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

KEY FINDINGS

• Expanded approval: On 10 July 2026 the FDA approved the use of pembrolizumab (Keytruda) or pembrolizumab plus berahyaluronidase alfa-pmph (Keytruda Qlex) together with enfortumab vedotin-ejfv (Padcev) both before (neoadjuvant) and after (adjuvant) cystectomy - the previous approval was limited to cisplatin-ineligible patients only.
• KEYNOTE-B15/EV-304 phase 3 (n=808): Statistically significant superiority with an event-free survival (EFS) HR of 0.53 (95% CI 0.41-0.70; p<0.0001) and an overall survival (OS) HR of 0.65 (95% CI 0.48-0.89; p=0.0029).
• International review: The assessment was conducted simultaneously with the regulatory agencies of Australia, Canada, Switzerland, the United Kingdom and Israel under the FDA's Project Orbis programme.

Study Design and Background

Muscle-invasive bladder cancer (MIBC) is a challenging clinical entity that follows a course with high recurrence and mortality rates even in patients treated with curative intent by radical cystectomy. Although cisplatin-based neoadjuvant chemotherapy has been the standard approach for many years, a substantial proportion of patients are not eligible for cisplatin because of nephrotoxicity, hearing loss or performance status; even among those who are eligible, response rates and survival gains can remain limited.

The KEYNOTE-B15/EV-304 trial randomized 808 previously untreated MIBC patients who were candidates for radical cystectomy with pelvic lymph node dissection and eligible for cisplatin-based chemotherapy 1:1 to one of two arms: (1) neoadjuvant pembrolizumab plus enfortumab vedotin-ejfv → surgery → adjuvant pembrolizumab plus enfortumab vedotin-ejfv, or (2) neoadjuvant gemcitabine plus cisplatin → surgery. The primary endpoint was event-free survival (EFS) measured by independent central review; overall survival (OS) was assessed as an additional efficacy measure.

Key Results

Safety profile: Similar to what has previously been observed with this combination in urothelial cancer; immune-related adverse events and skin reactions, hyperglycaemia, pneumonitis and peripheral neuropathy specific to enfortumab vedotin were seen.

Recommended dosing schedule: In cisplatin-eligible patients, the neoadjuvant phase consists of pembrolizumab 200 mg IV every 3 weeks (or 400 mg IV every 6 weeks) with enfortumab vedotin-ejfv 1.25 mg/kg (maximum 125 mg in patients ≥100 kg) on days 1 and 8 of a 21-day cycle, for a total of 4 cycles (12 weeks). In the adjuvant phase, enfortumab vedotin continues for 5 further cycles (15 weeks of combination in total), followed by pembrolizumab as a single agent to complete a total adjuvant treatment duration of 39 weeks.

Implications for Clinical Practice

Potential to change practice

This expanded approval is an important turning point for the uro-oncology community: the perioperative immunotherapy plus antibody-drug conjugate combination is no longer restricted to cisplatin-ineligible patients but has become an option in all MIBC patients who are candidates for cystectomy. When neoadjuvant treatment preference is discussed in multidisciplinary uro-oncology boards, the significant gains demonstrated in EFS and OS make this regimen a serious alternative to classical cisplatin-based chemotherapy.

Re-evaluating the choice of neoadjuvant protocol in the light of these data in patients scheduled for robotic radical cystectomy is important for surgical timing and multidisciplinary coordination. Because of the adverse event profile, patient selection and close follow-up will be decisive for the sustainability of treatment success.

Conclusion

This FDA approval rests on strong phase 3 evidence reinforcing the role of perioperative immunotherapy combinations in the treatment of muscle-invasive bladder cancer. The indication, extended to cover all cystectomy candidates regardless of cisplatin eligibility, is an important development expected to prompt updates in treatment algorithms and international guidelines (EAU, AUA/SUO) in the period ahead. In uro-oncology practice these data once again underline the importance of individualised perioperative treatment planning on a patient-by-patient basis.

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
• FDA approves enfortumab vedotin plus pembrolizumab for MIBC. Urology Times. - urologytimes.com
• FDA Approves Perioperative Enfortumab Vedotin Plus Pembrolizumab for Cisplatin-Ineligible MIBC (previous approval, for comparison). OncLive. - onclive.com
• FDA Approves Pembrolizumab with Enfortumab Vedotin-ejfv for Muscle Invasive Bladder Cancer. ESMO. - esmo.org