Bispecific Antibody Inhibiting PD-1 and CTLA-4 Demonstrates Effectiveness Against Advanced Kidney Cancer in Early Study - Martin Voss
November 22, 2023
Pedro Barata engages in a discussion with Martin Voss about volrustomig, a novel PD-1/CTLA-4 bispecific antibody for advanced clear cell RCC. Dr. Voss provides an overview of volrustomig, highlighting its unique ability to inhibit PD-1 and selectively bind CTLA-4 on cells co-expressing both receptors, aiming for targeted action in the tumor microenvironment. He reviews the dose-finding study's progression, noting the shift to lower doses (500 and 750 milligrams) due to high efficacy but limiting toxicity at higher levels. Dr. Voss shares that both doses showed promising efficacy, with response rates in the 40s and lower progressive disease rates compared to standard treatments. However, he notes a dose-dependent increase in treatment-related adverse events. Looking ahead, Dr. Voss mentions ongoing trials combining volrustomig with other therapies and its development in various cancers beyond RCC. Drs. Barata and Voss conclude by emphasizing the importance of balancing efficacy and tolerability in novel cancer treatments.
Biographies:
Martin Voss, MD, Medical Oncologist, Clinical Director, Genitourinary Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York City, NY
Pedro C. Barata, MD, MSc, Associate Professor of Medicine at Case Western University and the Director of Clinical Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, Cleveland, OH
Biographies:
Martin Voss, MD, Medical Oncologist, Clinical Director, Genitourinary Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York City, NY
Pedro C. Barata, MD, MSc, Associate Professor of Medicine at Case Western University and the Director of Clinical Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, Cleveland, OH
Read the Full Video Transcript
Pedro Barata: Hi there. My name is Pedro Barata. I'm a GU oncologist at the Seidman Cancer Center, University Hospitals, Case Western Reserve University in Cleveland, Ohio. I'm so happy to be joined today by Dr. Martin Voss, a big kidney cancer expert and researcher out of Sloan Kettering in New York. Martin, welcome again.
Martin Voss: Thank you, Pedro. Always good talking to you and thanks for the invitation.
Pedro Barata: Absolutely. Congratulations on the great work, great presentation at this last ESMO. You talked this time about Volrustomig, which is a novel PD-1/CTLA-4 bispecific antibody. We've seen a little bit of data on that, but I think it's quite remarkable the data on the new doses that you've presented at ESMO. So perhaps, let's start there, and let me ask you, do you mind providing some kind of introduction or context to the folks who are hearing us who might be less familiar with this compound. Can you tell us what led you to this dose-finding study?
Martin Voss: Yes, of course. It's my pleasure. So, I presented the data on behalf of a group of investigators at the ESMO meeting in Madrid just a few weeks ago. So let's talk a little bit about Volrustomig. So we've heard a little bit about this compound now in recent years, as it's been in development across a number of different entities. And we have previously shown some kidney data also, that I can remind the audience of. So this is a drug previously called MEDI5752. It just got its name now as the generic name being Volrustomig. And this is a monovalent bispecific antibody that inhibits both PD-1 and CTLA-4, which obviously is an important set of targets in RCC based on all the data we've seen from the ipi/nivo program. So what's unique about this bispecific antibody is that it fully inhibits PD-1 on its target cells, but it binds to CTLA-4 preferentially on cells that co-express both receptors. And why was that done? So it is meant to specifically bind cells in the tumor microenvironment and less so cells in the periphery, where there should be fewer cells co-expressing both. And with that, it is meant to be more targeted towards the relevant cells in the vicinity of the cancer. And it's supposed to be more tolerable by activating fewer naive T cells in the periphery. Now this drug has been under development, like I said, for some time.
The dose escalation has been reported upon and even the expansion cohorts have been, so those escalations have been completed and went all the way from two and a quarter milligrams up to 2500 milligrams. And we had previously presented data from an expansion cohort in IO-naive, clear cell RCC that was conducted at the 1500 milligram cohort level. Dr. Louis presented that data last year at ESMO. And what we had seen at the time for clear cell RCC was a high level of efficacy, almost 60% response rates, CRs, low upfront failure rate, and so forth. But a toxicity profile that was limiting at that dose level with a high percentage of patients discontinuing therapy for treatment-emergent adverse events. And with that then, we went back and performed additional expansion cohorts at lower dose levels. Because at the same time, what had happened was that more pharmacodynamic data had emerged from the dose escalation efforts. And the team at AstraZeneca had figured out that biologically relevant doses of CTLA-4 inhibition were clearly demonstrable at dose levels of 500 milligrams and up. So the two dose cohorts that we presented at ESMO this year were flat dosing of 500 milligrams every three weeks and flat dosing of 750 milligrams every three weeks.
Pedro Barata: So let me ask you, Martin, I mean, great context. Thank you for that. So literally, as you said, it's very interesting because you're really showing this data with 500 and 750. You have about 3000 patients in each one of those cohorts, right? And I'll let you summarize what, to you, are the take-home points. I took it like, responses in the very high 40s. One interesting aspect to me was actually the lower progressive disease rates. It's from almost half to what we're trying to think when we're expecting with... For example, the ipi/nivo, right? So about half of that. And also, I'd love to hear a little bit about what you have to say about the safety profile for these new two doses, right? Thoughts about that?
Martin Voss: Yeah, I think you're absolutely right, Pedro. So the efficacy bar that we are looking at is set by Ipilimumab and Nivolumab, which is very well-defined from all the data we've seen come out of CheckMate 214. And we know that with standard Ipilimumab in the front line, we achieved objective responses at around 40%. But we do see that a fifth up to a quarter of patients do not benefit from that regimen and suffer primary disease progression, right? The PD rate is 20% and higher. And those were the things we were interested to see here. This is obviously early development of this compound in this disease. But we are keenly interested to see, can we hit similar or better response rates and lower failure rates. And then, secondly, look at the toxicity. So, at 750 and 500, the responses were each in the 40s, and there were CRs seen on both dose levels. The PD rate was different across the two dose levels in that there was a lesser PD rate at the higher dose. It was 750 milligrams at a 12% upfront PD rate, 24% at 500 milligrams. And similarly, the CR rate was a little bit higher also with the higher doses. So there was the sense that dose matters in terms of efficacy. If we look at other efficacy endpoints, selling points to Ipilimumab, CTLA-4 PD-1 inhibition, obviously being durability of responses. And we could see with limited follow-up, and we have more follow-up for the 750 cohort than the 500, that these responses for the time that we have are primarily durable.
We have very nice spider plots that we showed during the presentations where you could see that. I think it's too early for us to look at median time to response, because we're not so far into the follow-up. And then your second question was about toxicity. So, the toxicity had been dose-limiting at the 1500 milligram level that we presented last year. And both cohorts looked a lot better than that, but still had quite a bit of treatment-related adverse events. So grade three, four events, treatment-emergent, were about 75%, 63% for the 750 and 500. And then people-related adverse events that were high grade was about 60% for the higher dose, 750, and about 33% for the lower dose, 500. Discontinuation rate, when we presented last year at the very high dose of the 1500 milligrams, over 70% of patients discontinued due to related adverse events. Here, that has come down considerably. It's down to about 40% with 750, and 30% with 500. So, what's interesting to see is that treatment toxicity with this, and I think it's the CTLA-4 inhibition that drives this, is dose-dependent truly. If we look at last year's data, and then these two cohorts, you can see the tox space go up, the discontinuation rate go up as you go from 500 to 750 to 1500. Which is exactly what we saw when we did dose escalation for Ipilimumab back in the day. And we tend to see a sense that the efficacy tracks with that a little bit.
Pedro Barata: Right, no that's fantastic. I mean, it sounds like you guys found the dose that is manageable and can be further developed as the drug development for this program moves forward. So I guess my last question, Martin, before I let you go, is can you tell us a little bit about what the plans are for the future? I mean, this is being explored. You explored this now in the frontline setting, right? Obviously, we're seeing an emergence of many different combination approaches. I would say probably combination is something very interesting to explore. Can you tell us a little bit about what are the plans for the Volrustomig program?
Martin Voss: Yes. Yeah, of course. So for the monotherapy, we are following these cohorts, right, the median follow-up. I mentioned this before, it's fairly short. So it'll be interesting to see how these patients fare. A lot of the discontinued patients, for instance, have not started any other therapy yet. So the median time of duration for patients who have come off therapy has not been reached. And less than half of those patients have had to start other therapies, right? This speaks a little bit to the treatment-free survival data from CheckMate 214. So, I think it'll be interesting to see what happens with these patients. My impression is that for single-agent development, 750 is the way to go, because I think it sort of keeps that balance of high efficacy, which looks promising compared to the historical controls of it being evil, and manageable toxicity in my experience. For combination, and we spoke to that briefly only at the session because it was a very short presentation.
This is now being paired with TKI therapy in the frontline. So there's a dose-escalating trial that has been growing for some time now, that pairs this agent with Lenvatinib. So effectively, it's triplet therapy by target, although it's only two drugs, right? So, VEGF TKI plus PD-1 plus CTLA-4. And that is ongoing internationally. So there are centers in Europe, the US, Australia that are contributing to that study, and it's been a great collaboration. Happy to be a part of that also. Programmatically for the drug, Volrustomig beyond RCC is being developed actually already in the phase three space. So there is a phase three trial, a randomized study going on in non-small cell lung cancer, one in head and neck cancer, and one in the GYN malignancies. And those are looking at combinations and single-agent therapy. So clearly, the drug is going places beyond RCC.
Pedro Barata: Right. It's so exciting, right? I mean, we're always trying to optimize the potential for these durable remissions, as you may name it, right? So it's important to look at the long-term results for the patients who receive these novel bispecific combo drugs. So I completely agree with you. Let's see what the utility curve looks like for the monotherapy. And then, it's so exciting to explore novel combinations and see if we can get the balance between greater efficacy and tolerability. Martin, it has been a pleasure as always to get your insights. Thank you so much for breaking it down for us. Very, very exciting data about these compounds. And again, congrats on your fantastic presentation, and I'm looking forward to chatting with you again soon.
Martin Voss: Okay, well, great. Thank you so much for all your questions, for your interest in our data, and of course, for having me on the program. It's always a pleasure. And looking forward to seeing you real soon.
Pedro Barata: Thank you.
Pedro Barata: Hi there. My name is Pedro Barata. I'm a GU oncologist at the Seidman Cancer Center, University Hospitals, Case Western Reserve University in Cleveland, Ohio. I'm so happy to be joined today by Dr. Martin Voss, a big kidney cancer expert and researcher out of Sloan Kettering in New York. Martin, welcome again.
Martin Voss: Thank you, Pedro. Always good talking to you and thanks for the invitation.
Pedro Barata: Absolutely. Congratulations on the great work, great presentation at this last ESMO. You talked this time about Volrustomig, which is a novel PD-1/CTLA-4 bispecific antibody. We've seen a little bit of data on that, but I think it's quite remarkable the data on the new doses that you've presented at ESMO. So perhaps, let's start there, and let me ask you, do you mind providing some kind of introduction or context to the folks who are hearing us who might be less familiar with this compound. Can you tell us what led you to this dose-finding study?
Martin Voss: Yes, of course. It's my pleasure. So, I presented the data on behalf of a group of investigators at the ESMO meeting in Madrid just a few weeks ago. So let's talk a little bit about Volrustomig. So we've heard a little bit about this compound now in recent years, as it's been in development across a number of different entities. And we have previously shown some kidney data also, that I can remind the audience of. So this is a drug previously called MEDI5752. It just got its name now as the generic name being Volrustomig. And this is a monovalent bispecific antibody that inhibits both PD-1 and CTLA-4, which obviously is an important set of targets in RCC based on all the data we've seen from the ipi/nivo program. So what's unique about this bispecific antibody is that it fully inhibits PD-1 on its target cells, but it binds to CTLA-4 preferentially on cells that co-express both receptors. And why was that done? So it is meant to specifically bind cells in the tumor microenvironment and less so cells in the periphery, where there should be fewer cells co-expressing both. And with that, it is meant to be more targeted towards the relevant cells in the vicinity of the cancer. And it's supposed to be more tolerable by activating fewer naive T cells in the periphery. Now this drug has been under development, like I said, for some time.
The dose escalation has been reported upon and even the expansion cohorts have been, so those escalations have been completed and went all the way from two and a quarter milligrams up to 2500 milligrams. And we had previously presented data from an expansion cohort in IO-naive, clear cell RCC that was conducted at the 1500 milligram cohort level. Dr. Louis presented that data last year at ESMO. And what we had seen at the time for clear cell RCC was a high level of efficacy, almost 60% response rates, CRs, low upfront failure rate, and so forth. But a toxicity profile that was limiting at that dose level with a high percentage of patients discontinuing therapy for treatment-emergent adverse events. And with that then, we went back and performed additional expansion cohorts at lower dose levels. Because at the same time, what had happened was that more pharmacodynamic data had emerged from the dose escalation efforts. And the team at AstraZeneca had figured out that biologically relevant doses of CTLA-4 inhibition were clearly demonstrable at dose levels of 500 milligrams and up. So the two dose cohorts that we presented at ESMO this year were flat dosing of 500 milligrams every three weeks and flat dosing of 750 milligrams every three weeks.
Pedro Barata: So let me ask you, Martin, I mean, great context. Thank you for that. So literally, as you said, it's very interesting because you're really showing this data with 500 and 750. You have about 3000 patients in each one of those cohorts, right? And I'll let you summarize what, to you, are the take-home points. I took it like, responses in the very high 40s. One interesting aspect to me was actually the lower progressive disease rates. It's from almost half to what we're trying to think when we're expecting with... For example, the ipi/nivo, right? So about half of that. And also, I'd love to hear a little bit about what you have to say about the safety profile for these new two doses, right? Thoughts about that?
Martin Voss: Yeah, I think you're absolutely right, Pedro. So the efficacy bar that we are looking at is set by Ipilimumab and Nivolumab, which is very well-defined from all the data we've seen come out of CheckMate 214. And we know that with standard Ipilimumab in the front line, we achieved objective responses at around 40%. But we do see that a fifth up to a quarter of patients do not benefit from that regimen and suffer primary disease progression, right? The PD rate is 20% and higher. And those were the things we were interested to see here. This is obviously early development of this compound in this disease. But we are keenly interested to see, can we hit similar or better response rates and lower failure rates. And then, secondly, look at the toxicity. So, at 750 and 500, the responses were each in the 40s, and there were CRs seen on both dose levels. The PD rate was different across the two dose levels in that there was a lesser PD rate at the higher dose. It was 750 milligrams at a 12% upfront PD rate, 24% at 500 milligrams. And similarly, the CR rate was a little bit higher also with the higher doses. So there was the sense that dose matters in terms of efficacy. If we look at other efficacy endpoints, selling points to Ipilimumab, CTLA-4 PD-1 inhibition, obviously being durability of responses. And we could see with limited follow-up, and we have more follow-up for the 750 cohort than the 500, that these responses for the time that we have are primarily durable.
We have very nice spider plots that we showed during the presentations where you could see that. I think it's too early for us to look at median time to response, because we're not so far into the follow-up. And then your second question was about toxicity. So, the toxicity had been dose-limiting at the 1500 milligram level that we presented last year. And both cohorts looked a lot better than that, but still had quite a bit of treatment-related adverse events. So grade three, four events, treatment-emergent, were about 75%, 63% for the 750 and 500. And then people-related adverse events that were high grade was about 60% for the higher dose, 750, and about 33% for the lower dose, 500. Discontinuation rate, when we presented last year at the very high dose of the 1500 milligrams, over 70% of patients discontinued due to related adverse events. Here, that has come down considerably. It's down to about 40% with 750, and 30% with 500. So, what's interesting to see is that treatment toxicity with this, and I think it's the CTLA-4 inhibition that drives this, is dose-dependent truly. If we look at last year's data, and then these two cohorts, you can see the tox space go up, the discontinuation rate go up as you go from 500 to 750 to 1500. Which is exactly what we saw when we did dose escalation for Ipilimumab back in the day. And we tend to see a sense that the efficacy tracks with that a little bit.
Pedro Barata: Right, no that's fantastic. I mean, it sounds like you guys found the dose that is manageable and can be further developed as the drug development for this program moves forward. So I guess my last question, Martin, before I let you go, is can you tell us a little bit about what the plans are for the future? I mean, this is being explored. You explored this now in the frontline setting, right? Obviously, we're seeing an emergence of many different combination approaches. I would say probably combination is something very interesting to explore. Can you tell us a little bit about what are the plans for the Volrustomig program?
Martin Voss: Yes. Yeah, of course. So for the monotherapy, we are following these cohorts, right, the median follow-up. I mentioned this before, it's fairly short. So it'll be interesting to see how these patients fare. A lot of the discontinued patients, for instance, have not started any other therapy yet. So the median time of duration for patients who have come off therapy has not been reached. And less than half of those patients have had to start other therapies, right? This speaks a little bit to the treatment-free survival data from CheckMate 214. So, I think it'll be interesting to see what happens with these patients. My impression is that for single-agent development, 750 is the way to go, because I think it sort of keeps that balance of high efficacy, which looks promising compared to the historical controls of it being evil, and manageable toxicity in my experience. For combination, and we spoke to that briefly only at the session because it was a very short presentation.
This is now being paired with TKI therapy in the frontline. So there's a dose-escalating trial that has been growing for some time now, that pairs this agent with Lenvatinib. So effectively, it's triplet therapy by target, although it's only two drugs, right? So, VEGF TKI plus PD-1 plus CTLA-4. And that is ongoing internationally. So there are centers in Europe, the US, Australia that are contributing to that study, and it's been a great collaboration. Happy to be a part of that also. Programmatically for the drug, Volrustomig beyond RCC is being developed actually already in the phase three space. So there is a phase three trial, a randomized study going on in non-small cell lung cancer, one in head and neck cancer, and one in the GYN malignancies. And those are looking at combinations and single-agent therapy. So clearly, the drug is going places beyond RCC.
Pedro Barata: Right. It's so exciting, right? I mean, we're always trying to optimize the potential for these durable remissions, as you may name it, right? So it's important to look at the long-term results for the patients who receive these novel bispecific combo drugs. So I completely agree with you. Let's see what the utility curve looks like for the monotherapy. And then, it's so exciting to explore novel combinations and see if we can get the balance between greater efficacy and tolerability. Martin, it has been a pleasure as always to get your insights. Thank you so much for breaking it down for us. Very, very exciting data about these compounds. And again, congrats on your fantastic presentation, and I'm looking forward to chatting with you again soon.
Martin Voss: Okay, well, great. Thank you so much for all your questions, for your interest in our data, and of course, for having me on the program. It's always a pleasure. And looking forward to seeing you real soon.
Pedro Barata: Thank you.