Avelumab’s Survival Impact in Diabetic vs Non-Diabetic Bladder Cancer Patients - Shilpa Gupta
March 5, 2025
Ashish Kamat speaks with Shilpa Gupta about the JAVELIN trial and its impact on bladder cancer treatment. Dr. Gupta discusses how this study established avelumab maintenance therapy following platinum-based chemotherapy as a standard of care, improving both overall and progression-free survival. She highlights an abstract examining outcomes in diabetic patients, which shows maintenance avelumab provides survival benefits without increased adverse events regardless of diabetes status. The conversation addresses global access challenges, with Dr. Gupta noting that platinum chemotherapy followed by avelumab remains a reasonable option in regions where enfortumab vedotin plus pembrolizumab is unavailable. They discuss treatment sequencing for metastatic bladder cancer, including the role of genomic testing for targeted therapies like erdafitinib for FGFR3 alterations and T-DXd for HER2-positive tumors, with special attention to observed resistance patterns in younger patients.
Biographies:
Shilpa Gupta, MD, Director, Genitourinary Medical Oncology, Taussig Cancer Institute, Co-Leader of the Genitourinary Oncology Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH
Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX
Biographies:
Shilpa Gupta, MD, Director, Genitourinary Medical Oncology, Taussig Cancer Institute, Co-Leader of the Genitourinary Oncology Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH
Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX
Related Content:
ASCO GU 2025: Avelumab First-Line Maintenance in Patients With Advanced Urothelial Carcinoma With or Without Diabetes Mellitus: Long-Term Outcomes From JAVELIN Bladder 100
ASCO GU 2024: Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Long-Term Patient-Reported Outcomes in the Phase 3 JAVELIN Bladder 100 Trial
Long-Term Follow-up from the JAVELIN Bladder 100 Trial - Srikala Sridhar
ASCO GU 2025: Avelumab First-Line Maintenance in Patients With Advanced Urothelial Carcinoma With or Without Diabetes Mellitus: Long-Term Outcomes From JAVELIN Bladder 100
ASCO GU 2024: Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Long-Term Patient-Reported Outcomes in the Phase 3 JAVELIN Bladder 100 Trial
Long-Term Follow-up from the JAVELIN Bladder 100 Trial - Srikala Sridhar
Read the Full Video Transcript
Ashish Kamat: A warm welcome to all of you from the UroToday Studios. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center, and we are here live in San Francisco at ASCO GU 25. And it's a pleasure to welcome to the UroToday studios, Professor Shilpa Gupta. Shilpa, thank you for being here.
Shilpa Gupta: Thank you, Ashish. It's my honor to be here.
Ashish Kamat: So the meeting is really busy for you. You've got a lot of stuff going on. But today in this thing we're going to talk about JAVELIN, right? So share with us some of the background behind JAVELIN, and then what you're going to be talking about at the meeting here.
Shilpa Gupta: So JAVELIN was a key study which moved the field forward a few years ago, where in the past, after frontline platinum-based chemotherapy like gemcitabine and cisplatin or gemcitabine and carboplatin, if patients had a response or stable disease, we would just monitor them. And then if they progress, we would use immunotherapies. But this was the study which moved avelumab immunotherapy into the maintenance setting to prolong the response that we get with chemotherapy.
And it was a positive study. It improved median overall survival and progression-free survival in all comers as well as patients with PD-L1 positive tumors. So that became the standard of care up until recently, when EV-302 was the pivotal study that made enfortumab vedotin plus pembrolizumab the standard of care.
Ashish Kamat: So in the abstract that you're presenting, you did some interesting subset analyses. Share with us why you did it and what the results were.
Shilpa Gupta: So now that the study's been out for so long, we're doing some long-term follow-up data. And we've seen that overall survival is maintained. And this abstract that we're presenting tomorrow is specifically looking at patients with diabetes and without diabetes, because these patients have more comorbidities. And with immunotherapy, sometimes they can have more side effects.
And this was just a retrospective ad hoc analysis, and it showed that regardless of whether patients had diabetes or not, they had the median overall survival improvement compared to observation. And also there were not increased rates of treatment-related adverse events. In fact, only less than 2% of patients—that is, one patient out of all the diabetics—had worsening of diabetes.
So that is really encouraging news, and I know enfortumab vedotin plus pembrolizumab is used a lot in the US, but in the rest of the world it's different. And so that just gives reassurance. And that can be true for any immunotherapy, but looking at this study, it looks like it really did make a difference.
Ashish Kamat: And it's interesting that you bring that up, because you brought up enfortumab vedotin plus pembrolizumab, which clearly, based on the data and the data we're going to see here at GU ASCO, is entrenched as the standard of care. But access is a big thing, and you're a big proponent of equity and access in all the work you do globally.
So in the global perspective, how would you use the data from JAVELIN and all the updated survival to counsel patients and practitioners that may not have access to enfortumab vedotin?
Shilpa Gupta: So I think one thing to know is that in the EV-302 study, the control arm did not have maintenance avelumab built in. Because while the protocol was halfway, that's when avelumab got approved, and while they amended the protocol to allow it, it wasn't a part of the study.
So only less than 30% of patients actually got maintenance avelumab. So we can't really say that everybody got avelumab, so that's the comparison. And I think when you look at the cost analysis, as we did at the IBC forum last year at AUA, it's really impossible to afford enfortumab vedotin plus pembrolizumab in countries outside of the US and Europe once it gets reimbursed there.
So I think platinums followed by avelumab is still a very reasonable option in the rest of the world if somebody cannot afford the enfortumab vedotin plus pembrolizumab.
Ashish Kamat: Yeah, and I think that's critical to keep in mind. So, since the patients in EV-302 were not getting maintenance avelumab, we can't really make that comparison. But you've treated a lot of patients. Where do you think the bar or the level of the Kaplan-Meier would be if they had gotten enfortumab vedotin? Like, what sort of a bump would you expect?
Shilpa Gupta: I think because the difference was so substantial, we know that even if it had been there, it would still be a positive study—if not to this magnitude—just because of the tremendous difference in the control arm. And so I think compared to CheckMate 901, we can safely say that it would have been positive regardless.
Ashish Kamat: And again, CheckMate 901, and we of course have the CheckMate 274. I mean, different studies coming in. What do you advise folks when they ask you the question, “Are these all interchangeable? Can I interchange ipilimumab for durvalumab or nivolumab?”
What's your gestalt there? I know the studies haven't been done, but clinically speaking, people get familiar with one agent, and in that case, do you caution them, “No, don't switch”? Let's assume the payers would pay—what would you recommend?
Shilpa Gupta: So switching from one IO to another IO, I would not recommend under any circumstance because there's no data to show that. But if somebody from the rest of the world was asking me which immunotherapy to use in a refractory setting, I would say whatever is accessible and affordable, because they all have activity and they're more similar than different. Just because enfortumab vedotin was studied with pembrolizumab doesn't mean that it won't work with any other checkpoint inhibitor.
Ashish Kamat: Exactly. And just for our audience now, what's your algorithm for first-line, second-line, third-line therapy in a newly metastatic or locally advanced bladder cancer?
Shilpa Gupta: Frontline therapy patients who don't have any contraindications to enfortumab vedotin plus pembrolizumab—which are very few patients, I would say around 10% who are really frail on a chronic basis, not somebody who was very functional and now, because of metastatic disease, has become very frail—those patients really turn around quickly with enfortumab vedotin plus pembrolizumab. So we still give those.
So I use enfortumab vedotin plus pembrolizumab. And in those patients who don't respond, which we are seeing—quite a few, especially our younger patients—then platinums are certainly very important. In the EV-302 study, 30% of patients got subsequent platinums, and they had around 30% responses. So that is my go-to drug.
If we need to do genomic testing, if they have FGFR3 alterations, we use erdafitinib. And now we have the luxury of using T-DXd, which is the HER2-directed antibody-drug conjugate. So we are also testing for HER2 by immunohistochemistry for our subsequent-line therapy patients, and of course clinical trials.
Ashish Kamat: And there will be some interesting data here on T-DXd and some of the other HER2-directed therapies. You mentioned something about younger patients needing more of them requiring cisplatin—did I miss something here? Is there some sort of a differential?
Shilpa Gupta: This is anecdotal, but I've seen—and you and I are working on the young onset bladder cancer—that we are seeing these younger female patients who just have more aggressive disease, and they have some kind of a primary resistance. In our experience of many patients we've treated, they just progress on enfortumab vedotin plus pembrolizumab. And we are actually collecting baseline and serial blood and tissues on these patients so we can understand the mechanisms of resistance to enfortumab vedotin plus pembrolizumab, which we don't know yet, because most patients do respond. And it's those patients who don't that we really have to worry about.
Ashish Kamat: Absolutely. Thank you again for taking the time. Any closing thoughts you want to share with our audience on your abstract?
Shilpa Gupta: No, I think it's just reassuring. And there's no new long-term safety signals or efficacy signals, so that's a good thing to keep in mind.
Ashish Kamat: Great. Thank you once again.
Shilpa Gupta: Thank you, Ashish.
Ashish Kamat: A warm welcome to all of you from the UroToday Studios. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center, and we are here live in San Francisco at ASCO GU 25. And it's a pleasure to welcome to the UroToday studios, Professor Shilpa Gupta. Shilpa, thank you for being here.
Shilpa Gupta: Thank you, Ashish. It's my honor to be here.
Ashish Kamat: So the meeting is really busy for you. You've got a lot of stuff going on. But today in this thing we're going to talk about JAVELIN, right? So share with us some of the background behind JAVELIN, and then what you're going to be talking about at the meeting here.
Shilpa Gupta: So JAVELIN was a key study which moved the field forward a few years ago, where in the past, after frontline platinum-based chemotherapy like gemcitabine and cisplatin or gemcitabine and carboplatin, if patients had a response or stable disease, we would just monitor them. And then if they progress, we would use immunotherapies. But this was the study which moved avelumab immunotherapy into the maintenance setting to prolong the response that we get with chemotherapy.
And it was a positive study. It improved median overall survival and progression-free survival in all comers as well as patients with PD-L1 positive tumors. So that became the standard of care up until recently, when EV-302 was the pivotal study that made enfortumab vedotin plus pembrolizumab the standard of care.
Ashish Kamat: So in the abstract that you're presenting, you did some interesting subset analyses. Share with us why you did it and what the results were.
Shilpa Gupta: So now that the study's been out for so long, we're doing some long-term follow-up data. And we've seen that overall survival is maintained. And this abstract that we're presenting tomorrow is specifically looking at patients with diabetes and without diabetes, because these patients have more comorbidities. And with immunotherapy, sometimes they can have more side effects.
And this was just a retrospective ad hoc analysis, and it showed that regardless of whether patients had diabetes or not, they had the median overall survival improvement compared to observation. And also there were not increased rates of treatment-related adverse events. In fact, only less than 2% of patients—that is, one patient out of all the diabetics—had worsening of diabetes.
So that is really encouraging news, and I know enfortumab vedotin plus pembrolizumab is used a lot in the US, but in the rest of the world it's different. And so that just gives reassurance. And that can be true for any immunotherapy, but looking at this study, it looks like it really did make a difference.
Ashish Kamat: And it's interesting that you bring that up, because you brought up enfortumab vedotin plus pembrolizumab, which clearly, based on the data and the data we're going to see here at GU ASCO, is entrenched as the standard of care. But access is a big thing, and you're a big proponent of equity and access in all the work you do globally.
So in the global perspective, how would you use the data from JAVELIN and all the updated survival to counsel patients and practitioners that may not have access to enfortumab vedotin?
Shilpa Gupta: So I think one thing to know is that in the EV-302 study, the control arm did not have maintenance avelumab built in. Because while the protocol was halfway, that's when avelumab got approved, and while they amended the protocol to allow it, it wasn't a part of the study.
So only less than 30% of patients actually got maintenance avelumab. So we can't really say that everybody got avelumab, so that's the comparison. And I think when you look at the cost analysis, as we did at the IBC forum last year at AUA, it's really impossible to afford enfortumab vedotin plus pembrolizumab in countries outside of the US and Europe once it gets reimbursed there.
So I think platinums followed by avelumab is still a very reasonable option in the rest of the world if somebody cannot afford the enfortumab vedotin plus pembrolizumab.
Ashish Kamat: Yeah, and I think that's critical to keep in mind. So, since the patients in EV-302 were not getting maintenance avelumab, we can't really make that comparison. But you've treated a lot of patients. Where do you think the bar or the level of the Kaplan-Meier would be if they had gotten enfortumab vedotin? Like, what sort of a bump would you expect?
Shilpa Gupta: I think because the difference was so substantial, we know that even if it had been there, it would still be a positive study—if not to this magnitude—just because of the tremendous difference in the control arm. And so I think compared to CheckMate 901, we can safely say that it would have been positive regardless.
Ashish Kamat: And again, CheckMate 901, and we of course have the CheckMate 274. I mean, different studies coming in. What do you advise folks when they ask you the question, “Are these all interchangeable? Can I interchange ipilimumab for durvalumab or nivolumab?”
What's your gestalt there? I know the studies haven't been done, but clinically speaking, people get familiar with one agent, and in that case, do you caution them, “No, don't switch”? Let's assume the payers would pay—what would you recommend?
Shilpa Gupta: So switching from one IO to another IO, I would not recommend under any circumstance because there's no data to show that. But if somebody from the rest of the world was asking me which immunotherapy to use in a refractory setting, I would say whatever is accessible and affordable, because they all have activity and they're more similar than different. Just because enfortumab vedotin was studied with pembrolizumab doesn't mean that it won't work with any other checkpoint inhibitor.
Ashish Kamat: Exactly. And just for our audience now, what's your algorithm for first-line, second-line, third-line therapy in a newly metastatic or locally advanced bladder cancer?
Shilpa Gupta: Frontline therapy patients who don't have any contraindications to enfortumab vedotin plus pembrolizumab—which are very few patients, I would say around 10% who are really frail on a chronic basis, not somebody who was very functional and now, because of metastatic disease, has become very frail—those patients really turn around quickly with enfortumab vedotin plus pembrolizumab. So we still give those.
So I use enfortumab vedotin plus pembrolizumab. And in those patients who don't respond, which we are seeing—quite a few, especially our younger patients—then platinums are certainly very important. In the EV-302 study, 30% of patients got subsequent platinums, and they had around 30% responses. So that is my go-to drug.
If we need to do genomic testing, if they have FGFR3 alterations, we use erdafitinib. And now we have the luxury of using T-DXd, which is the HER2-directed antibody-drug conjugate. So we are also testing for HER2 by immunohistochemistry for our subsequent-line therapy patients, and of course clinical trials.
Ashish Kamat: And there will be some interesting data here on T-DXd and some of the other HER2-directed therapies. You mentioned something about younger patients needing more of them requiring cisplatin—did I miss something here? Is there some sort of a differential?
Shilpa Gupta: This is anecdotal, but I've seen—and you and I are working on the young onset bladder cancer—that we are seeing these younger female patients who just have more aggressive disease, and they have some kind of a primary resistance. In our experience of many patients we've treated, they just progress on enfortumab vedotin plus pembrolizumab. And we are actually collecting baseline and serial blood and tissues on these patients so we can understand the mechanisms of resistance to enfortumab vedotin plus pembrolizumab, which we don't know yet, because most patients do respond. And it's those patients who don't that we really have to worry about.
Ashish Kamat: Absolutely. Thank you again for taking the time. Any closing thoughts you want to share with our audience on your abstract?
Shilpa Gupta: No, I think it's just reassuring. And there's no new long-term safety signals or efficacy signals, so that's a good thing to keep in mind.
Ashish Kamat: Great. Thank you once again.
Shilpa Gupta: Thank you, Ashish.