5-Year Survival Outcomes in Cisplatin-Ineligible Patients from EV-103 - Jonathan Rosenberg
November 4, 2024
Alicia Morgans hosts Jonathan Rosenberg to discuss the five-year outcomes from EV-103 Cohort A, examining enfortumab vedotin plus pembrolizumab in cisplatin-ineligible advanced urothelial cancer patients. The conversation highlights unprecedented long-term results, with over 40% of patients alive at five years—a dramatic improvement from historical survival rates of approximately 3% with traditional chemotherapy. The discussion explores the durability of responses, with many patients maintaining ongoing responses past four years without additional therapy, suggesting potential disease-modifying or even curative effects in some cases. Dr. Rosenberg emphasizes how this combination therapy may be transforming the natural history of advanced urothelial cancer, potentially surpassing outcomes seen in other solid tumors. Drs. Rosenberg and Morgans conclude by discussing the implications for future treatment approaches and the need to consider survivorship care for this previously poor-prognosis population.
Biographies:
Jonathan Rosenberg, MD, Chief, Genitourinary Oncology Service, Division of Solid Tumor Oncology, Enno W. Ercklentz Chair, Memorial Sloan Kettering Cancer Center, New York, NY
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Biographies:
Jonathan Rosenberg, MD, Chief, Genitourinary Oncology Service, Division of Solid Tumor Oncology, Enno W. Ercklentz Chair, Memorial Sloan Kettering Cancer Center, New York, NY
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Related Content:
ESMO 2024: Study EV-103 Dose Escalation/Cohort A: 5y Follow-Up Of First-Line Enfortumab Vedotin + Pembrolizumab in Cisplatin-Ineligible Locally Advanced Or Metastatic Urothelial Carcinoma
EV-103 Study Update: Impressive Four-Year Data on Enfortumab Vedotin and Pembrolizumab Combination in Urothelial Cancer - Shilpa Gupta
ESMO 2024: Study EV-103 Dose Escalation/Cohort A: 5y Follow-Up Of First-Line Enfortumab Vedotin + Pembrolizumab in Cisplatin-Ineligible Locally Advanced Or Metastatic Urothelial Carcinoma
EV-103 Study Update: Impressive Four-Year Data on Enfortumab Vedotin and Pembrolizumab Combination in Urothelial Cancer - Shilpa Gupta
Read the Full Video Transcript
Alicia Morgans: Hi, I'm so excited to be here today with Professor Jonathan Rosenberg, who is joining me from Memorial Sloan Kettering after a wonderful presentation at ESMO 2024, where he gave us an update on EV-103 Cohort A and some five-year outcomes. Thank you so much for being here, and please take it away.
Jonathan Rosenberg: Thank you so much, Alicia. It's great to be here to talk and update people about the five-year outcomes. In the first trial of Enfortumab and Pembrolizumab, people remember, this data was initially presented with a 73% response rate at ESMO just about five years ago. And so, here we're presenting the five-year update of the outcomes of patients in this first trial of Enfortumab Vedotin and Pembrolizumab in cisplatin-ineligible, locally advanced or metastatic urothelial cancers.
And just to level set here, we expect patients who received gemcitabine and carboplatin to have a response rate of about 40%, and median survival of anywhere from 10 to 14 months at the longest.
And in the modern era, they might get avelumab maintenance, so they probably would do better if they responded, but if they didn't respond, their outcomes are pretty dismal.
So the first study showed a response rate of 73%, but we really haven't seen any sort of individual patient data looking at what happened to patients on this initial cohort. And so we see here this is the time-to-response and duration-of-response. And the green arrows show ongoing responses, and we see that many patients who responded, probably about 30% of them, have ongoing responses past four years. This is something we hadn't seen before in patients treated with carboplatin-based chemotherapy. And the responses, in general, are very fast. We also see that the duration of therapy didn't go much past two years here. That's included by the dark lines. And so, these are patients who we expected to do relatively poorly, and here we see many of them doing incredibly well.
We also looked at the duration of responses and the duration. The five-year percent of patients whose response is still ongoing is 47% based on Kaplan-Meier estimates, like, really profound there. This is just the responders though. These are the responders—33 responders—only 15 of them have had events. Really very exciting to see this.
Also, progression-free survival at five years. Again, in a modest cohort, the median was 12.7 months, but at five years, 38% of patients were expected to be progression-free. Now again, small numbers—45 patients—but really provocative and nothing that we've seen before. And I think the most interesting thing, and if this holds up in EV-302, the randomized phase-three trial, really is we'll have to change how we think about the disease, that we had over 40% of patients alive at five years of this cohort, based on the statistical analysis. Over 40% alive at five years—we really now might need to be thinking about survivorship for these patients in ways we never did before.
Who are they? What are they going to be like? What's their quality of life like? How much do they have? How long do you need to stay on therapy to get that? These are all questions we're going to see answered as time goes on, particularly from further data from this study in Cohort K, as well as EV-302 long-term outcomes. So at five-year follow-up, there's durable responses in a subset of patients and meaningful survival—that's something that we haven't seen before.
And 41.5% of patients in this cohort were expected to be alive at five years based on Kaplan-Meier estimates. And the median follow-up was about five years in this trial. This exceeds the historical data from the phase 2/3 EORTC study where 3% of patients were alive. Now, that was a very poor prognosis population, so maybe the number is a little higher than that with GemCarbo, but boy, this is a game changer in my opinion. So time will tell—is this an exceptional cohort of patients, or are we going to see similar results from EV-302 as time goes on? I think the latter, and I look forward to seeing the ongoing follow-up from these data sets as time, as time passes.
Alicia Morgans: Wow, Jonathan, that's truly exceptional. Because if we think about it, at least in the lay public's eyes, five years of survival is, in some settings, especially if there's no measurable disease—and we can get into the weeds on these particular patients—but if there's no measurable disease, people think that that's a cure. And certainly 40% of people being alive, at least, is an incredible win for this patient population that has historically had a really pretty dismal and unfortunate situation happening. So, I wonder, how was it that these patients had such a long response? Was it an ongoing response to EV as it sort of appeared in that swimmer's plot? Or were there subsequent treatments that continued to be effective for patients? Did they get re-treatment with EV? Do you have any more information? Because this is incredible.
Jonathan Rosenberg: Most of the time post-study therapies are not that well recorded. And so, it's very hard to know what happened to the patients who would be alive but perhaps didn't have durable long-term responses. But it appears that this drug, this combination, is changing the natural history of the disease. And there are a chunk of patients where they have these durable remissions that are off-therapy—they're unmaintained, those gray tracks, light gray tracks. Those are all people who never received any more therapy for their advanced urothelial cancer and they were alive.
And so this is the goal, right? We want systemic therapy in metastatic patients that is curative, right? We have it for germ cell cancer. We don't have it for many other diseases when we think about this, right? A few other exceptions for solid tumors, but maybe we're leapfrogging a lot of cancers in this novel combination approach. And so I am very curious—is this just a highly selected population in a small trial, or is this now changing how we're thinking about metastatic urothelial cancer, where cure is at least on the table for some patients? And it's unfortunately not enough—never is enough, obviously, in our field. But are we actually thinking that we're able to eradicate all cancer cells in patients who are receiving EV and pembro together?
Alicia Morgans: Well, I have to say, of all cancers, I would not necessarily think that urothelial cancer would be the one to, as you said, leapfrog others and get to this point. But amazing things happen, and this truly is incredible, particularly for those patients who have those long-term responses. So, what is your message? It sounds like more work always needs to be done. What is your message to listeners around these findings and next steps?
Jonathan Rosenberg: I think the real message here is, this clearly is the most active treatment for advanced urothelial cancer, and there are going to be patients—similar to single-agent checkpoint therapy—people will get durable remissions. It looks like the number of patients who get into that category here, it's probably double or triple that of single-agent checkpoint inhibitor. There probably is more than additive activity between the two, and that we have to be thinking strategically about subsequent therapies, but also trying to maximize the benefits of the current—that treatment, EV and pembro together—because for some patients, it really is a game-changer.
Alicia Morgans: Fantastic. Well, thank you so much for this update, and we really look forward to hearing, certainly, about additional EV studies over time. Congratulations to you, to the investigators, and certainly to the patients who participated. Thank you.
Jonathan Rosenberg: Thank you.
Alicia Morgans: Hi, I'm so excited to be here today with Professor Jonathan Rosenberg, who is joining me from Memorial Sloan Kettering after a wonderful presentation at ESMO 2024, where he gave us an update on EV-103 Cohort A and some five-year outcomes. Thank you so much for being here, and please take it away.
Jonathan Rosenberg: Thank you so much, Alicia. It's great to be here to talk and update people about the five-year outcomes. In the first trial of Enfortumab and Pembrolizumab, people remember, this data was initially presented with a 73% response rate at ESMO just about five years ago. And so, here we're presenting the five-year update of the outcomes of patients in this first trial of Enfortumab Vedotin and Pembrolizumab in cisplatin-ineligible, locally advanced or metastatic urothelial cancers.
And just to level set here, we expect patients who received gemcitabine and carboplatin to have a response rate of about 40%, and median survival of anywhere from 10 to 14 months at the longest.
And in the modern era, they might get avelumab maintenance, so they probably would do better if they responded, but if they didn't respond, their outcomes are pretty dismal.
So the first study showed a response rate of 73%, but we really haven't seen any sort of individual patient data looking at what happened to patients on this initial cohort. And so we see here this is the time-to-response and duration-of-response. And the green arrows show ongoing responses, and we see that many patients who responded, probably about 30% of them, have ongoing responses past four years. This is something we hadn't seen before in patients treated with carboplatin-based chemotherapy. And the responses, in general, are very fast. We also see that the duration of therapy didn't go much past two years here. That's included by the dark lines. And so, these are patients who we expected to do relatively poorly, and here we see many of them doing incredibly well.
We also looked at the duration of responses and the duration. The five-year percent of patients whose response is still ongoing is 47% based on Kaplan-Meier estimates, like, really profound there. This is just the responders though. These are the responders—33 responders—only 15 of them have had events. Really very exciting to see this.
Also, progression-free survival at five years. Again, in a modest cohort, the median was 12.7 months, but at five years, 38% of patients were expected to be progression-free. Now again, small numbers—45 patients—but really provocative and nothing that we've seen before. And I think the most interesting thing, and if this holds up in EV-302, the randomized phase-three trial, really is we'll have to change how we think about the disease, that we had over 40% of patients alive at five years of this cohort, based on the statistical analysis. Over 40% alive at five years—we really now might need to be thinking about survivorship for these patients in ways we never did before.
Who are they? What are they going to be like? What's their quality of life like? How much do they have? How long do you need to stay on therapy to get that? These are all questions we're going to see answered as time goes on, particularly from further data from this study in Cohort K, as well as EV-302 long-term outcomes. So at five-year follow-up, there's durable responses in a subset of patients and meaningful survival—that's something that we haven't seen before.
And 41.5% of patients in this cohort were expected to be alive at five years based on Kaplan-Meier estimates. And the median follow-up was about five years in this trial. This exceeds the historical data from the phase 2/3 EORTC study where 3% of patients were alive. Now, that was a very poor prognosis population, so maybe the number is a little higher than that with GemCarbo, but boy, this is a game changer in my opinion. So time will tell—is this an exceptional cohort of patients, or are we going to see similar results from EV-302 as time goes on? I think the latter, and I look forward to seeing the ongoing follow-up from these data sets as time, as time passes.
Alicia Morgans: Wow, Jonathan, that's truly exceptional. Because if we think about it, at least in the lay public's eyes, five years of survival is, in some settings, especially if there's no measurable disease—and we can get into the weeds on these particular patients—but if there's no measurable disease, people think that that's a cure. And certainly 40% of people being alive, at least, is an incredible win for this patient population that has historically had a really pretty dismal and unfortunate situation happening. So, I wonder, how was it that these patients had such a long response? Was it an ongoing response to EV as it sort of appeared in that swimmer's plot? Or were there subsequent treatments that continued to be effective for patients? Did they get re-treatment with EV? Do you have any more information? Because this is incredible.
Jonathan Rosenberg: Most of the time post-study therapies are not that well recorded. And so, it's very hard to know what happened to the patients who would be alive but perhaps didn't have durable long-term responses. But it appears that this drug, this combination, is changing the natural history of the disease. And there are a chunk of patients where they have these durable remissions that are off-therapy—they're unmaintained, those gray tracks, light gray tracks. Those are all people who never received any more therapy for their advanced urothelial cancer and they were alive.
And so this is the goal, right? We want systemic therapy in metastatic patients that is curative, right? We have it for germ cell cancer. We don't have it for many other diseases when we think about this, right? A few other exceptions for solid tumors, but maybe we're leapfrogging a lot of cancers in this novel combination approach. And so I am very curious—is this just a highly selected population in a small trial, or is this now changing how we're thinking about metastatic urothelial cancer, where cure is at least on the table for some patients? And it's unfortunately not enough—never is enough, obviously, in our field. But are we actually thinking that we're able to eradicate all cancer cells in patients who are receiving EV and pembro together?
Alicia Morgans: Well, I have to say, of all cancers, I would not necessarily think that urothelial cancer would be the one to, as you said, leapfrog others and get to this point. But amazing things happen, and this truly is incredible, particularly for those patients who have those long-term responses. So, what is your message? It sounds like more work always needs to be done. What is your message to listeners around these findings and next steps?
Jonathan Rosenberg: I think the real message here is, this clearly is the most active treatment for advanced urothelial cancer, and there are going to be patients—similar to single-agent checkpoint therapy—people will get durable remissions. It looks like the number of patients who get into that category here, it's probably double or triple that of single-agent checkpoint inhibitor. There probably is more than additive activity between the two, and that we have to be thinking strategically about subsequent therapies, but also trying to maximize the benefits of the current—that treatment, EV and pembro together—because for some patients, it really is a game-changer.
Alicia Morgans: Fantastic. Well, thank you so much for this update, and we really look forward to hearing, certainly, about additional EV studies over time. Congratulations to you, to the investigators, and certainly to the patients who participated. Thank you.
Jonathan Rosenberg: Thank you.