Pembrolizumab–Enfortumab Vedotin-ejfv Combination Approved for Muscle Invasive Bladder Cancer
Expert Perspectives
By Lyn Brook
Published
The FDA has approved pembrolizumab (Keytruda®, Merck) or pembrolizumab and berahyaluronidase alfa‑pmph (Keytruda Qlex™, Merck) in combination with enfortumab vedotin‑ejfv (Padcev®, Astellas) as neoadjuvant therapy, followed by adjuvant therapy after cystectomy, for adults with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin.
Why This Approval Matters
For patients with MIBC, cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is the standard approach, but a substantial proportion are ineligible for cisplatin due to comorbidities, organ dysfunction, or decline this treatment. Historically, these patients have proceeded directly to surgery, with inferior long-term outcomes. The approval of pembrolizumab (or pembrolizumab/berahyaluronidase alfa-pmph) plus enfortumab vedotin as both neoadjuvant and adjuvant therapy introduces a systemic option that significantly prolongs event-free survival (EFS) and overall survival (OS) compared with cystectomy alone, addressing a major unmet need in cisplatin-ineligible MIBC.
Breaking Down KEYNOTE-905/EV-303
Efficacy was based on KEYNOTE‑905/EV‑303 (NCT03924895), a phase 3, open‑label, randomized, multicenter, active‑controlled trial that enrolled 344 patients with previously untreated MIBC who were candidates for radical cystectomy (RC) with pelvic lymph node dissection (PLND) but were either ineligible for or declined cisplatin‑based chemotherapy.
Patients were randomized 1:1 to either receive:
- Experimental arm: Neoadjuvant pembrolizumab plus enfortumab vedotin‑ejfv for three cycles, followed by RC and PLND, then adjuvant enfortumab vedotin‑ejfv plus pembrolizumab, followed by pembrolizumab monotherapy.
- Control arm: Immediate RC with PLND alone.
The primary efficacy end point was EFS by Blinded Independent Central Review, and the key secondary end point was OS. The regimen of perioperative pembrolizumab plus enfortumab vedotin‑ejfv produced clinically and statistically significant improvements in both EFS and OS compared with surgery alone:
- EFS: Median EFS was not reached in the pembrolizumab/enfortumab vedotin arm versus 15.7 months in the surgery-alone arm.
- OS: Median OS was not reached in the pembrolizumab/enfortumab vedotin arm versus 41.7 months in the surgery‑alone arm.
Managing Adverse Events
The overall safety profile was similar to what was observed in previous trials of enfortumab vedotin-ejfv in advanced urothelial cancer. Pembrolizumab’s prescribing information includes warnings and precautions for immune-mediated adverse events, infusion-related reactions, allogeneic hematopoietic stem cell transplantation complications, and embryo-fetal toxicity. Enfortumab vedotin-ejfv’s prescribing information includes warnings and precautions for skin reactions, hyperglycemia, pneumonitis/interstitial lung disease (ILD), peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.
Dosing and Administration
For the neoadjuvant phase, the recommended regimen is:
- Pembrolizumab: 200 mg IV every three weeks
- Enfortumab vedotin‑ejfv: 1.25 mg/kg IV (maximum 125 mg for patients ≥100 kg) on Days 1 and 8 of a 21‑day cycle
Neoadjuvant treatment is given for three cycles (total nine weeks) prior to RC with PLND.
In the adjuvant phase following surgery:
- Enfortumab vedotin‑ejfv is administered every three weeks for six additional cycles in combination with pembrolizumab.
- Pembrolizumab may be given as either:
- 200 mg IV every three weeks for 14 cycles
- 400 mg IV every six weeks for seven cycles
The combination phase in the adjuvant setting lasts 18 weeks. The total duration of adjuvant therapy, including subsequent pembrolizumab monotherapy, is 42 weeks. When both agents are administered on the same day, pembrolizumab should be given after enfortumab vedotin‑ejfv.