Okay, good morning, everyone, and welcome back to day one of the Cantor Conference. My name is Eric Schmidt. I'm one of the biotechnology analysts with the firm, and it's my distinct pleasure to welcome our next presenting company for a fireside chat. We're delighted to have with us Bicara Therapeutics and delighted to welcome the company's CEO, Claire Mazumdar, as well as A.J. Sacks, who heads up the corporate development team at Bicara. Claire, maybe you can just start with a kind of brief overview of state of affairs, and then we'll go into it from there.
Happy to. So Bicara is a clinical-stage company focused on what we term targeted tumor modulation. Our lead program is an EGFR TGF-beta trap, which entered the clinic in the summer of 2020. We are now building momentum and enrolling in a pivotal study for the potential accelerated approval of ficerafusp alfa, which is our EGFR TGF-beta plus Pembro, compared to Pembro control in frontline HPV-negative recurrent and metastatic head and neck, which we believe has the potential for accelerated approval.
Okay, we're going to go deep, deep, deep, of course, into ficerafusp alfa and everything about this drug. But before we lose sight of the forest and the trees, just size up for us this frontline head and neck cancer marketplace and what the unmet need is.
Yeah, so it's a very large unmet need. It's a large indication where in the recurrent and metastatic setting, you have about 30,000 patients a year in the U.S. alone, and it's much bigger globally given the preponderance of smoking and chewing tobacco. So there are really two subsets of patients in the head and neck setting. You have the HPV positive patients who actually make up the minority of the recurrent and metastatic setting because most of those patients tend to be cured with surgery and radiation in the locally advanced setting. They, of course, have the HPV infection or human papilloma virus and tend to respond better to frontline and second line therapies, and then the vast majority of the recurrent and metastatic market is the HPV negative subset.
These are patients typically with a history of chewing tobacco, smoking, and alcohol use who are about 80% of the frontline opportunity in the U.S. and 90%-95% in Europe and Asia where you see more smoking. These patients respond worse to immunotherapy and other therapies. In fact, the standard of care across both today, just because we don't have many good standard of care, is Pembro, which shows about a 12-month median OS in the total population and a nine-month median OS in the HPV-negative.
Okay, you spoke about ficerafusp alfa's mechanism addressing both EGFR as well as TGF-beta in a bispecific format. Why is that mechanism more relevant to the HPV-negative subpopulation?
Yeah, so the HPV negative subpopulation is known to be a very immunosuppressive tumor type. Head and neck is a squamous cell carcinoma. Those are known to have almost oftentimes full EGFR overexpression. In head and neck, it's about 95% of head and neck tumors overexpress EGFR. Those levels are much higher in HPV negative, but importantly, they have higher TGF-beta signatures and serum TGF-beta as well, which is driving this more immunosuppressive tumor microenvironment. They tend to be, again, very immunosuppressive, more necrotic and fibrotic tumor microenvironments, which are driven by both the EGFR and TGF-beta pathways.
How clinically is HPV status assessed?
Great question. So typically, the way you think about it is there are four subsets of head and neck where Pembro is approved today. There are five across the major head and neck. Nasopharyngeal, which is the fifth one, is predominantly a tumor type that's large in Asian populations, predominantly China, which is driven by EBV. But today, globally, Pembro is approved in the hypopharynx, larynx, oropharyngeal, and oral cavity. Three of those subsets are assumed to be HPV negative from the get-go, and then only one of those subsets do you typically test when a patient is newly diagnosed in the locally advanced setting. The way I like to just speak to it is if a patient is walking into a clinic, if you have 10 patients walking into a clinic, seven of those are deemed HPV negative from the very get-go and are not tested.
Only in three of those patients does a community doctor test them. Previously, the community clinics would do what's known as a p16 immunohistochemistry or IHC, which is from an actual tumor biopsy. The field is moving to an HPV PCR, which is exactly like the COVID test we used to take. And we anticipate that that will actually move into the locally advanced setting as well.
Maybe just in terms of testing, one thing I would add, I think we also get the question of whether this is potentially going to cause a delay. And I think one of the things that you also have to keep in mind is most of these patients are getting tested for their CPS status. And what we've seen just from our Fortify study is that the turnaround time for doing the CPS testing is basically the same for the HPV diagnostic. So it doesn't actually pose any delays in terms of putting patients on study or even as we think about the commercial implications for that.
Since you brought up testing to that level, A.J., you're co-developing your own test. Tell us about the regulatory path and validation process for that?
Yeah, so this has been a validated test that's been validated by our collaborator that has developed an HPV PCR. So again, far more sensitive, covers a lot more of the HPV variants than just the P16 immunohistochemistry. While we are collecting samples within our study, at the time of our potential accelerated approval, we would submit that companion diagnostic. But we anticipate while it will be part of our label that that testing will also move into the earlier locally advanced setting in the patient journey.
Okay, all right, let's get into your clinical program. You mentioned, Claire, that ficerafusp alfa is in a phase three study in frontline disease in combination with Pembro, of course. Just remind us of the data that support that phase three program.
Happy to. So we first began with studies in dose escalations in combination with Pembro in head and neck. These were late line patients. We had seen a number of those patients achieve deep and durable, in some cases complete responses after failing frontline Pembro, second line cetuximab. And so we started to build a confidence that there was a path to moving into the frontline setting. At ASCO this year, we shared an update in an oral presentation of our 1,500 milligram weekly dose in combination with Pembro. It was about 30 patients who are HPV negative, of which had at least two years' worth of follow-up. We've shown a greater than 50% response rate, so more than doubling what you'd expect with Pembro. But more importantly, we've showed a tripling of PFS and more than doubling of both durability and median OS at this point.
It was just the consistency across all of these endpoints that has, to us, really spoken to this TGF-beta arm driving both the depth and durability of response that is leading to outsized OS.
Those data were probably a little less well received than I would have liked. Maybe you can give us a recap of your views on why that might have been the case?
Yeah, so we have a competitor in a company by the name of Merus that has been developing a bispecific EGFR LGR5 molecule. Their first approach was to test their molecule in monotherapy and second line and have recently also moved to the frontline setting. I would highlight that these are quite different molecules in terms of mechanism of actions. This was developed really, our molecule was developed really as an immunotherapy to lead to these deep and durable responses. The petosemtamab molecule was developed in some ways as a better EGFR. And so what they were able to show, they've showed, I would say in terms of equivalence, in terms of data sets, we've shown consistency across overall response rates. We've shown better depth of response with a higher complete response rate, very similar median PFSs.
But they showed one outsized short-term landmark and a 12-month landmark OS at about 75%, while we shared about just over 60%. We were bullish going into ASCO given we had received the oral presentation, felt great about our durability and our OS, really the consistency of those data sets. And that resonated very well with investigators who have many times been burdened by short-term endpoints. But I credit them with an excellent PR to creating a 12-month landmark, turning that endpoint into something that felt meaningful to investors, though it wasn't as meaningful to investigators.
You mentioned maybe two benchmarks there, both ORR as well as shorter-term 12-month OS landmark analysis. Why is either or both less relevant, in your opinion, in judging success from an early study?
I mean, I think many head and neck investigators have been burned with these Pembro combinations. I would point people to the IDO inhibitors that people were excited about. Those saw improvements in response rates, never translated to meaningful improvements in overall survival. We saw the same thing recently with lenvatinib, TIGIT, LAG-3, and so investigators have been burned many times with these short-term endpoints that haven't led to meaningful durability or meaningful overall survival, which is why I think we were going into ASCO quite bullish for our own data set, but I think missed the PR campaign that was made around 12-month landmark OS, and I think we've been trying to remedy that ever since.
What evidence do you have that ficerafusp alfa is working through an IO mediated effect?
We have a lot of translational data. So we shared at AACR this year that not only are we able to inhibit TGF-beta within the tumor itself, which is in some ways unprecedented for a TGF-beta inhibitor. There have been a number of TGF-beta inhibitors that have burnt investors and investigators in the past, but those never showed clear tumor target engagement. With that tumor target engagement, we're actually able to show reactivation and penetration of the tumor from these immune cells. So we're really remodeling the tumor microenvironment. To that end, the biggest proof of that in the clinical data is really the depth of response we've seen. Of all our responses that we shared, the vast majority, 80% of those had at least 80% depth of response, and we saw 25% complete response rate. That's in some ways unheard of in head and neck.
But the additional part is really the durability. We're seeing a Pembro-like durability at greater than 20 months, which is very much that of an immunotherapy.
Yeah, maybe just one thing I would add is I think we have the benefit of seeing some proof of concept phase one IST studies, which looked at the combination of cetuximab with pembrolizumab. And I think just looking at those studies and comparing, as Claire mentioned, the depth of response and also the durability, it gives us a proxy for what that TGF beta contribution is actually doing in the clinical data. And what we've seen is not just, I think, the depth that Claire mentioned, but we know cetuximab in combination with Pembro in the front line does about 12 months in terms of the duration of response. So seeing that 21-22-month durability to us is really that IO-like effect that you're getting from the synergy between the TGF beta with the PD1.
How should we think about depth of response? On the one hand, you argue that response alone, an ORR cutoff of RECIST criteria 30% isn't that relevant here, but getting up to 80% plus is. So what's sort of in your mind mechanistically or biologically when you explain that, wow, if you get to a certain depth of response, it can be durable?
I mean, what we've seen is if we look at the deepest responses, we see a clear correlation today that our deepest responses are our patients with the highest PFS, the highest DOR, and the highest OS. In fact, patients who achieve a complete response with our molecule have more than two-year median overall survival, close to 26 months. That's unheard of in HPV negative disease where the median OS with Pembro is only nine months, so we've seen that, but we've also seen it again back to the translational data. You can see that transcriptomic data really showing tumor remodeling and tumor penetration, and that was very much the intent of what our mechanism of action was. We developed this as a targeted tumor modulator, and so the TGF beta is doing what we anticipated it would do.
You've called out some of the baseline prognostic variables that patients had upon entry into your study. Maybe you can just recap why those are of interest.
Yeah, happy to. So as we look at HPV negative disease, first of all, that's probably the most important prognosticator for difficult, high unmet medical need. But there are, I would say, three other aspects of patient baseline characteristics that are very important to look at. And we were very transparent in how we shared our data at ASCO, not just to highlight that these were patients with a high unmet need, but also to show the activity of ficerafusp alfa across these patient populations. So the first of which is CPS score. Typically, patients with what's known as the combined PD-L1 score of 1 to 19 respond far less well to Pembro monotherapy. Investigators tend to put them on chemo just to get some type of response, but those responses are not durable at all.
Even in the 1 to 19 category, we're seeing a median DOR and a median OS in excess of 20 months, which is again unheard of, and our approach there was really to show investigators that they don't need to use chemo and can get these deep durable responses in IO refractory patients. The second of which is the location of the tumor. Typically, patients with local regional disease, as cancer biologists, I've often found this a bit confounding, but patients with distant metastases in head and neck actually respond better to Pembro monotherapy. And the idea here is that patients who have local regional involvement tend to be highly irradiated, very fibrotic, and those respond less well, in fact, are driven more by TGF-beta. We had a skewing of about 70% of our patients were actually patients with local regional involvement.
And even there, we saw a greater than 60% response rate and very deep responses. The third, which was actually to address, I think, some investor skepticism, is that we were seeing such a high rate of complete responses. So we were being asked, are these CRs only happening in patients with a low tumor burden with small tumors, or are you seeing this across the board? And in fact, why we shared the tumor volume was really because we were seeing this in patients with five large tumors. Even in those patients, we're seeing a very high depth of response. So those three factors really pointed to the fact that we had a very sick population. And these were the patients who are most refractory to Pembro, yet despite that, we're seeing very high and deep responses.
Two criticisms that we have heard about the data set is number one, it's sort of modest in size, 28 patients total, and two, that the HPV designation was done post hoc that you did enroll some HPV-positive patients. I know you've got a couple of upcoming data sets. Maybe walk us through the additional phase 1/2 results that we're going to see and how they may address these criticisms.
Yeah, so we will have an additional 60 patients, so a total of 90 HPV-negative patients across frontline head and neck in combination with Pembro. The other two data sets that we're sharing are both 30-patient HPV-negative prospectively chosen. One is our alternative dose for our pivotal study, so 750 milligrams weekly that will likely be presented at a medical meeting at the end of this year or beginning of next year. The second of which is another dosing schedule. So it's a 2000 milligram every two weeks. And that's really to speak to the potential of being able to move to an alternative dosing schedule. And I think to your point, we'll increase the n to 90 and to us really show that in HPV-negative disease, we have a very active molecule in a very difficult to treat patient population.
So what kind of follow-up will we have on these cohorts when we see data, and what can we learn?
Yeah, the initial data sets that we will present will be focused really on response rates and depth of response. We anticipate being able to update both data sets in terms of at least one year's worth of follow-up in the first half of next year.
So what would constitute good data from an investment standpoint?
Yeah, I mean, I think really being able to show that we have an active molecule. Our hypothesis was, as we think about the contribution of the EGFR and TGF beta, we know that at the 750 milligram dose, we are fully saturating the EGFR receptor. So it's really to better understand how the TGF beta is contributing, whether it's on response rate, depth of response, durability. Our hypothesis going into our studies was that we would actually see responses similar to that of cetuximab, and the TGF beta would really drive depth and durability. So I think what would, to me, drive is a strong response rate that speaks to an activity, but are we seeing similar safety, similar all of those things?
So a strong response rate with good depth of response as well at this stage, and then we'll follow up patients for durability.
Yeah, I mean, I think just to your point about the small end, I think if we're able to see high response rates across not just 30 patients, but 60 or 90 patients, you think about the confidence interval around the response rates, especially as we think about the interim analysis for the pivotal, which is an ORR-based endpoint, being able to potentially tighten those confidence intervals to get more conviction around actually the response rate endpoint in the phase two, three is another thing we would hope to see from a larger sample size.
Great, let's talk about the phase two, three and the design, and let's start with the phase two lead-in.
Yeah, so it starts as it's a seamless phase two, three design with the phase two portion being a three-arm study, so looking at the 1,500 milligram weekly, which is the data we presented in open label at ASCO, the 750 milligram dose versus Pembro control. We will enroll 10 to 20 patients across these three arms and with 12 weeks of follow-up in the two ficerafusp alfa containing arms, unblind only the ficerafusp alfa containing arms to our unblinded team, and then we'll recommend our dose in addition to the open label data set to the FDA, and during that time, we anticipate we will likely over-enroll at the non-optimal dose, an additional 20 to 40 patients, and then declare our selected dose, and then in the phase three portion of the study, it becomes a two to one randomization of ficerafusp alfa to Pembro control.
But by doing this in this design, the patients enrolled from day one at the optimal dose will contribute to the interim analysis for accelerated approval and the confirmatory approval endpoint.
What will you be communicating to investors at the time of dose selection?
The only thing we will be able to communicate is X dose is selected and we continue to enroll towards.
The unselected patients will just.
Will remain at that dose and will not be unblinded.
They'll remain at the unselected dose.
Correct.
They'll continue on the study, but they won't be part of the eventual analysis of the data. How has enrollment gone? Where are you with site enrollment, site activations, excuse me?
We continue to feel very good about the momentum we're building in terms of site activation and enrollment. What we can highlight is we continue to be on track to select our dose in the first half of next year and for the interim analysis in 2027.
And can you speak to things like study powering both for the ORR interim? Well, let's talk about accelerated approval first.
What we have guided to is that the interim is predicated on an approximate doubling of response rates with six months of durability. At the time that that interim would be done, we would be close to fully enrolled, if not fully enrolled in the study, given that the FDA as part of Project FrontRunner is looking for at least a descriptive analysis of overall survival at that time. This study is really designed and powered for the confirmatory endpoint of overall survival. What I can point you to is that we took a slightly more conservative assumption than the KEYNOTE-048 median overall survival of 12 months, but have every reason to believe that our Pembro control arm will not outperform like it did in the LEAP study at 18 months.
So I would use those 12 and 18 months in some ways as bookends for how we're expecting our control arm to.
In terms of the Accelerated Approval outcome, you can forgive investors for being a little bit gun shy these days with regard to potential moving targets of the FDA. How do you give us confidence that this is still an appropriate pathway if you are to double the response rate?
Yeah, I mean, I do think it again will be the totality of the data. So I do think durability and overall survival are an important aspect where ficerafusp alfa has really shown a very differentiated profile on both of those aspects. And so even if the FDA does keep changing how they think about overall survival, we've always thought about overall survival as the most important aspect. So we feel very well sized for that interim analysis to show that there will be a significant OS benefit at that time.
A significant OS benefit at the time of the interim analysis, or do you need a certain number of OS events at the time of the interim analysis? How are we thinking about that?
So while we will not be using alpha on the overall survival, we do anticipate that the FDA will look at that themselves. And at that time point, given the data sets we've seen and the more than doubling of overall survival, that we will be in a good position to really show benefit.
How does your phase three design compare to your competitor's design?
Yeah, so there are two big differences in, I guess, three big differences in terms of design that are important to highlight. The first of which is, of course, we're going into an HPV negative only patient population. Again, we did see activity in HPV positive, including two complete responses, but we believe that we would see an improved efficacy in the HPV negative, and we didn't want to see an improved control arm with the inclusion of HPV positive. The second of which is our study is also larger than that of our competitor, which we think is appropriately sized for overall survival benefit. And the third, which I think is an important nuance, is our study is a blinded study while that of Merus is an open label study that has a significant impact on subsequent therapies that can, of course, affect overall survival.
Since patients would know that they were on the control arm, that might create a bias for investigators for subsequent therapies to be cetuximab based in the control arm, which could lead to, again, outsized control arm performance.
You mentioned dose selection occurs in the first half of next year. The interim analysis is expected to, well, actually first completion of enrollment is expected to occur when?
Both of those are expected to occur in 2027.
Enrollment would have to be completed prior to the interim analysis or not necessarily?
Around the same time.
Okay, and first half or second half of 2027 for the year of those?
2027.
Final OS analysis data ballpark?
We're anticipating that actually more rapidly than we initially had guided to. Initially, we believe we had highlighted 29, and we think it could happen earlier given events, so 28.
Okay. When will you be applying for a breakthrough designation?
Our current plan is to do so, or we've disclosed previously to do so at the time of dose selection.
Why not sooner than that?
We are exploring other opportunities, but our current thinking was to do so at the time with the data set from our selected dose for phase 3.
So looking ahead to potential commercial competition and opportunity, how do you see ficerafusp alfa stacking up in the marketplace?
Yeah, I mean, I think in terms of significantly differentiated in terms of overall survival and durability, we feel very confident that ficerafusp plus Pembro is going to become the standard of care in HPV-negative frontline head and neck. I think an important aspect that is often lost is that in the CPS one to 19, many investigators do use chemo in that regimen. But what we've shown with our molecules, even into the one to 19, we see very high activity, very high durability in OS, and those responses are happening very rapidly. And these patients don't typically by first scan, you can get to CR. So the rapidity of that, which is why investigators often use chemo, we feel is being addressed with the ficerafusp combo.
So if we can displace chemo in that market as well, it would give us a very large proportion of the patient population.
You've also begun to enroll a CPS zero cohort. Can you remind us of the rationale for that?
Yeah, so the CPS zero cohort is again based off of the TGF-beta biology. In many ways, we see it as our monotherapy cohort to really speak to synergy with Pembro, but also the activity of ficerafusp alfa. So in the CPS zero patients, Pembro is not approved. The response rates to Pembro are actually 0%. These patients typically see chemo containing regimens. The typical one is chemo plus cetuximab, where response rates are really in the 10%. We had a few patients as part of our dose escalation who were cetux and PD-1 refractory who achieved CRs in our dose escalation. So we anticipate being able to disclose early data from that next year as well.
Outside of head and neck cancer, you got a couple of other studies ongoing in colorectal in particular. Remind us what you hope to see there.
Yeah, so there again, the bar is quite low. These are two third-line cohorts of cetuximab-experienced patients, again to test the TGF-beta biology. So TGF-beta is known to be the key driver of resistance to cetuximab. This is both a monotherapy cohort and a combination with Pembro cohort. Again, Pembro has shown no activity in this setting, but it's really to speak to the inherent synergy we've seen both preclinically and clinically with TGF-beta. So the bar for third line is really Bev plus Lonsurf, which is single-digit responses. I would say our hope is to see something above 10%-15% to build excitement.
We got 10 seconds left, and I don't think we need to bring up your CFO for this question, but can you remind us of your cash and cash runway?
Yeah, as of Q2, we disclosed north of $440 million, which would fully fund our pivotal study and the signal seeking cohorts we discussed today. It is not predicated on a commercial buildout.
Claire, Ivan Li, thank you very much for being here today.
Thank you.
Thanks.