BioAtla, Inc. (BCAB) Earnings Call Transcript & Summary

Good morning, and welcome to the BioAtla R&D Day. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the BioAtla website following the conclusion of the event. I'd now like to turn it over to Jay Short, Chief Executive Officer of BioAtla. Please go ahead, Jay.

Thank you, and welcome to BioAtla's R&D Day presentation. Today, we will be covering 2 of our Phase II assets, CAB-AXL-ADC and CAB-CTLA-4, with our Chief Medical Officer, Dr. Eric Sievers; and 3 distinguished key opinion leaders, Dr. Yau, Dr. Hamid and Dr. Mangla. Earlier this week, we shared that we received a fast track designation for our ROR2 ADC, which has now also been accepted for presentation at ESMO in September. So you will be learning more about that particular asset in September at ESMO. But before I begin, if I could look at the next slide, I would like to remind everyone, next slide, please, to review our safe harbor disclaimers and notices because we will be making forward-looking statements. With that, if I could just go to a brief introduction here on the next slide, please. Oops, back one slide. Perfect. Thank you. I'll start off by reminding everyone we're -- BioAtla is an oncology company focused on the treatment of solid tumors. We are leveraging our proprietary CAB technology, which takes advantage of a universal characteristic of all cancer cells, which is acidity, by allowing -- by engineering antibodies such that they can only bind to targets on acidic cancer cells, which is essentially all cancer cells, but not on normal cells. In this way, we increase the therapeutic window or therapeutic index, which allows us to increase safety as well as potency of the therapy. We are on track for multiple FDA meetings later this year to help guide our design for potentially registrational trials. We also remain on track to establish a partnership this year with at least one of our CAB assets. Our current cash position takes us into the second half of 2025, but we aim to extend this time line later this year through a new collaboration or collaborations. So we continue to remain on track, and I'm pleased today to invite you to listen to the clinical data update stuff. And I'm going to now hand the presentation over to Dr. Eric Sievers, our Chief Medical Officer, who will start with today's agenda. Eric?

Thank you, Jay. So we'll be talking about 2 of our clinical assets today: mecbotamab vedotin that targets AXL, and we'll be giving an update about our new findings in non-small cell lung cancer. We have an emerging finding in the KRAS mutant population that's particularly interesting, and we'll get into that in considerable detail. And then second, we'll be talking about the CTLA-4 asset, evalstotug, also conditionally binding. And we have 2 investigators that will be sharing an update of these trials. And let's go to the next slide. So as Jay mentioned, the conditionally binding technology widens the therapeutic index. And the simplest way to think about this is that we're knocking out the binding at a normal tissue pH of 7.4. So we select our antibodies so that they bind preferentially in a low pH environment consistent with the Warburg effect. And it's important to note that this is not a masking or a caging technology. And so this is inherent to the CDR regions of the antibodies that they bind the low pH environment and avoid binding in the normal tissue microenvironment, thus improving the therapeutic index. Next slide. Now we'll be talking about the first of the 2 assets, mecbotamab vedotin, which is a conditionally binding AXL-targeted ADC. Next slide. I'd like to introduce Dr. Edwin Yau. Dr. Yau is one of our investigators, a physician-scientist at Roswell Park. He's the Chief of Thoracic Medicine. And very appropriately for the conversation we're having today, he's an expert in KRAS mutant lung cancers and has also served as the principal investigator of multiple clinical trials evaluating KRAS inhibitors. Dr. Yau, please go ahead.

Hi. Thank you for the invitation to speak. If we can go to the next slide, please. So happy to share some of the data from the Phase II trial, looking at the AXL antibody drug conjugates, mecbotamab vedotin. So we know a lot about the mutational landscape of non-small cell lung cancer, especially non-squamous non-small cell lung cancers. And the dominant mutations all involve alterations in cancer-signaling pathways and especially in the MAPK, MAP kinase pathway, with the most common oncogenic mutations in non-squamous non-small cell lung cancer in oncogenes such as KRAS and EGFR on this pathway. And the activation of these oncogenic signaling is what gives cancer cells their properties to be able to proliferate unchecked and invade other structures and also resist treatment. AXL is a receptor tyrosine kinase. It's expressed on the surface of cells and is also known to be expressed in some lung cancers, some non-small cell lung cancers. And emerging preclinical data suggests really involved in as a mechanism of resistance, of cancer cell resistance to treatments, especially to tyrosine kinase inhibitors. Next slide, please. So mecbotamab vedotin is a AXL-targeted antibody-drug conjugate where a cytotoxic payload, the MMAE payload is linked to the conditionally active antibody that binds AXL in the acidic tumor microenvironments. So -- and leading to cell death, so once these cancer cells are exposed to the cytotoxic payload. I'll refer to mecbotamab vedotin as the AXL-ADC most of the time. Next slide, please. And so I'll be sharing some preliminary data from the Phase II trial in non-small cell lung cancer. This is an open-label trial with multiple arms in advanced non-small cell lung cancer patients who have progressed on checkpoint inhibitors and targeted therapies as appropriate. Just point out that there are multiple dosing cohorts. So there is a monotherapy arm and a combination arm with the PD-1 inhibitor, nivolumab. And then the study was amended later to have a second monotherapy dose. So one monotherapy dose is every other week, and the other is twice in 3 weeks; so 2 weeks on and 1 week off. And that 2 weeks on and 1 week off dosing cohort, the protocol was amended to allow both AXL-positive and AXL-negative patients to enroll. The initial 2-week cohorts only had AXL-positive as an entry requirement into the trial. And the endpoints here for preliminary efficacy are objective response rate, and the main endpoint was a tolerability of the drug and then there are a variety of efficacy secondary endpoints. Next slide, please. So looking at that second cohort where second monotherapy dosing cohort, 2 weeks on and 1 week off dosing cohort where both AXL-positive and AXL-negative patients were enrolled, you can see that this is the demographics. And this is a heavily pretreated population with most patients getting over 3 or 4 lines of therapy. Next slide, please. And looking at -- comparing AXL-positive versus AXL-negative patients, note that all the responders were in AXL-positive patients, which makes sense with the mechanism of the drug. And so that's good to see. Next slide, please. And looking at all of the dosing cohorts in the monotherapy arms in non-squamous non-small cell lung cancers, again, you can just see that the blue is AXL-positive and the green is AXL-negative. And you can see that all the responders were AXL-positive, suggesting that clinical benefit in AXL-positive patients. Next slide, please. As far as the dosing cohorts, it didn't look like there was a terrible amount of difference. We saw responders in both dosing cohorts with objective -- a confirmed objective response rate of 24% and a disease control rate which is stable disease and responders of over 80%. Next slide, please. Some preliminary exploratory analyses suggest that mutations in KRAS might be an interesting subset for this AXL-targeted ADC. Looking across at all the different cohorts, there were significant amounts with known KRAS mutational status, but still some patients that are being evaluated. And a total -- out of the 77 patients that were dosed, there were 20 -- 27 with KRAS mutations. KRAS mutations, again, is -- are the most common alteration in non-squamous non-small cell lung cancers. And there is some association with AXL expression in KRAS mutant lung cancers, especially in the age when we have direct KRAS G12C inhibitors. Seems like those patients with KRAS G12C mutations who have AXL expression seem to respond less well to the G12C inhibitors and develop acquired resistance faster and being evaluated in the preclinical space for -- as a mechanism of resistance to some of our targeted therapies. Next slide, please. And so looking at the KRAS mutant patients in the Phase II trial, we can see significant responses in multiple different KRAS mutant variants, with one patient in the combination arm with a complete response and a long duration on the response. And you can see the objective response rate in the KRAS mutants with progression-free survival of 4.5 months that compares in the overall survival of over a year that compares favorably to some of our G12C inhibitors. Next slide, please. And this is just showing that -- some preliminary data showing that overall survival seems to be numerically longer in mutant KRAS patients compared to wild-type KRAS patients. And we're continuing to look and look for more of KRAS mutational status in this population. Next slide. Overall, the AXL-ADC is well-tolerated with around 30% of severe AEs and a very low treatment discontinuation of 5% related to AEs. None of the Grade 3 or 4 adverse events seem -- nothing seem to jump out. There is a smattering of different Grade 3 toxicities. No toxicities that led to deaths. And overall, the toxicity profile is favorable compared to other drugs like the KRAS G12C inhibitors in the second line. This toxicity profile is -- compares favorably. Next slide, please. And you can see a breakdown of all the various adverse events. And again, no one of these adverse events reached double-digits in the severe category, with the most common being neutropenia and elevated liver enzymes. But no dominant pattern in these adverse events are kind of expected with the profile of the antibody-drug conjugates. Next slide. So in summary, from the data for the Phase II trial of mecbotamab vedotin in non-small cell lung cancer, it seems like AXL expression correlates with the response to this drug. And we saw responses in -- regardless of the dosing in the monotherapy arms. Seems like mutant KRAS is associated with AXL expression with exploratory analysis showing none of the mutant KRAS patients were AXL-negative on the trial. And we saw some encouraging antitumor activity in this highly pretreated patient population with a good safety profile. We had responders with multiple KRAS mutant patients with one achieving and maintaining a complete response for over 2 years. On a personal note, one of my own patients had a KRAS mutation and had a good response to this drug. That patient also had a co-mutation in STK11, which we have increasing knowledge of poor prognostic co-mutations in KRAS mutant lung cancers. And so that was a difficult lung cancer to treat, and so that patient derived pretty good benefit from this drug. Thank you for the invitation to present. I think this is the end of lung cancer data.

Wonderful. Thank you, Dr. Yau. I really appreciate it. Moving now to evalstotug, our conditionally binding CTLA-4 antibody. Next slide, please. I'd like to now introduce Dr. Hamid, who is the Chief of Translational Research and Immunotherapy and the Director of the Melanoma Therapeutics at The Angeles Clinic and Research Institute. I'm really gratified that he's here to join us today. He has been instrumental in bringing multiple new treatments to the clinic, from checkpoint inhibitors to targeted agents for BRAF and MEK. And please proceed, Dr. Hamid.

Thank you so much, Dr. Sievers, for that wonderful introduction. I'm proud to present our initial work with evalstotug here. As you know, this is a conditionally active CTLA-4 that's active in tumor microenvironment only, thereby reducing immune-related adverse events, as you can see here, that not affecting a normal cell, but affecting the tumor in an acidic microenvironment. And that's really what we've been searching for. As you can see, historically, this data that was presented with ipilimumab, we have understood the ability to dose higher and get improved overall survival and long-term benefit. But the prohibitive toxicities that we've seen in single agent, as you can see here, Grade 3 to 4 adverse events increasing significantly and discontinuation increasing. These adverse events have made it difficult for us to utilize anti-CTLA-4 therapy at appropriate dosages and have limited our ability to utilize it in combination with anti-PD-1 therapy. What we've seen here is evalstotug providing similar PK exposure at 5 and 10 milligram per kilogram dosing levels to ipilimumab. So as I present this data, it's important to understand the thought that the 210 milligram is equivalent to 3 milligram per kilogram, and the 700 milligram is equivalent to 10 milligram per kilogram of traditional anti-CTLA-4 with ipilimumab. In our Phase I dose escalation and Phase II monotherapy portion of the study, you can see here the key eligibility is ECOG 0 or 1, anti-CTLA-4 naive, measurable disease and advanced unresectable or metastatic solid tumors in Phase II melanoma and carcinoma. And as we have begun treatment with single agent and then the red arrows coming into evalstotug plus nivolumab at 240 milligrams, you can see here, we are now up to tolerable doses at 700 milligrams, which is 10 milligrams per kilogram of anti-CTLA-4 therapy, along with 240 milligrams. So in the traditional doses that we use right now of ipilimumab at 3 milligrams and nivolumab at 1 milligram per kilogram, we are getting ipilimumab at 10 milligrams per kilogram. So CTLA-4, similar at 10 milligrams per kilogram, and then a 3 milligram per kilogram dosing of nivolumab. So we have now increased a single agent at 1,000 milligrams and have moved on to Phase II monotherapy. And as we've gone on, this is our demographics. You can see here that there are 21 patients with all of them having prior anti-PD-1 therapy. These are heavily pretreated patients with, you can see here, up to 6 prior lines of therapy, 7 prior in the lung cancer. And as we have followed them, we have found that this regimen is very tolerable. Most related adverse events were low grade. There is no Grade 4 or 5 events here. All -- there are 4 Grade 3-related events, CRS-like events with new onset atrial fibrillation and readily reversible hypertension have been seen. The immune-mediated adverse events have been hyperglycemia/DKA and Grade 1 lipase increases, including gastritis and diarrhea, with only 2 patients discontinuing due to adverse events, those are the atrial fibrillation and the gastritis. And when you look at the incidence of toxicities that we see common with the anti-CTLA-4 therapies, what we're seeing here is an indication of a more tolerable regimen as we have gone to the higher doses. Interestingly, in this early Phase I study where our main goal is to see tolerability and toxicity, we've been fortunate to see confirmed responses in 3 patients and stable disease in 8 patients amongst 19 evaluable patients. At the 350 milligram, which is consistent with 5 mg per kg, there was 1 CR and 2 partial responses, all confirmed. This is a complete response in a cervical cancer patient, partial response in gastric and melanoma, and there are multiple patients that have been dosed and tolerable for greater than a year, and one uveal melanoma patient ongoing for 9.8 months. And that has given us the ability to now move on to the Phase II portion, which is an open-label evalstotug in combination with PD-1 to look at patients with untreated Stage III unresectable or Stage IV melanoma. And this is at a 700 milligram dosing with pembrolizumab at its standard dose. And then evalstotug and pembrolizumab in chemotherapy in first-line Stage IV non-small cell lung cancer. We're looking for primary endpoints of response, adverse events and secondary endpoints of duration of response PFS. We're looking forward to accruing and presenting this data at upcoming meeting.

Wonderful. Thank you, Dr. Hamid. I'd like to now introduce Dr. Mangla. Dr. Mangla is the Co-Director of the Sarcoma and Cutaneous Oncology Disease team at University Hospitals Seidman in Cleveland. And he's an institutional PI on several trials. He's working with us on both our antibody-drug conjugate program as well as the CTLA-4 antibody. And we've invited him today to speak to some of his personal experiences on the trial, both including the Phase I and to review the overall findings that are evolving from the Phase II monotherapy across a wide variety of patients with very heavily pretreated cancers. Dr. Mangla?

Thank you, Dr. Sievers. Thank you so much for having me on this platform. Next slide, please. So I wanted to present to this. This is the very first patient we treated on this -- on the clinical trial. She actually started with the first baseline dose of 70 milligrams of evalstotug. And she initially had presented with the melanoma, Stage IIIB melanoma, which started on her nose. And that was resected by the surgeons with sentinel lymph node biopsy. She had multiple reconstructions that were happening in the nose and receiving an adjuvant therapy with an anti-PD-1 monotherapy. And then in the midst of all this, within 11 cycles, she started relapsing. So we took her to this trial, which was testing the monotherapy with this novel anti-CTLA-4. And with the first dose, we started seeing responses in the patient, which actually lasted until almost 7 months. And that was like the most -- the baseline dose of 70 milligrams, which is equivalent to ipi 1. And then we escalate -- then at the time of relapse, we -- there was a relapse that was happening on the inside of the nose, which we biopsied and we found out that, that was melanoma. Then we increased the dose to 210 milligrams, and we saw a response happening again. So this was -- this is something we know about anti-CTLA-4 behavior that they are -- so the responses to tumor is associated with the amount of anti-CTLA-4 you introduce, and we are seeing the same behavior with this newer drug. And she has been in response for over 1 year now, and we escalated dose to 350 monotherapy, which she has been receiving without any side effects. She has had some rash and an occasional diarrhea, which is Grade 1 and very tolerable, and we use mostly conservative measures to help her, which she has been tolerate -- but otherwise, she has been tolerating the drug pretty nicely, and she's approaching almost 2 years now. Clinically -- I mean, radiologically, that reconstructed flap is there, so you will always see some changes in her nose. But clinically speaking, she is completely like -- I think she's in complete clinical response at this point. I mean, one of the most important things I want to say over here is that this was something which was a life-changing event for her because at the time of the relapse, the surgeons offer to take away the nose and replace it with a prosthesis or a flap. And I can tell you from personal experience that this woman did not want that. Nobody wants the disfigurement of their face at any point of time. So -- but this drug has helped her to retain the sanctity of her face, facial features as well as giving her a complete response. Now one other thing about immunotherapy in general is that this is a kind of treatment that will create immune memory. So even at the end of 2 years, if there is a plan to stop the drug, we expect that she will probably stay in response for a very long time. But that's the beauty of the drug is that it can bring that kind of a response to the table and can keep the patient in that response for a very long time. But that is yet to be established, but we think that that's going to happen. I have also treated like other patients, melanoma patients, I principally treated melanoma in my clinic. So we treated almost 7 patients on this trial, and we have had complete responses. Also, and we actually have treated a patient with 700 milligram along with an anti-PD-1 most recently that are just beginning to get their first evaluations with, again, with minimal side effects. Everything is Grade 1, mostly limited to skin rashes and occasional chills after infusion, but everything very manageable. Nothing is preventing us from treating them -- continue the treatment. I mean, one of our patients is actually an Olympian and has participated in the Pan American Games recently and had a pole vaulting event, won a bronze medal, came for the infusion, and then went again next day for a 400-meter relay, and I got a message that he won a bronze there too. So I think you can imagine the amount of physical exertion that's involved in those things. And despite of taking an infusion smack in the middle at 700-milligram dose with an anti-PD-1 and dealing with a metastatic melanoma, he was still able to achieve all that, which kind of speaks for the efficacy and the tolerance of the drug. So that is something which I want to bring out is -- and one other thing I would like to say here, and I mean Dr. Hamid is here and he's much more senior to me, but I think one of the biggest advantages -- I'll tell this to my fellows is that if Jim Allison received a Nobel Prize for developing ipilimumab for that effort, then he deserved it because that kind of a drug, it can be given in any place in the world, and all you need is an infusion center and a well-trained nurse to give the drug. You don't need -- there are other molecules out there, there are other therapies out there, which are developing in melanoma, but they are very resource-intensive. But this is a drug that can overshadow the existing anti-CTLA-4s and still be given in those areas where the reach of this drug will be in those areas where resources are not that many. So that's something which I wanted to say about evalstotug. So next slide, please. And as you can see in the monotherapy cohort, we have enrolled like 17 patients in the 350-milligram cohort and 2 patients in the 700-milligram so far that are being evaluated. Equal distribution amongst men and women. And ECOGs were also equally distributed amongst ECOG 0 and 1. 11 patients had prior anti-PD-1 therapy in the 350-milligram monotherapy cohort, and 1 patient had a prior anti-PD1 in the 700-milligram cohort. And as you can see, there are a multitude of cancers that have been treated over here, including the adenocarcinoma of adrenal gland, which is a pretty rare cancer, cholangiocarcinomas, metastatic acral lentiginous melanomas and heavily pretreated melanomas and sertoli cell cancer. Some of these are -- pleomorphic adenoma of sphenoid sinus. Some of these are extremely rare tumors, like you don't have many classical therapies or standard-of-care therapies for these kind of glands and -- for these kind of cancers. And when they come to our clinic, I mean, we often wonder -- we often look back at limited literature, retrospective studies to treat some of these tumors. But -- and again, like the heavily pretreated population in melanoma that has responded also with radiological responses have been seen in this monotherapy cohort. So next slide, please. And the grade -- so we have not encountered any Grade 3 or 4 colitis. We have not had any Grade 4 or 5 adverse event during the entire trial. The only Grade 3 event that is listed over here is the cytokine release syndrome in the monotherapy cohort with 350 milligrams, and then no Grade 3 event was seen in the 700 milligrams. Now one interesting thing about the cytokine release, Grade 3 CRS event in the 350-milligram monotherapy cohort was that this was happening in a patient who already had adrenal insufficiency. So just to give a background on that is that adrenal glands make steroids for all of us, right? So when we have stress responses, the ideal responses for the adrenal gland to start pumping a little bit more steroid, but that's not happening in a patient who has insufficiency already for whatever reason, prior checkpoint inhibitor therapy or whatnot, but then that kind of leads to excessive hypotension, excessive drop in the blood pressure, which can be mimic a more severe CRS. So that's a confounding factor over there because if you see, out of the 17 patients we treated on 350-milligram cohort and 2 patients in the 700 cohort, everybody had a little bit of chills and fever, which kind of led to early Grade 1 or Grade 2 CRS, but never a Grade 3 CRS. But other than that, we have not registered any Grade 3 event, which is excellent. I mean, one of the biggest limitations of giving ipi in clinic despite of being a go-to drug for melanoma is, of course, the Grade 3, Grade 4 events, which if you look back at the CheckMate 067 trial, many patients dropped out of treatment after using ipi 3 dose. There, we are giving 350 and 700 doses without interruptions and continuing treatment. And ipi, if you'll -- again, at CheckMate 067, we have to stop ipi after 4 cycles, whereas these patients continue getting treatment even beyond 4 cycles and beyond. So that kind of talks about the promise of the drug and the off-target, the reduction in off-target toxicity, which talks about the quality of life that the patient will enjoy. Next slide, please. And like I said, I mean, these are -- again, this is a monotherapy overview, which talks about the Grade 3, Grade 4 events, and no -- again, serious adverse events were amongst 4, and one was directly related to the drug. But again, there is no adverse event leading to treatment discontinuation or adverse event leading to death in the patient. And most adverse events were low grade, which, again, I'm saying this is no Grade 3 -- Grade 4 or 5 event. 10 stable diseases were seen across 14 different cancer types. 6 patients had prior anti-PD-1 treatment, of which 1 with ipilimumab and 1 with relatlimab. And there was BRAF-negative patients who had treatment -- BRAF-negative melanoma patient who had a treatment with nivolumab, NKTR-214, and from May to June -- from May '21 to June '22 and like nivo, ipi and sarilumab in June to November '23. But despite of that, like they had a good response like after that. So the crux of the slide is basically we have had a lot of stable disease, good responses and mostly very, very minor side effects, which speak for the efficiency of the drug. Next slide. So in conclusion, we have high doses of evalstotug are associated with manageable safety that allow patients to continue treatment for extended intervals. And we have encountered low incidence and severity of immune-related adverse events, which were observed in our Phase I and Phase II experience. And multiple patients have experienced prolonged progression-free survival with some more than 40 weeks also, and confirmed responses were observed in patients receiving high doses. And now we have our Phase II dose, which is -- Phase II study, which is exploring 700-milligram dose with pembrolizumab in the first-line non-small cell lung cancer and melanoma, which is currently enrolling and open multiple institutions, including ours. Thank you.

Wonderful. Thank you. I want to thank all of our investigators and experts for joining us today.

And we're now in the question-and-answer period. If each of the investigators could return to the screen, then I will distribute questions. And the first question comes from Kaveri Pohlman at BTIG, and this is for Dr. Yau. Dr. Yau, can you share your thoughts on how you expect efficacy of mecbotamab vedotin in patients who have been pretreated with KRAS inhibitors versus KRAS naive patients? Go ahead, please.

Yes. So there is some preclinical data looking at AXL expression in G12C inhibitor resistance. So it does seem like it's a mechanism -- it's a potential mechanism of resistance to that class of medications. And so in the data we presented, I believe there was one patient who was one of the partial responses that had prior sotorasib exposure. So definitely, you could see in the small data set, at least one responder who had previously received a G12C inhibitor. And there's ongoing preclinical studies looking at AXL expression where it starts to be up-regulated in that whole treatment phase. But yes, given the mechanism, I would expect there would be some responders to even after G12C inhibitor.

Excellent. And I have another follow-up question from Kaveri Pohlman. Can you share any additional thoughts on the median duration of response at 4.8 months as a point estimate? And then how does it compare with currently available treatment options?

Yes. So I think, obviously, this is a preliminary data set without a lot of numbers. But duration of response here is perhaps a smidge lower than with the second-line G12C inhibitors. I think the duration of response there was more around 7, 8 months. But if you compare progression-free survival and overall survival, pretty similar, compares favorably with the second-line G12C inhibitors. Obviously, this is an exploratory analysis with limited numbers. So I would say that preliminary data-wise, it looks like there's a possible signal. Obviously, there's a lot more work to dissect out, maybe perhaps which subset of KRAS mutants might have the best chances of response and, obviously, more numbers with -- these are very small numbers right now for comparing across trials, which is always dangerous. But I would say the preliminary is somewhat promising compared to the G12C inhibitors.

And Dr. Yau, just continuing with this theme, Brian Cheng of JPMorgan was wondering where this AXL-ADC might fit into the treatment paradigm for KRAS patients. You've touched on this. But Brian was also wondering if you could help walk us through how you think about KRAS and how this ADC then interacts and how we tackle the KRAS segment in non-small cell lung cancer.

Yes. So obviously, the KRAS segment in recent years with the direct inhibitors has changed. It's definitely a heterogeneous group. So I think going forward, we're always very interested in kind of finding this -- KRAS is not one monolithic disease, but KRAS, I mean, lung cancer is very heterogeneous. And so finding the exact subset that benefits the most is, whether it's immunotherapy or targeted therapies or antibody drug conjugates, is important. So I think there's a lot to dissect out there in the landscape. And for right now, we'd be looking at third -- second, third line and beyond in this setting, depending on the specific KRAS mutation. Obviously, we have limited KRAS mutations that we can directly target. And so I think understanding more about the biology would be useful here and where to slot it and where to target this ADC. But certainly, AXL is also implicated in immunotherapy resistance. We know there are a lot of patients with KRAS mutations that respond well to immunotherapy. But we're always looking for options for patients who progress on immunotherapy. And so AXL has also been studied in mouse models of KRAS mutant lung cancer and has been shown as a potential mechanism of resistance to PD-1 inhibitors, especially in some of the sub -- genomic subsets of KRAS mutants that respond poorly to immunotherapy.

And I know we're peppering you with most of these questions, Dr. Yau, but I'll give one more and then we'll move to CTLA-4 and then back. This question comes from Dev Prasad from Jefferies. What is the percentage of mutated KRAS patients that have AXL expression? And then building on that as well, how many patients' worth of data do you think will help determine the efficacy in this patient population?

Yes. I mean that's also my question. So I think there, BioAtla is looking at the screening and looking through the mutation data to see how many of these patients have AXL positivity. In the literature, a lot of these studies are done without -- we don't see a lot of AXL mutations in lung cancer. And so I don't have a lot of data in terms of how many -- what percentage of patients are AXL-positive. Obviously, with all of these assays, the question is always, what antibody is the right one and how do you determine what a sufficient amount of expression is? So most of these studies have been looking at treatment response, looking at AXL expression after a certain treatment and up-regulation. So I don't have the data off hand on how many might be -- what percentage of mutant KRAS patients. And I think BioAtla is looking at -- trying to tease that out a little bit. And I know in this limited cohort, I believe, all kind of limited KRAS mutants, but all of whom I think were AXL high. And obviously, we need to look closer at the data.

Wonderful. Thank you. Let's shift over to CTLA-4 now. And this is a question for Dr. Hamid, if I could, please. And this comes from Kaveri Pohlman at BTIG. Dr. Hamid, can you share your thoughts on RELATIVITY-038 -- 048 data? And what you think about the addition of LAG-3 to CTLA-4 and PD-1 combination, especially in patients with BRAF mutations?

Yes, sure. Not quite the scope of this presentation, but an interesting thought. So let me bring it back to what we're doing here. If you look at the anti-CTLA-4 dosing there, it is a very low dosing. It is 1 milligram every 8 weeks. So barely they're dosing. And most of us feel that what we're lacking is the ability to get CTLA-4 in combination in appropriate dosing. And so clearly, in response to the tox, the dose of ipilimumab there has been decreased so much. And what we're looking for here is to -- the ability to reintroduce appropriate doses of anti-CTLA-4 in the melanoma paradigm so that we do not overlook its effectiveness and efficacy.

Thank you. And continuing on that theme, Reni Benjamin from Citizens JMP asks, what would be the next step for commercialization of evalstotug? Maybe Dr. Hamid and then Dr. Mangla, you can add if you choose?

Yes, I'm very interested in seeing how this Phase II combination untreated compares with what we have seen historically with the CheckMate 067 data and the RELATIVITY-047 data. And then what it would lead to is a likely a randomized Phase III.

Thank you. Dr. Mangla?

Yes. No, I completely agree with Dr. Hamid. I mean, this is an exciting molecule and I think one of the futuristic molecules where one of the biggest limitations, like I said before, with CTLA-4 was that not being able to continue with the treatment in most of the patients. And I think one thing, one of my experiences in treating a large number of melanoma patients on a Phase I setting especially is that we did not have to discontinue the drug. And that kind of speaks for one of the biggest advantages of using an anti-CTLA-4. Now comparing to an anti-LAG-3 molecule, of course, we know that anti-CTLA-4 molecules have more efficiency than anti-LAG-3. I mean, if you look at the exposure data out there, like previously treated patients -- LAG-3 patients treated with anti-CTLA-4 and vice versa, you can kind of make out like not a statistical model, but you can make out -- like it gives you an impression that anti-CTLA-4 may be more effective than anti-LAG-3. And when you -- and this is like already approved drugs. Now when you have a molecule like this that is not giving you side effects that you can continue throughout and possibly has enough efficiency in it and almost even replicating what is there on the market and maybe even better, then you are excited about the future of this molecule and maybe becoming the next standard of care. So as everybody on the call is saying like we are looking forward to Phase II data as well as opening a much larger Phase III trial and in various cancers, especially immunogenic cancers like melanoma and lung cancer.

Thank you. Thank you both. And sticking with evalstotug, there's an interesting question about if there's an opportunity to move into earlier lines. Now we certainly are using it in the early lines in non-small cell lung cancer and melanoma. But maybe each of you could share some thoughts on where you'd like to see a better-tolerated CTLA-4 across the board.

Yes. What I would say to you is that CTLA-4 has shown efficacy in other solid tumors and including renal. The immunotherapeutic paradigm is important in other skin cancers and may have been overlooked in the 19 cancers where checkpoint inhibition is important. And clearly, if we can get appropriate dosages in combination, it would be appropriate to return to look at them in all of those tumors. We've chosen lung cancer and melanoma, but obviously, endometrial cancers and other squamous cancers, gastric, esophageal, et cetera, would be an open look. And we've seen that response to cervical cancer and gastric cancer already.

Thank you. Excellent. Dr. Mangla?

Yes. So again, I mean, I completely agree with Dr. Hamid. But this is -- I think, in my opinion, one of the biggest limitations of the existent anti-CTLA-4 was a dosing issue. So if you look at other trials, lung cancer trials or cervical cancer trials, I think ipi 3 has not been evaluated as much as it should have been, whether it is side effects, discontinuation rate or whatever it is. I mean, I think there is a potential here where we can explore a higher dose of anti-CTLA-4 in these other cancers and see exactly what it brings to the table. So there is a very high scope of this molecule being explored at higher doses, which may be efficacious in other cancers and may even -- like some of these are very immunogenic cancers and may respond better in the future. But of course, it will all need to be shown in a proper clinical trial. So -- but that is -- it is showing -- the molecule currently is showing all the features that can be explored in other cancers.

Wonderful. Thank you both. I appreciate that. The next question for Dr. Yau, and this comes from Arthur He from H.C. Wainwright. And the question is, as you've looked across the dosing intensity of the every-other-week dosing and the days 1 and 8 dosing on a 3-week cycle, what is your impression of the toxicity differences and the benefit of those 2 regimens in moving forward?

I don't think they saw much difference. Obviously, the every-2-week is a little bit more convenient. And so I believe that's the dose that's going forward since the response rates didn't look much different, but both seem tolerable.

Okay. Excellent. And then another question. Do you perceive any clinical benefit of the AXL-ADC in AXL-negative patients from the data you presented today?

Again, I think that -- I don't recall if -- I know on the analysis of all the non-squamous, we didn't see any responders that were AXL-negative. But obviously, looking for AXL expression makes it a bit more difficult if you need to find the -- so I think the argument in the antibody-drug conjugate drug development is whether we need to test for the target or do testing agnostic. And obviously, you can treat more patients if it's agnostic. I think if there's an alternative biomarker, so the KRAS data is intriguing since we always get KRAS mutation status. If we don't have to then test again for AXL, if we can establish that sufficient amount of these AXL-positives, just sort of like DLL3 in small cell where initially we were testing and ultimately ended up without needing to test. So I think antibody-drug conjugates always make sense to look for the targets. But in practical -- clinical practice would be nice if we could identify the subset that would benefit that we can identify with our standard-of-care testing already without having to look for another biomarker to add on top, but certainly reassures us when we find the target for the antibody-drug conjugate clinically. But...

Excellent. So it sounds like the KRAS finding, if it matures, might then represent a reasonable way to identify patients likely to benefit from the ADC much easier than the immunohistochemistry for AXL. So very good. I'd like to conclude the question-and-answer session here. Much appreciated to the 3 investigators who joined us today to provide their insights on the drugs that we're testing, our technology and their vision for how we can better help cancer patients in the future. And I'd like to offer Jay, if you'd like to make any closing comments before we close the call?

I'll just thank everyone for joining today, and we're very much looking forward to continuing to update you in not only in our earnings call in August, but also at ESMO in September. So looking forward to further communication in the near future. Thank you for attending.

Wonderful. Thanks.