FDA Expands Perioperative Pembrolizumab Plus Enfortumab Vedotin Approval in Muscle-Invasive Bladder Cancer to All Cystectomy Candidates

KEY FINDINGS

• Expanded access: On 10 July 2026 the FDA expanded the perioperative use of pembrolizumab (Keytruda) or pembrolizumab/berahyaluronidase alfa-pmph (Keytruda Qlex) with enfortumab vedotin-ejfv (Padcev) to cover all muscle-invasive bladder cancer (MIBC) patients who are candidates for cystectomy, regardless of cisplatin eligibility.
• Basis: The approval is based on the results of the phase 3 KEYNOTE-B15/EV-304 trial in 808 patients - the first instance in 25 years in which a platinum-free regimen outperformed cisplatin-based neoadjuvant chemotherapy in cisplatin-eligible patients.
• Efficacy: Statistically significant benefit with an event-free survival (EFS) HR of 0.53 (p<0.0001) and an overall survival (OS) HR of 0.65 (p=0.0029).
• Pathological complete response: 55.8% (EV/pembrolizumab) versus 32.5% (gemcitabine/cisplatin).

Background and Study Design

The standard treatment approach in muscle-invasive bladder cancer has for more than two decades been cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy. However, because a substantial proportion of patients are not eligible for cisplatin or cannot tolerate its toxicity, the need for effective alternatives for this population has long persisted. In November 2025 the FDA approved pembrolizumab plus enfortumab vedotin only in cisplatin-ineligible patients. The decision of 10 July 2026 expands this indication to all MIBC patients who are cystectomy candidates, regardless of cisplatin eligibility.

The basis for this expanded approval is the open-label, randomized, active-controlled, multicentre phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124). The trial enrolled 808 previously untreated patients who were candidates for radical cystectomy with pelvic lymph node dissection and eligible for cisplatin-based chemotherapy.

Study Design

Key Results

For the primary endpoint of EFS, the median was not reached in the EV/pembrolizumab arm, while median EFS in the gemcitabine/cisplatin arm was 48.5 months. The 35% reduction in the risk of death for overall survival is notable.

In terms of the safety profile, a higher rate of grade ≥3 adverse events was reported in the experimental arm (2 treatment-related deaths versus 1 in the control arm); this profile was found to be consistent with previous trials of the combination in urothelial cancer, and no new safety signal was identified.

Implications for Clinical Practice

1. A fundamental change in the treatment algorithm

This approval marks a fundamental change in the treatment algorithm for uro-oncological surgeons performing radical cystectomy. Cisplatin eligibility is no longer a determining criterion for access to the perioperative immunotherapy-antibody drug conjugate combination; this widens treatment options particularly in patients with limited renal function, advanced age or a high comorbidity burden.

2. Surgical and follow-up planning

The marked increase in the pathological complete response rate (55.8% versus 32.5%) establishes a new reference point in the assessment of cystectomy specimens and in discussions of possible bladder-sparing strategies. The adjuvant phase extending to 39 weeks requires post-surgical multidisciplinary follow-up planning to begin earlier and in a more structured way.

3. Multidisciplinary coordination

The increase in the rate of grade ≥3 adverse events once again underlines the need for close coordination between oncology and urology teams in the perioperative period; decisions on surgical timing must be individualised taking into account the immunotherapy-related toxicity profile.

Conclusion

The KEYNOTE-B15/EV-304 data and the expanded FDA approval based on them represent a clear turning point in the perioperative treatment paradigm for muscle-invasive bladder cancer, where cisplatin-based chemotherapy has been the standard for more than twenty-five years. Opening access to all cystectomy candidates regardless of cisplatin eligibility has the potential both to improve oncological outcomes and to reduce inequalities in access to treatment.

References

• FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. U.S. Food and Drug Administration. 10 July 2026. - fda.gov
• Clarke H. FDA approves enfortumab vedotin plus pembrolizumab for MIBC. Urology Times. 22 July 2026. - urologytimes.com
• Galsky MD, Pérez-Valderrama B, Maruzzo M, et al. Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab for participants with muscle-invasive bladder cancer who are eligible for cisplatin: KEYNOTE-B15 study. Abstract LBA630. 2026 ASCO Genitourinary Cancers Symposium.
• FDA Approves Pembrolizumab with Enfortumab Vedotin-ejfv for Muscle Invasive Bladder Cancer. ESMO. - esmo.org