy improvements, a clear trend of improved duration of response, progression-free survival, and overall survival at doses with greater TGF-beta inhibition, and deep responses translating into meaningfully better long-term outcomes across all three endpoints. The totality of these data reflects an efficacy and safety profile that has strengthened over time and with broader patient exposure, and positions ficara as a potentially best-in-class option in this disease.
We also believe that these data strongly validate the FORTIFY-HN01 design, giving us conviction in both the ORR-based interim analysis as well as the confirmatory overall survival endpoint. I'll now turn it back over to Claire for closing remarks.
Thanks, Bill. Before I turn the call back to the operator, let me just close by reiterating the significance of what we're presenting this week at ASCO. Three years ago, we began enrolling patients in a disease with a median overall survival of seven to nine months. Today, the data speaks for itself and we believe make a compelling case for Ficera differentiated, potentially best-in-class profile. We extend our sincere gratitude to the patients, families, and investigators whose participation and partnership are the foundation of this work and the hope it represents for the broader head and neck cancer community. We are excited about what these data mean for our pivotal study, FORTIFY-HN01, and we look forward to continuing to update you on our progress. Thank you.
We'll now begin the question and answer session. Our first question comes from Tyler Van Buren with TD Cowen.
Hey, guys. Good morning, thanks very much for the presentation. Just curious, why do you think you're seeing greater depth of response at 24 weeks or even similar depth, frankly, with the 2,000 mg dose group compared to the 1,500 mg dose group? Even though the dose itself is higher, of course, the exposure over time is lower, given that it's dosed every two weeks instead of every one week with the 1,500 mg dose. Could this be due to the pulsatile nature of higher TGF-beta inhibition? Could the biology here be different than what we typically think about in oncology?
Thanks for the question, Tyler. As we look at it and we continue to characterize the exposure-response relationships of both components, the EGFR as well as the TGF-beta, I think it's one of the things that I think there's far more kind of known pharmacodynamic biology associated with EGFR. We continue to characterize, with our various data sets, TGF-beta. I think what it does begin to make us think is that there's probably some Cmax related effect that you're getting with TGF-beta. You're absolutely right. From an exposure perspective, it comes in lower than the 1,500 mg dose, but there is a higher Cmax, obviously. We continue to see dose responsiveness, clearly up to 2,000 mg across the various dose groups.
Our next question comes from Eric Schmidt with Cantor.
Thanks. Congrats on a really clear and consistent data set. I continue to be encouraged by your biomarker data. I'm just wondering if, on an individual patient basis, you can correlate some of these phospho-Smad2 reductions with greater tumor control or depth of response. Then maybe second, based on everything you've shown us today, how can you tie this back to, or what's the learning in terms of the viability of the Q3 week maintenance dosing strategy that you intend to execute on? Is there some correlation to evidence of support for that dosing? Thank you.
Thanks, Eric, for your question. I'll answer the first question first, which is around individual results of phospho-Smad2. We do have individual results from a number of paired biopsies. Unfortunately, the N is small since we weren't able to get too many biopsies from these patients. In many cases, especially in our rapid deep responses with complete responses, we're unable to get a second on-treatment biopsy.
From the data that we have, there does seem to be an early correlation that our deepest responders have the highest phospho-Smad2 inhibition. Again, tying back to the data we presented today, showing that at the higher doses, we are seeing more TGF-beta inhibition, higher depth of response, and it's that depth of response that's leading to outsized durability seen with increased median PFS, median DOR, and median OS in the cases where the data is mature.
Yeah. Go ahead.
If Q3 dosing, I'll pass that over to Ryan.
Yeah, Eric, from your question around the every three weeks, the dose again, as a reminder, that we're taking into the maintenance phase of that is 2,250 every three weeks. We ultimately landed on that dose because, i t does replicate on an exposure basis the 750 mg weekly data. As you look at the update that we provided at ASCO, you see meaningful durability even at the 750 mg dose, which gives us confidence as we go into that, essentially from a pharmacokinetic perspective, every three weeks.
In a lot of ways, I think it's important to note in that 750 mg cohort that we presented, you're basically starting at 750 mg from the very beginning. With the approach that we are taking, where we were going to initiate with 1,500 mg weekly, where we're seeing rapid deep responses. By the time we transition to every three weeks, in many, many patients, those tumors have reduced to 80% reduction and in one in five patients, a complete response.
That data that we've seen with 1,500 mg accompanied with the data and durability that we're seeing at 750 gives us a high degree of confidence that we're able to get rapid deep responses and then maintain them in the maintenance phase.
Thank you and congrats again.
Thank you.
Our next question comes from Stephen Willey with Stifel.
Yeah, good morning. Think the graphs on slide 21 kind of summarize this quite nicely. Can you just remind us of the dosing schedule at which pembro's being administered in FORTIFY? Just given the potential Cmax-driven benefit of TGF-beta inhibition that was just discussed, wondering if you think there's any potential synergy or additivity to extract by coupling the higher maintenance dose that you're planning to use with the higher bolus of pembrolizumab that's administered on the Q6W schedule. I know that was the pembrolizumab dosing schedule used in the 2,000 mg cohort.
Great. Actually, I'll start and then I'll pass over to Bill to speak to it a little bit as well. What we see is pembrolizumab can be dosed either every three or every six. In the FORTIFY trial, we're dosing it every three weeks. I think it's interesting, your question around the pulse style nature and potentially Cmax benefit. I think as you get out there to those maintenance phase patients.
I think one of the things that's really important is by that point in time, we have dramatically reduced the overall tumor burden in these patients. I do think that the higher pulse, I think we believe that you will be able to continue to maintain, not only maintain, but potentially even some of the patients who haven't been able to get to complete responses by the time you transition to the 2250.
We do believe with the data that we've seen across our various cohorts, including in the 2,000, that we may be able to, even in the maintenance phase, continue to drive deeper responses. I think it's notable with this update across all three cohorts, you've seen additional patients get to complete responses. We really like, again, the possibility of being able to do that with the regimen that we've determined and kind of the alternative schedule with an initiation and a maintenance phase. I don't know, Bill, if you want to add anything incremental to that.
Yeah. Thanks, Ryan. In terms of the alternative dosing study, as we've discussed in the past, there'll be a loading dose for 12 weeks of 1,500 mg followed by the maintenance phase. The question regarding Cmax and synergy with pembrolizumab, we've modeled, as Ryan said, an exposure response that steady states are achieved by the time we get to the Q3 dosing. We give 2,250 in that study every three weeks along with pembrolizumab. We're maximizing the TGF-beta inhibition and maximizing the exposure-response characteristics to drive these deep and durable responses that are demonstrated in these data here.
Okay. That's helpful. Thanks. Just curious if we should be expecting to see another cut of this data. Obviously, median OS hasn't been reached in a couple of the dose cohorts, and I know you're still tracking longer term landmark OS. Is this another, or will there be another cut of this that we should expect to see at some point going forward? Thanks.
Yeah. I think, Stephen, from that perspective, we have continued to update when there's been meaningful changes. I think obviously this is one of them. I think we will continue to track against the cohorts. All these patients remain in long-term follow-up. I think that, again, as data continues to mature and inform the story, I think we'll, consistent with what we've done in the past, I think we'll make updates when they make sense and add to the story.
All right. Thanks for taking the questions.
Our next question comes from Tazeen Ahmad with Bank of America.
Hi. Good morning. A couple questions. You talked about the deep responses that you've observed so far. I wanted to ask if you've been able to identify any predictors of who could have such deep responses just based on the data you've collected so far. Second, you've presented a lot of data already today, should we expect to see any additional data at ASCO itself? A third one, if you could, can you just talk about the timelines for the maintenance dose study and what level of data you think you'll be available. At the time of approval there. Thank you.
Thank you for your question, Tazeen. The first question was related to predictors of response. As you know, we have selected it for HPV-negative patients who have high overexpression of both EGFR and TGF-beta. What we typically seen, which is related to Eric Schmidt's question from Cantor, is that patients with the highest degree of phospho-Smad2 inhibition tend to be some of our deepest responders. With the higher baseline phospho-Smad2, which is a correlate for TGF-beta activity, we typically see those as our deepest responders. In general, this is again, highly overexpressed in HPV-negative patients, which is why we focused on this HPV-negative population. Your second question was will there be additional data at ASCO?
The presentation this morning was a combination of our two data posters presented by Dr. Deborah Wong from UCLA and Dr. John Kaczmar, which is a combination of the two posters that will be presented at ASCO. I think last but not least, you asked a question around the Q3W maintenance study. As we highlighted on our Q1 earnings call, the intent is to begin the design of that study in Q3 of this year and have the data in hand in terms of PFS by the time of our ultimate approval. Thank you for your questions.
It comes from Brad Canino with Guggenheim.
Thank you. Good morning. You gave a lot of information on tumor burden and extensive disease. I think that's on slide 18. Can you speak to the importance of including a broad population across all three of your cohorts and how that shapes your confidence in your phase I signal as we get nearer and nearer your interim phase III readout next year? Thank you.
Thanks for the question, Brad. We find it important to be able to demonstrate, again, the consistency of activity regardless of whether we have small tumors, big tumors, locoregional, and local tumors. It really speaks to, again, the consistency across all of the various different subsets that we know are kind of out there in the community. That we've been able to demonstrate, again, that consistency. I think particularly from overall target size or tumor size is, we recognize in today's treatment paradigm that many physicians are choosing chemotherapy-based regimens in those patients where the tumor burden is higher. Being able to demonstrate that you see good activity, you continue to see rapid responses in those patients, regardless of even if they have a high tumor burden.
We do think that we provide an opportunity to be able to provide an alternative to chemotherapy-based regimens where you see durable responses, rapid responses. I think one of the things that has been a shortcoming in those patients who receive chemotherapy, you saw it in the KEYNOTE-048 study, is that many of them have to come off because of tolerability. With us being able to show great durability, we think that that's an important element as we think about being able to treat across a range of patients, including those today who are getting chemotherapy-based regimens.
Our next question comes from Kelsey Goodwin with Piper Sandler.
Oh, hey, good morning. Thanks for taking our questions. Congrats on the update. I think two questions from us. First, we still sometimes get questions about safety for TGF-beta traps. I guess, across these 91 patients, I think, what do you think that you can say definitively now for Ficera versus some of the prior TGF-beta traps? Then, secondly, as we see some changes across some of the key competitor trials, what do you hear in your channel checks in terms of Ficera relative competitive positioning, and how has that changed, say, from this time last year? Thanks so much.
Great. I'll start with your second question and then ask Bill to elaborate on the safety profile related to TGF-beta. I think we definitely, as we continue to develop the drug and make updates, I think what we're consistently hearing, both in the KOL community, we do as well as our research with community oncologists is, I think the durability certainly stands out. I think there continues to be confirmation, the difference between HPV-positive and HPV-negative disease. I think we continue to be validated amongst the KOL community and even as the data is emerging, I think we're seeing it within other investigational agents that the profile stands out, the ability to show in a more difficult population, extended durability.
I think that the other thing that is standing apart is the depth that we believe is squarely driving the durability and ultimately the long-term outcomes. As that data continues to mature, we believe our profile and the KOL community, I think is supportive of that this is a profile that is standing apart, really based upon the contribution that we think is being driven by the TGF-beta biology. With that, I'll ask Bill to speak and elaborate on the TGF-beta profile from a safety perspective.
Thank you. With respect to the safety profile, what we're seeing is that the AE profile, TRAE profile is consistent with what we'd expect from the mechanistic action of Ficera, with skin toxicity being the most common with EGFR inhibition. With TGF-beta, we're seeing some anemia and low-grade non-mucosal bleeds. With respect to anemia, it's important to contextualize that in this patient population, HPV-negative patients, baseline anemia is more common related to their comorbidities and prior therapies, and underlying disease state.
With respect to TGF-beta, we're seeing some increase in anemia related to effect on red blood cell production, but this has been well managed with iron supplementation, and general supportive measures. The overall safety profile, though, has been generally well managed, and as you've seen, there's been consistent and very low discontinuation rates related to the TRAEs and the less than 10% and less range. Overall, there's been a consistently, generally well-tolerated and manageable profile with low discontinuation rates.
I think, Kelsey, what I'd add to that as well, again, with the design of this molecule, we designed it in such a way where the trap is the extracellular domain of TGF-beta receptor two, and we did that purposefully in order to be able to dial out some of that historical both cardiomyopathy and some of the bleeding that was associated with TGF-beta. I think what we're seeing as the profile continues to evolve is that by making that design choice very early in the construct of this molecule, I think we've been effective in being able to really begin to mitigate some of the stuff that was historically seen with TGF-beta.
Great. Thank you so much. Congrats again.
Thank you.
Our next question comes from Judah Frommer with Morgan Stanley.
Hi, guys. This is Parth on for Judah. Thanks for taking my question. Just one from us. On the 1,500 mg group, are you guys seeing any differences in OS trending between CPS 1-19 and CPS greater than 20 patients? Thank you.
Thank you for your question. I'll ask Bill. Again, at this point, I don't believe we've disclosed the difference between the two populations. I'll ask Bill to elaborate if there's anything that we have yet seen there.
Yeah. Specifically related to the 1,500-mg cohort, we're seeing a generally consistent efficacy in patients with CPS low versus the CPS high. As Ryan commented before, this is also consistent across other tumor characteristics, including patients with bulkier tumors and more poor prognostic characteristics.
Our next question comes from Reni Benjamin with Citizens Bank.
Hey, guys. Thanks for taking the questions and congratulations on this data. As we think about the FORTIFY study, and this data as it pertains to the FORTIFY study, how should we be thinking about other selection criteria that you might be employing so that we might not see a diminution in terms of response rates and activity, given the larger patient population and the potential for heterogeneous disease? Thanks.
Yeah. I think what I would say is, again, the inclusion/exclusion criteria that is in the FORTIFY trial is very consistent with what we've had in the phase I-B trial. I think in terms of the way we thought about the population, again, we did so recognizing that probably the best anchoring study historically was the KEYNOTE-048 trial. As we think about being able to have a reproducible control outcome, I think that was important to us. I'd say that what you see in baseline characteristics of the data that we presented across these three cohorts, I would say that you could expect to see a consistent demographic profile. Again, that is very consistent with what we've seen in the KEYNOTE-048 trial.
Got it. Maybe just as a follow-up, as we think about the ORRs that we're seeing, it seems like there's a step down in the ORRs as we go up in dose, but then the CR rates and the depth of responses kind of go the other way, right? We start seeing an improvement in those. Can you maybe just help me reconcile how that might be working?
Yeah. I'd say it really is, again, consistent with what we have seen with the pharmacodynamics of TGF beta. I think similar to a question we received earlier around, is there a Cmax dynamic that's driving those deeper responses. I think the nice thing across these three data sets is it really has allowed us to characterize the contribution of TGF beta. I don't know, Claire, if you have anything else that you'd like to add to that. Again, I think we really attribute it to the TGF beta across and the PD of the TGF beta.
Yeah, very much so. I think what we know is responses are predominantly driven by the EGFR arm. We've seen strong consistency across those, very similar to other EGFR inhibitors. If you really see what the differentiating profile of Ficera is, it's really predicated on the TGF-beta arm, where we've seen higher TGF-beta inhibition at both the 1,500 mg weekly and the 2,000 mg every two-week dose. Consistent with that, those are the two cohorts where we've seen not only improved depth but improved durability and ultimately overall survival. I think the goal of this data set was really to speak to, again, TGF-beta inhibition driving depth of response and ultimately durability and overall survival benefit. Thank you for your question.
Our next question comes from Jeet Mukherjee with BTIG.
Great. Thanks for taking the question. We spoke a lot about drug exposure levels and its relationship with efficacy, but have you seen any trends on exposure levels as it relates to safety and tolerability, particularly as it relates to anemia and the bleeding events? Ultimately, just your confidence around the safety profile for the maintenance 2,250 dose? Thank you.
Yeah. Good question. I think what I would point to is, again, data that we previously presented at the 2,000 mg where you did see a slight increase in Grade 3 anemia as those doses went higher. I think two things that I would say there is that you don't see meaningful differences between 750 and 1,500 mg from a safety perspective, which, again, when we align with the FDA for Project Optimus, the key thing the FDA is looking for is the risk-benefit of the two doses. It was clear in the data that we've demonstrated and agreed to by the FDA that the benefit associated with 1,500 mg with greater depth, greater durability, ultimately outweighed any incremental tolerability profile that the 1,500 mg picked up, given that it was so minimal.
I think also it's key to look at those AEs that required discontinuation or dose holds. Again, as you compare between 750 and 1,500 mg, there was minimal differences, while at the same time we saw a benefit in efficacy. In terms of what gives us our confidence as we go to a 2,250 maintenance dose, again, part of the thing that gives us that confidence is our exposure-response modeling, recognizing that the 2,250 is stretched out to every three weeks.
From an overall exposure basis, it then again replicates a profile that's more comparable to 750. We have not seen anything from a Cmax-related tox perspective that gives us concern. Again, across the totality of the data that we have, it's allowed us to do robust exposure-response modeling. We've got a lot of confidence in the approach that we're taking.
Our next question comes from Boris Peaker with Jones Trading.
Great. I just want to follow up on your prior comment. Talking about discontinuation, I know the rate was relatively low, are there any strategies that you could implement in the planned studies to reduce the discontinuation rate across the board?
Yeah. I think it's certainly something that we have interrogated deeply from our phase I-B experience. I would say generally, the discontinuations have been very low. There's been no consistent thing that has led to those discontinuations, so it's not like there's a specific area. One of the things, Bill Schelman spoke to the anemia. One of the things that we're doing proactively is you see a lot of baseline anemia in head and neck patients. We're looking at that closer as they come on to study in order to make sure that if a patient has come on at initial screening and they're already running with a low hemoglobin, that we're being more proactive with oral iron to bring that hemoglobin up.
That being said, anemia hasn't led to discontinuations, and so I think that while we continue to monitor the overall profile of these patients as they come onto therapy, I'd say that there's nothing in particular that we're seeing within the profile that you're able to kind of mitigate prospectively.
Great. My second question is you run the FORTIFY study as well as the loading and maintenance dose studies. Are some of those both trials going to be running at individual clinical sites? I'm just trying to understand if there could be potential competition between two studies for the same patients, and if so, how would those investigators kind of decide which way to randomize a patient, and if that could somehow induce some bias in patient selection?
Yeah. It's definitely something that we're very mindful of in terms of the overall operational plan of those two trials, recognizing that we're looking to rapidly enroll both. I'd say that in many cases, we'll be looking at alternative sites in order to do that to mitigate that potential risk. I think that being said, the every three-week trial also for patients where their proximity to the clinic is a little further, I think that is an option for them. Again, it's something that we're incredibly deliberate and intentional about as we think about the operational plan for both trials and being able to maximize enrollment.
Great. Well, congratulations on the data again, and thanks for taking my questions.
Our next question comes from Eva Fortea with Wells Fargo.
Good morning. Thanks for taking our question. A very quick one from us. I forget, are there any plans for a potential subcutaneous formulation for Ficera? Thanks.
Thanks for the question. We absolutely are doing feasibility work around sub-Q. I think the initial focus here was for us to, again, be able to develop the every three-week maintenance regimen, which I think meaningfully improves on the overall convenience and administration schedule. That being said, we are doing work as it relates to understanding the feasibility and our ability to potentially offer a subcutaneous formulation in the future.
Got it. Thanks.
That concludes today's question and answer session. I'd like to turn the call back to Claire Mazumdar for closing remarks.
Thank you all for listening in today, and we look forward to seeing many of you at ASCO. Thank you.
This concludes today's conference call. Thank you for participating. You may now disconnect.