New FDA Approval Expands Access to Powerful Perioperative Immunotherapy Combo, EV+P, for Bladder Cancer

The FDA has approved pembrolizumab (Keytruda) — including the subcutaneous Keytruda Qlex formulation — combined with enfortumab vedotin‑ejfv (Padcev) (EV+P) as both neoadjuvant and adjuvant therapy for adults undergoing cystectomy for muscle‑invasive bladder cancer (MIBC).

“This is a transformative FDA approval that completely changes the standard of care for this aggressive disease,” Dr. Peter O’Donnell, a medical oncologist at UChicago Medicine, tells SurvivorNet Connect.

This decision broadens the regimen’s use beyond cisplatin‑ineligible patients, making it an option for all surgical candidates with MIBC.

“Patients now have an additional, platinum‑free option before and after bladder‑removal surgery,” Dr. David Aggen, an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City, tells SurvivorNet Connect.

The Evidence Behind the Approval

The phase III KEYNOTE‑B15/EV‑304 trial enrolled 808 cisplatin‑eligible patients with previously untreated MIBC. Those who received perioperative pembrolizumab plus enfortumab vedotin‑ejfv experienced significantly better outcomes than patients treated with standard neoadjuvant gemcitabine and cisplatin.

Event‑free survival (EFS) was the primary endpoint, with overall survival (OS) also evaluated.

Patients in the EV+P arm showed statistically significant improvements in both EFS and OS:

• Median EFS: Not reached (95% CI: NR, NR) with EV+P vs. 48.5 months (95% CI: 43.3, NR) with gemcitabine/cisplatin (HR 0.53; 95% CI: 0.41–0.70; p < 0.0001).
• Median OS: Not reached in either arm (HR 0.65; 95% CI: 0.48–0.89; p = 0.0029).

Dr. Aggen notes that more patients achieved a pathologic complete response, fewer experienced recurrence, and overall survival improved with the EV+P combination.

Implications for Clinical Practice

According to Dr. Jeffrey Holzbeierlein, Vice President and Physician-in-Chief at the University of Kansas Cancer Center, perioperative enfortumab vedotin plus pembrolizumab now represents the new standard of care, offering significantly improved response rates both before and after cystectomy.

EV+P “replaces traditional chemotherapy and is generally well tolerated by patients, without many of the side effects commonly associated with classical chemotherapy,” Dr. O’Donnell adds.

Dr. Aggen stresses that clinical judgment remains essential. Without validated predictive biomarkers, factors such as cisplatin eligibility, renal function, neuropathy, hearing status, and glycemic control help guide regimen selection.

Toxicity profiles differ, and comorbidities may influence tolerance.

What This Means for Patients

Dr. Aggen explains that EV+P avoids cisplatin‑specific toxicities such as kidney injury, hearing loss, tinnitus, and hematologic suppression.

However, the combination carries its own risks, including skin reactions, peripheral neuropathy, and hyperglycemia — side effects that typically can be monitored and managed.

Overall, Dr. Holzbeierlein says the regimen delivers “significantly more efficacy without additional — and perhaps even less — toxicity than the previous standard,” improving cure potential for patients with MIBC.

For most U.S. patients with muscle‑invasive disease, the recommended approach is EV+P followed by radical cystectomy. Dr. Aggen underscores that the strong outcomes observed in trials come from the full sequence of systemic therapy plus surgery.

Looking Ahead

Research continues to explore whether certain patients with exceptional responses to EV+P might delay or even avoid cystectomy, though this remains investigational, Dr. Aggen says.

Outside of clinical trials, surgery remains a critical component of care.

As Dr. Aggen summarizes, enfortumab vedotin and pembrolizumab have transformed treatment for muscle‑invasive bladder cancer, but as of 2026, the standard of care still includes proceeding with cystectomy as well.