The July 2026 FDA approval of perioperative pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) in combination with enfortumab vedotin-ejfv (Padcev) represents the most significant advance in the treatment of muscle-invasive bladder cancer (MIBC) in recent memory, according to Matthew Galsky, MD.1
“This is the first non–cisplatin-based chemotherapy regimen to be approved in the neoadjuvant/perioperative setting in patients with MIBC,” Galsky said in an interview with OncLive®. “It's the first time that we've displaced the standard treatment that's been present for decades and decades; it really represents a turning point in the care of patients with MIBC.”
In the interview, Galsky discussed the significance of the approval, key data from the phase 3 KEYNOTE-B15/EV-304 study (NCT04700124) that supported the regulatory decision, and how the regimen will be integrated into clinical practice.
Galsky is a professor of medicine (hematology and medical oncology), director of genitourinary medical oncology, codirector of the Center of Excellence for Bladder Cancer, and deputy director at the Mount Sinai Tisch Cancer Center in New York, New York.
OncLive: What is the significance of this approval?
Galsky: In MIBC, radical cystectomy has been the standard treatment for a very long time. We know that patients treated with surgery alone have a risk of metastatic recurrence, and that provided the basis for the integration of systemic therapy.
There have been 3 major advances in systemic therapy in MIBC over the past 30-plus years. [First], there was cisplatin-based neoadjuvant therapy. [Data from the phase 3] SWOG 8710 trial [were] reported back in 2003; [this began the] cisplatin neoadjuvant cisplatin era, and then there were very few advances in systemic treatment for MIBC until the immune checkpoint blockade era.
We had studies with adjuvant immune checkpoint blockade, and then the addition of immune checkpoint blockade to cisplatin-based therapy. That was the second major advance, and this is the third major advance with the integration of enfortumab vedotin plus pembrolizumab into the perioperative systemic treatment of MIBC, and arguably it’s the most substantial of all those advances.
What were the key data that supported this approval?
KEYNOTE-B15 was a randomized, phase 3 study that enrolled patients with clinically localized MIBC [and evaluated] perioperative enfortumab vedotin plus pembrolizumab and cystectomy.2 There was a neoadjuvant portion of enfortumab vedotin plus pembrolizumab followed by cystectomy, and then an adjuvant portion of enfortumab vedotin plus pembrolizumab, and then a period of additional pembrolizumab monotherapy. The control arm was standard-of-care neoadjuvant gemcitabine/cisplatin followed by cystectomy.
The primary end point was event-free survival [EFS]. Key secondary end points were overall survival [OS] and pathological complete response rate [pCR].
The primary end point showed an improvement in EFS with a HR of 0.53 [95% CI, 0.41-0.70; P < .0001]. OS was also improved with perioperative enfortumab vedotin plus pembrolizumab, with a HR of 0.65 [95% CI, 0.48-0.89; P = .0029]; the pCR rate with perioperative enfortumab vedotin plus pembrolizumab was 55.8% [95% CI, 50.8%-60.7%].
What was the safety profile of the KEYNOTE-B15 regimen?
Enfortumab vedotin plus pembrolizumab has been integrated as standard treatment for first-line metastatic urothelial cancer now for several years, so many clinicians have had some experience with this regimen. The adverse effect [AE] profile of this regimen is certainly different than cisplatin-based chemotherapy.
When one looks at the risk for grade 3 or higher AEs in KEYNOTE-B15 study, you see that it's not that one regimen is associated with necessarily more severe AEs than the other, but the AEs are just very different. AEs to look out for with enfortumab vedotin plus pembrolizumab [include] a rash associated with enfortumab vedotin, mostly mild and controllable with topical medications, but sometimes more serious, requiring monitoring. There can be peripheral neuropathy that tends to be a dose-related cumulative AE. There can be hyperglycemia that develops in a small subset of patients, and then there's the full range of immune-related AEs that are possible that oncologists are now well-versed in.
Key Takeaways From the FDA Approval of Perioperative Enfortumab Vedotin Plus Pembrolizumab in MIBC
- Perioperative enfortumab vedotin plus pembrolizumab establishes a new standard of care in MIBC, becoming the first FDA-approved non–cisplatin-based neoadjuvant/perioperative regimen and replacing decades of cisplatin-based therapy for eligible patients.
- The approval was driven by data from the phase 3 KEYNOTE-B15/EV-304 trial, which demonstrated significant improvements in event-free survival (HR, 0.53), overall survival (HR, 0.65), and a 55.8% pathologic complete response rate vs neoadjuvant gemcitabine/cisplatin.
- The regimen expands access to perioperative systemic therapy across the MIBC population, eliminating the need to determine cisplatin eligibility before referral and underscoring the importance of coordinated care between urologists and medical oncologists to optimize treatment sequencing and surgical timing.
How does this approval change the timing of surgery and other perioperative care pathway considerations?
I don't think it changes things that markedly, although I think it sharpens the need for a few important transitions in ensuring that navigation is appropriate to make those transitions as seamless as possible. Those transitions are initially from the urologist to the medical oncologist at the time of diagnosis of MIBC. Patients need to see a medical oncologist to have that discussion about the risks vs benefits of the integration of systemic therapy for MIBC.
Then there's the transition back to the surgeon for surgical planning, and that can't wait until the last minute. Based on practical and medical reasons, and on how a patient's doing, a surgeon should be integrated into understanding whether or not a patient's experiencing any treatment-related AEs that could impact surgical timing. But more so, it's a practical matter [that includes] ensuring there's appropriate booking for the operating room to make the timing of surgery appropriate in terms of when systemic therapy ends, and then the important transition after surgery back to the medical oncologist so that pathology can be reviewed and the adjuvant portion of the perioperative regimen can be initiated.
