Outcomes of Enfortumab Vedotin After Platinum and Avelumab in Bladder Cancer - Amanda Nizam
March 1, 2024
Amanda Nizam presents findings from the UNITE study at GU ASCO 2024, exploring enfortumab vedotin's (EV) efficacy in patients with advanced urothelial carcinoma post-platinum-based chemotherapy and maintenance avelumab. This retrospective analysis, involving 633 patients across 16 US sites, reveals that EV's outcomes are consistent with previous trials, even after maintenance avelumab. Despite expectations, subgroup analyses show no significant differences in response based on platinum type, duration on avelumab, or initial response to platinum. Patients with fewer prognostic risk factors exhibit improved outcomes. Dr. Nizam discusses the evolving treatment landscape, including the recent approval of EV plus pembrolizumab for first-line therapy, and speculates on future directions, such as neoadjuvant settings and the potential for re-challenging with EV.
Biographies:
Amanda Nizam, MD, Oncologist, Cleveland Clinic, Cleveland, OH
Sam S. Chang, MD, MBA, Urologist, Vanderbilt University Medical Center, Nashville, TN
Biographies:
Amanda Nizam, MD, Oncologist, Cleveland Clinic, Cleveland, OH
Sam S. Chang, MD, MBA, Urologist, Vanderbilt University Medical Center, Nashville, TN
Related Content:
ASCO GU 2024: Outcomes in Patients with Advanced Urothelial Carcinoma Treated with Enfortumab Vedotin After Switch Maintenance Avelumab in the UNITE Study
ASCO GU 2023: Biomarkers of Response to Enfortumab Vedotin in Patients with Advanced Urothelial Carcinoma: Analysis of the UNITE Study
ASCO GU 2024: Outcomes in Patients with Advanced Urothelial Carcinoma Treated with Enfortumab Vedotin After Switch Maintenance Avelumab in the UNITE Study
ASCO GU 2023: Biomarkers of Response to Enfortumab Vedotin in Patients with Advanced Urothelial Carcinoma: Analysis of the UNITE Study
Read the Full Video Transcript
Sam Chang: Hello everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and we're at GU ASCO 2024. And I'm quite fortunate to have Dr. Amanda Nizam from the Cleveland Clinic, who is actually going to be focusing on her abstract, which was presented as a rapid early morning abstract session, looking at actually the use of EV, enfortumab vedotin, in those patients that have had first-line platinum-based therapy followed by maintenance avelumab that have had some progression. And this is actually entitled the UNITE trial, is that right?
Amanda Nizam: Yes. It's outcomes from the UNITE studies. So in this analysis, we looked at outcomes in the UNITE study. This is a multi-center, 16 US site retrospective cohort study, looking at patients with advanced urothelial carcinoma, who are treated with novel systemic therapies, such as enfortumab vedotin and sacituzumab govitecan.
So as you know, enfortumab vedotin garnered FDA approval in 2019 for patients post-platinum and checkpoint inhibitor therapy, with refractory disease to both of those agents. Now, in 2020, switch maintenance avelumab was approved for patients who did not have disease progression on first-line platinum-based chemotherapy. But given those overlapping timelines, those patients who received platinum-based chemotherapy and then maintenance avelumab were not included in the EV-301 trial.
Sam Chang: In the trial. I see.
Amanda Nizam: Exactly.
Sam Chang: I see.
Amanda Nizam: So we wanted to see, knowing that there's differing disease biology between platinum-responsive patients and platinum-resistant patients, we wanted to see what the outcomes with EV would look like post-maintenance setting. So that's how that came about.
The UNITE study was a great setting to do this. 16 US sites. We had patient EV outcomes. This registry is really geared toward looking at patients who were treated with EVs. So in our study, the maintenance avelumab, median to maintenance avelumab, was a little bit shorter than what we saw in the JAVELIN Bladder trial, because the patients we were capturing were getting EV soon.
Sam Chang: Were going to get. Sure.
Amanda Nizam: Yes.
Sam Chang: Absolutely.
Amanda Nizam: Yes.
Sam Chang: And then, so in looking at these results from, I guess there's a pool of more than 600 patients, tell us how EV actually was beneficial or not beneficial.
Amanda Nizam: So in this analysis, we identified, out of the 633 patients, we identified 49 patients who received sequential platinum-based chemotherapy, maintenance avelumab, and then enfortumab vedotin.
Sam Chang: All right.
Amanda Nizam: And then, we looked at observed response rate, progression-free and overall survival from EV start. And as an exploratory endpoint, overall survival from platinum-based chemotherapy start, in the overall cohort.
Sam Chang: Okay.
Amanda Nizam: In the subgroups, we also looked at subgroup analyses, so that was based on the type of platinum-based therapy used, and then the length of maintenance avelumab, best response to platinum-based chemotherapy, and then Bellmunt risk score.
Sam Chang: So a lot of basically different subgroup analyses to hopefully tease-
Amanda Nizam: Four different ones. Yes.
Sam Chang: Yeah. Hopefully to tease out who's obviously more or less likely to benefit from this.
Amanda Nizam: Correct.
Sam Chang: So what were the findings?
Amanda Nizam: Correct. So, in the overall cohort, what we saw was a pretty similar observed response rate to what we saw in EV-301. And then, just noting that our study did select for platinum-responsive patients, and EV-301 looked at those that were refractory to platinum and checkpoint inhibitor therapy. But despite that, we're seeing pretty similar responses.
So, in the 41 evaluable patients, we saw an observed response rate of 54%. Whereas, in the intention-to-treat population, we saw 45%. In EV-301, that was 41%. So pretty consistent.
Sam Chang: Yes.
Amanda Nizam: Median progression-free survival and median overall survival, those were all pretty similar to the EV-301 trial as well. So our median progression-free survival was seven months. Median overall survival was 13.3 months. In EV-301 it was 5.6 months and 12.9 months, respectively.
Sam Chang: So not too off at all.
Amanda Nizam: Not too far off, exactly.
Sam Chang: Okay. So, in looking at some of the subgroup analyses in terms of who, again, perhaps gained more or less benefit, were there certain subgroups that seemed to stick out?
Amanda Nizam: Yeah. So actually, when we looked at it, and within the confines of a limited sample size, we did not see any differences in the type of-
Sam Chang: The type of platinum.
Amanda Nizam: ... platinum used.
Sam Chang: Okay.
Amanda Nizam: Best response to platinum.
Sam Chang: Okay.
Amanda Nizam: Or time on maintenance avelumab. Whether it was greater than three months or less than three months. And I will note that most patients did have cisplatin-based chemotherapy in this study. And despite that, we did not see any differences.
Sam Chang: I see. Didn't see differences.
Amanda Nizam: Which we did actually think we would see.
Sam Chang: Yeah. You would think, perhaps.
Amanda Nizam: You would think.
Sam Chang: Yes.
Amanda Nizam: You would think. But we did not see anything. And that may be due to the limited sample size. But however, those patients with a Bellmunt risk score of zero or one. So when we look at the Bellmunt risk score, that is the presence of hemoglobin less than 10, ECOG performance status greater than zero, and/or the presence of liver metastases. So one point for each. So those patients with zero or one, so less of those prognoses.
Sam Chang: Yeah.
Amanda Nizam: Yeah. Exactly.
Sam Chang: Yeah, less.
Amanda Nizam: Yeah.
Sam Chang: Okay. Yeah.
Amanda Nizam: So they actually had improved progression-free and overall survival.
Sam Chang: So maybe those patients, early on, that their disease burden perhaps not as poorly predictive or poorly prognostic seem to respond better to this.
Amanda Nizam: Exactly. And while that score is not validated in this setting, it does tell us that those patients with those poor prognostic factors do have overall worse outcomes even with EV.
Sam Chang: Even with throwing in-
Amanda Nizam: Exactly.
Sam Chang: ... an ADC. I see.
Amanda Nizam: Yep.
Sam Chang: So, in accumulating and trying to evaluate now, in this ever-changing landscape, obviously, it had been historically, platinum-based chemotherapy was the backbone for the treatment of advanced urothelial carcinomas. We've got immunotherapies, we've got ADCs, we have all these that are second, third-line, et cetera, maintenance options. Now with the recent data, looking at the combination of EV plus pembrolizumab, where does this now fit in, in terms of maintenance therapy or third-line following maintenance therapy? Where does this now fit in, do you think?
Amanda Nizam: Yeah. That's a great question. So when we originally did this analysis, EV-302 had not come out yet. So, it was interesting.
Sam Chang: Sure. Absolutely. Right. Right.
Amanda Nizam: But now that that has evolved, and in December 2023, actually, the EV/pembrolizumab combination got FDA approval for the upfront treatment of advanced urothelial carcinoma. So where does that fit in-
Sam Chang: Right.
Amanda Nizam: ... is an excellent question.
Sam Chang: Right.
Amanda Nizam: While the EV/pembro, the data speaks for itself, and should be used in all patients who are eligible for that; the reality is, most of the world is not going to have access to EV/pembro.
Sam Chang: Sure. Sure.
Amanda Nizam: Much, even in rural areas where providers are not comfortable or familiar with using EV/pembro, we may still see a lot of situations where platinum, maintenance avelumab, and EV are being used in sequence.
Sam Chang: In that order.
Amanda Nizam: Exactly.
Sam Chang: Exactly.
Amanda Nizam: So clinically, we looked at EV outcomes here in a contemporary practice setting in the way it's being used in the real world right now.
Sam Chang: Sure.
Amanda Nizam: And until that real-world practice shifts, adopts, and access improves to EV/pembro, this is still relevant to know.
Sam Chang: Oh, sure.
Amanda Nizam: Exactly.
Sam Chang: We still have, I'm sure in the US, at least hundreds, thousands of patients that have started or received first-line therapy that are receiving some type of maintenance switch therapy that we need to know there is an advantageous benefit of adding then the EV following this kind of regimen. So I think that'll be helpful for years and years.
And your point about access, and clearly, cost is going to play a role as well, in allowing sequential therapy. It gives patients, obviously, options. It gives physicians options as well.
So as you look into the future, we are looking at everything in the advanced setting, maintenance line settings, third-line, et cetera.
Amanda Nizam: Yeah.
Sam Chang: And with EV/pembro now kind of becoming the first standard of care, first-line therapy for advanced disease, where do you think, and what do you think is going to be really kind of the neoadjuvant setting? So it has been platinum-based, we're waiting for the IO neoadjuvants. We're waiting for EV/pembro neoadjuvant. And as you have studied this kind of landscape, what do you think is most exciting in the neoadjuvant setting?
Amanda Nizam: Yeah. So I think, I have a strong feeling that the EV/pembro is going to shift to the perioperative setting, and that's going to upend our sequencing question.
Sam Chang: Again.
Amanda Nizam: All over again.
Sam Chang: Again.
Amanda Nizam: Very shortly. Yes.
Sam Chang: Yeah.
Amanda Nizam: So platinum I don't think is going anywhere, especially if it moves to the perioperative setting. The question is going to be, can you re-challenge with maintenance avelumab in patients who are getting platinum post-perioperative EV/pembro if that does get approved?
Sam Chang: Right.
Amanda Nizam: And the other question is, can you do EV re-challenge in the future? Because as you know, with patients who get platinum therapy in the perioperative setting now, further on, if they go down the road and develop metastatic disease, we have used platinum re-challenge in those who did have a response initially.
Sam Chang: Right.
Amanda Nizam: So you're going to have a whole sequencing, and basically, a Rubik's Cube.
Sam Chang: Right. And I think that's a great thing, I think, from a medical oncology standpoint. The trials in terms of setting that up, those real-world scenarios, the registry groups, those types of things, will really help answer those questions-
Amanda Nizam: Right.
Sam Chang: ... as you stack sequentially those patients who are now fortunately living longer. And obviously, we're going to also need to take into account toxicities. And what's going to happen with the neuropathy with EV? And how much longer can we treat? And what happens with the re-challenge? These are questions that I personally am not familiar with, and maybe as a field, we'll get more and more information in the future.
Amanda Nizam: It's an exciting time.
Sam Chang: It's always great to spend some time with you. And the people at Cleveland Clinic are quite fortunate to have you. And thanks again for spending some time with us.
Amanda Nizam: Thank you so much for the opportunity.
Sam Chang: Hello everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and we're at GU ASCO 2024. And I'm quite fortunate to have Dr. Amanda Nizam from the Cleveland Clinic, who is actually going to be focusing on her abstract, which was presented as a rapid early morning abstract session, looking at actually the use of EV, enfortumab vedotin, in those patients that have had first-line platinum-based therapy followed by maintenance avelumab that have had some progression. And this is actually entitled the UNITE trial, is that right?
Amanda Nizam: Yes. It's outcomes from the UNITE studies. So in this analysis, we looked at outcomes in the UNITE study. This is a multi-center, 16 US site retrospective cohort study, looking at patients with advanced urothelial carcinoma, who are treated with novel systemic therapies, such as enfortumab vedotin and sacituzumab govitecan.
So as you know, enfortumab vedotin garnered FDA approval in 2019 for patients post-platinum and checkpoint inhibitor therapy, with refractory disease to both of those agents. Now, in 2020, switch maintenance avelumab was approved for patients who did not have disease progression on first-line platinum-based chemotherapy. But given those overlapping timelines, those patients who received platinum-based chemotherapy and then maintenance avelumab were not included in the EV-301 trial.
Sam Chang: In the trial. I see.
Amanda Nizam: Exactly.
Sam Chang: I see.
Amanda Nizam: So we wanted to see, knowing that there's differing disease biology between platinum-responsive patients and platinum-resistant patients, we wanted to see what the outcomes with EV would look like post-maintenance setting. So that's how that came about.
The UNITE study was a great setting to do this. 16 US sites. We had patient EV outcomes. This registry is really geared toward looking at patients who were treated with EVs. So in our study, the maintenance avelumab, median to maintenance avelumab, was a little bit shorter than what we saw in the JAVELIN Bladder trial, because the patients we were capturing were getting EV soon.
Sam Chang: Were going to get. Sure.
Amanda Nizam: Yes.
Sam Chang: Absolutely.
Amanda Nizam: Yes.
Sam Chang: And then, so in looking at these results from, I guess there's a pool of more than 600 patients, tell us how EV actually was beneficial or not beneficial.
Amanda Nizam: So in this analysis, we identified, out of the 633 patients, we identified 49 patients who received sequential platinum-based chemotherapy, maintenance avelumab, and then enfortumab vedotin.
Sam Chang: All right.
Amanda Nizam: And then, we looked at observed response rate, progression-free and overall survival from EV start. And as an exploratory endpoint, overall survival from platinum-based chemotherapy start, in the overall cohort.
Sam Chang: Okay.
Amanda Nizam: In the subgroups, we also looked at subgroup analyses, so that was based on the type of platinum-based therapy used, and then the length of maintenance avelumab, best response to platinum-based chemotherapy, and then Bellmunt risk score.
Sam Chang: So a lot of basically different subgroup analyses to hopefully tease-
Amanda Nizam: Four different ones. Yes.
Sam Chang: Yeah. Hopefully to tease out who's obviously more or less likely to benefit from this.
Amanda Nizam: Correct.
Sam Chang: So what were the findings?
Amanda Nizam: Correct. So, in the overall cohort, what we saw was a pretty similar observed response rate to what we saw in EV-301. And then, just noting that our study did select for platinum-responsive patients, and EV-301 looked at those that were refractory to platinum and checkpoint inhibitor therapy. But despite that, we're seeing pretty similar responses.
So, in the 41 evaluable patients, we saw an observed response rate of 54%. Whereas, in the intention-to-treat population, we saw 45%. In EV-301, that was 41%. So pretty consistent.
Sam Chang: Yes.
Amanda Nizam: Median progression-free survival and median overall survival, those were all pretty similar to the EV-301 trial as well. So our median progression-free survival was seven months. Median overall survival was 13.3 months. In EV-301 it was 5.6 months and 12.9 months, respectively.
Sam Chang: So not too off at all.
Amanda Nizam: Not too far off, exactly.
Sam Chang: Okay. So, in looking at some of the subgroup analyses in terms of who, again, perhaps gained more or less benefit, were there certain subgroups that seemed to stick out?
Amanda Nizam: Yeah. So actually, when we looked at it, and within the confines of a limited sample size, we did not see any differences in the type of-
Sam Chang: The type of platinum.
Amanda Nizam: ... platinum used.
Sam Chang: Okay.
Amanda Nizam: Best response to platinum.
Sam Chang: Okay.
Amanda Nizam: Or time on maintenance avelumab. Whether it was greater than three months or less than three months. And I will note that most patients did have cisplatin-based chemotherapy in this study. And despite that, we did not see any differences.
Sam Chang: I see. Didn't see differences.
Amanda Nizam: Which we did actually think we would see.
Sam Chang: Yeah. You would think, perhaps.
Amanda Nizam: You would think.
Sam Chang: Yes.
Amanda Nizam: You would think. But we did not see anything. And that may be due to the limited sample size. But however, those patients with a Bellmunt risk score of zero or one. So when we look at the Bellmunt risk score, that is the presence of hemoglobin less than 10, ECOG performance status greater than zero, and/or the presence of liver metastases. So one point for each. So those patients with zero or one, so less of those prognoses.
Sam Chang: Yeah.
Amanda Nizam: Yeah. Exactly.
Sam Chang: Yeah, less.
Amanda Nizam: Yeah.
Sam Chang: Okay. Yeah.
Amanda Nizam: So they actually had improved progression-free and overall survival.
Sam Chang: So maybe those patients, early on, that their disease burden perhaps not as poorly predictive or poorly prognostic seem to respond better to this.
Amanda Nizam: Exactly. And while that score is not validated in this setting, it does tell us that those patients with those poor prognostic factors do have overall worse outcomes even with EV.
Sam Chang: Even with throwing in-
Amanda Nizam: Exactly.
Sam Chang: ... an ADC. I see.
Amanda Nizam: Yep.
Sam Chang: So, in accumulating and trying to evaluate now, in this ever-changing landscape, obviously, it had been historically, platinum-based chemotherapy was the backbone for the treatment of advanced urothelial carcinomas. We've got immunotherapies, we've got ADCs, we have all these that are second, third-line, et cetera, maintenance options. Now with the recent data, looking at the combination of EV plus pembrolizumab, where does this now fit in, in terms of maintenance therapy or third-line following maintenance therapy? Where does this now fit in, do you think?
Amanda Nizam: Yeah. That's a great question. So when we originally did this analysis, EV-302 had not come out yet. So, it was interesting.
Sam Chang: Sure. Absolutely. Right. Right.
Amanda Nizam: But now that that has evolved, and in December 2023, actually, the EV/pembrolizumab combination got FDA approval for the upfront treatment of advanced urothelial carcinoma. So where does that fit in-
Sam Chang: Right.
Amanda Nizam: ... is an excellent question.
Sam Chang: Right.
Amanda Nizam: While the EV/pembro, the data speaks for itself, and should be used in all patients who are eligible for that; the reality is, most of the world is not going to have access to EV/pembro.
Sam Chang: Sure. Sure.
Amanda Nizam: Much, even in rural areas where providers are not comfortable or familiar with using EV/pembro, we may still see a lot of situations where platinum, maintenance avelumab, and EV are being used in sequence.
Sam Chang: In that order.
Amanda Nizam: Exactly.
Sam Chang: Exactly.
Amanda Nizam: So clinically, we looked at EV outcomes here in a contemporary practice setting in the way it's being used in the real world right now.
Sam Chang: Sure.
Amanda Nizam: And until that real-world practice shifts, adopts, and access improves to EV/pembro, this is still relevant to know.
Sam Chang: Oh, sure.
Amanda Nizam: Exactly.
Sam Chang: We still have, I'm sure in the US, at least hundreds, thousands of patients that have started or received first-line therapy that are receiving some type of maintenance switch therapy that we need to know there is an advantageous benefit of adding then the EV following this kind of regimen. So I think that'll be helpful for years and years.
And your point about access, and clearly, cost is going to play a role as well, in allowing sequential therapy. It gives patients, obviously, options. It gives physicians options as well.
So as you look into the future, we are looking at everything in the advanced setting, maintenance line settings, third-line, et cetera.
Amanda Nizam: Yeah.
Sam Chang: And with EV/pembro now kind of becoming the first standard of care, first-line therapy for advanced disease, where do you think, and what do you think is going to be really kind of the neoadjuvant setting? So it has been platinum-based, we're waiting for the IO neoadjuvants. We're waiting for EV/pembro neoadjuvant. And as you have studied this kind of landscape, what do you think is most exciting in the neoadjuvant setting?
Amanda Nizam: Yeah. So I think, I have a strong feeling that the EV/pembro is going to shift to the perioperative setting, and that's going to upend our sequencing question.
Sam Chang: Again.
Amanda Nizam: All over again.
Sam Chang: Again.
Amanda Nizam: Very shortly. Yes.
Sam Chang: Yeah.
Amanda Nizam: So platinum I don't think is going anywhere, especially if it moves to the perioperative setting. The question is going to be, can you re-challenge with maintenance avelumab in patients who are getting platinum post-perioperative EV/pembro if that does get approved?
Sam Chang: Right.
Amanda Nizam: And the other question is, can you do EV re-challenge in the future? Because as you know, with patients who get platinum therapy in the perioperative setting now, further on, if they go down the road and develop metastatic disease, we have used platinum re-challenge in those who did have a response initially.
Sam Chang: Right.
Amanda Nizam: So you're going to have a whole sequencing, and basically, a Rubik's Cube.
Sam Chang: Right. And I think that's a great thing, I think, from a medical oncology standpoint. The trials in terms of setting that up, those real-world scenarios, the registry groups, those types of things, will really help answer those questions-
Amanda Nizam: Right.
Sam Chang: ... as you stack sequentially those patients who are now fortunately living longer. And obviously, we're going to also need to take into account toxicities. And what's going to happen with the neuropathy with EV? And how much longer can we treat? And what happens with the re-challenge? These are questions that I personally am not familiar with, and maybe as a field, we'll get more and more information in the future.
Amanda Nizam: It's an exciting time.
Sam Chang: It's always great to spend some time with you. And the people at Cleveland Clinic are quite fortunate to have you. And thanks again for spending some time with us.
Amanda Nizam: Thank you so much for the opportunity.
