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Enfortumab Vedotin Plus Pembrolizumab FDA-Approved for Cisplatin-Ineligible MIBC - Matthew Galsky

November 26, 2025

Elizabeth Plimack speaks with Matthew Galsky about the FDA approval of enfortumab vedotin (PADCEV®) with pembrolizumab (Keytruda®) for cisplatin-ineligible muscle-invasive bladder cancer based on the KEYNOTE-905/EV-303 trial. Dr. Galsky emphasizes this represents the first phase three perioperative systemic therapy study in patients who cannot receive neoadjuvant cisplatin-based chemotherapy, filling a treatment gap for a population previously sent directly to surgery. The regimen achieved pathologic complete response rates approaching 65% in patients who underwent cystectomy. Both physicians discuss implications for bladder-sparing approaches, with Dr. Galsky questioning whether surgery remains necessary for patients achieving deep responses. The conversation addresses expectations for upcoming data in cisplatin-eligible patients, with Dr. Galsky noting potential differences in tumor biology and staging between these populations.

Biographies:

Matthew Galsky, MD, Professor of Medicine, Director of GU Medical Oncology, Tisch Cancer Center, Mount Sinai, New York, NY

Elizabeth Plimack, MD, MS, Professor, Deputy Director, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA

Related Content:

U.S. FDA Approves PADCEV® plus Keytruda® for Certain Patients with Bladder Cancer

ESMO 2025: Perioperative Enfortumab Vedotin (EV) plus Pembrolizumab (Pembro) in Participants with Muscle-Invasive Bladder Cancer (MIBC) Who Are Cisplatin-Ineligible: The Phase 3 KEYNOTE-905 Study

ESMO 2025: KEYNOTE-905 Study Discussion - Perioperative EV + Pembro in Participants with MIBC Who Are Cisplatin-Ineligible

Pfizer and Astellas’ PADCEV® (enfortumab vedotin-ejfv) plus KEYTRUDA® (pembrolizumab) Shows Long-Term Efficacy in First-Line Treatment of Locally Advanced or Metastatic Urothelial Cancer (la/mUC)

Pembrolizumab Plus Enfortumab Vedotin-ejfv Reduced Risk of Event-Free Survival Events by 60% and Risk of Death by 50% for Certain Patients with MIBC When Given Before and after Surgery
Read the Full Video Transcript

Elizabeth Plimack: Hi everyone. I'm Elizabeth Plimack. I'm at Fox Chase Cancer Center. I'm a GU medical oncologist. I'm joined by my good friend and colleague, Matthew Galsky from Icahn School of Medicine at Mount Sinai. And we're both really excited to learn on Friday that there was a new approval in muscle-invasive bladder cancer. So the KEYNOTE-905/EV-303 study, results of which we are both in the audience to see at ESMO this year are pretty exciting, yielded an early approval for enfortumab vedotin with pembrolizumab with a sandwich approach pre-surgery and post-surgery in the curative setting for muscle-invasive bladder cancer. So Matt, what were your thoughts on the approval on Friday?

Matthew Galsky: So this is a really important study. This is really the first phase three that I know of to be done exploring a perioperative systemic therapy regimen in patients with muscle-invasive bladder cancer who can't receive neoadjuvant cisplatin-based chemotherapy. So this is not comparing to a different neoadjuvant strategy, but this is taking a patient population who historically we have not had neoadjuvant therapy because we haven't had regimens that don't involve cisplatin that have been shown to be beneficial and showing that you can improve outcomes in this patient population. So incredibly important and impactful.

Elizabeth Plimack: Yeah, I agree. I mean, this was a population we really reluctantly sent straight to surgery because we didn't feel they could tolerate the only perioperative therapy that we thought was feasible and successful in this space. So I think the results show we are increasing cure rates in this population significantly. The delta between the control arm and the treatment arm was significant. But also I think some of what we learned from the study might pertain to some of the work you and I are both doing together and in tandem with bladder sparing. So the pathologic complete response rate, if you take only the patients who all went to surgery, approached 65%, the best we've ever seen. What do you think this means, Matt, for the study that you're leading in future approaches using this regimen in this space?

Matthew Galsky: So this really shows that we're achieving deeper and deeper responses in individuals with muscle-invasive bladder cancer to the extent that when the bladder's removed, the pathologist really can't find any evidence of cancer. And that raises the question, is surgery needed in those patients? Historically, there have been barriers to implementing an approach with transurethral resection plus systemic therapy in this patient population. I think better regimens is one of those barriers. And now we have a better regimen that we really need to start thinking about how we achieve those bladder sparing outcomes for our patients.

Elizabeth Plimack: Yeah, absolutely. Anything else you need to see before you start using this in the clinic and patients who are cisplatin-ineligible?

Matthew Galsky: There's really not. This is a regimen that we have a lot of experience with in the metastatic setting. And of course, with any new regimen, there's a learning curve, but I think all of us who treat bladder cancer have a lot of experience with this regimen now. So transitioning it to the perioperative setting is a relatively straightforward approach. As you pointed out, this study included both neoadjuvant and adjuvant therapy. That has been a subject of a lot of discussion. Does everyone need the adjuvant component? Do we make that decision based on surgical pathology? Do we make that decision based on ctDNA? Lots of unknowns, but this is the data that we have from this study. And again, really impressive result.

Elizabeth Plimack: You're right, sounds good. So we're also expecting another study. Similar approach in cisplatin-eligible patients. What are your expectations of those data when we get to see it?

Matthew Galsky: So I think that's going to be, of course, a really important study because that does have a comparator arm with another neoadjuvant regimen with cisplatin-based chemotherapy. I think there are two potential considerations. One is the effect size for time to event endpoints like event-free survival and overall survival similar when you're comparing against an active comparative regimen. But the other issue is that I think that we might have underestimated the relationship, at least in muscle-invasive bladder cancer, which I think is different than in metastatic bladder cancer between cisplatin eligibility and tumor biology or tumor stage. I think in metastatic bladder cancer, there's lots of reasons for cisplatin ineligibility. I think in muscle-invasive bladder cancer, a lot of times it's based on renal insufficiency based on local tumor causing ureteral obstruction, which is related to the size and location of the local tumor. And that's my long-winded way of saying that it's possible that the stage of patients, the T stage is higher in this study overall than in the other study. That might have some implications for the outcomes. It might have some implications for the path CR rate as well. We might even see higher path CR rates, but of course that remains to be seen.

Elizabeth Plimack: Yeah. Those are all good thoughts. I hadn't thought about this staging being different between the two groups, but absolutely creatinine can be elevated by disease-specific factors, not just intrinsic. So that makes a lot of sense. That's great. Well, I mean, I share your enthusiasm. I think the whole bladder cancer community does. These data were truly groundbreaking and practice changing when we saw them presented. Really proud of the US FDA for approving this so quickly so that we can effectively get it into patients and we hope to expand it in the next few, hopefully very soon to patients who are cisplatin-ineligible. Great. Well, thank you so much, Matt. This was a great conversation as always. Fun to talk about these data and excited for our patients and for the field.

Matthew Galsky: Thank you.