U.S. — The United States Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa (Keytruda Qlex) in combination with enfortumab vedotin (Padcev) as a perioperative treatment for adults with muscle-invasive bladder cancer. This approval applies regardless of a patient's eligibility for cisplatin.

This decision expands the regimen's prior indication, which previously covered only cisplatin-ineligible patients, to include all patients with muscle-invasive bladder cancer who are candidates for cystectomy. The expanded indication was based on data collected from the KEYNOTE-B15/EV-304 trial.

The KEYNOTE-B15/EV-304 trial was an open-label, randomized, multicenter study that included 808 patients with previously untreated muscle-invasive bladder cancer. Participants were eligible for cisplatin-based chemotherapy and were candidates for radical cystectomy with pelvic lymph node dissection.

In the trial, the median event-free survival was not reached for patients who received the PD-1 inhibitor and antibody-drug conjugate combination. For patients treated with gemcitabine and cisplatin, the median event-free survival was 48.5 months. The hazard ratio for event-free survival was 0.53 (95% CI 0.41-0.70, P<0.0001).

Event-free survival rates at 12 months were 86% with the combination therapy, compared to 75.4% with standard chemotherapy. At 24 months, these rates were 79.4% for the combination therapy and 66.2% for standard chemotherapy. Patients in the intervention group demonstrated a 35% reduced risk of death compared to those in the control group, with a hazard ratio for overall survival of 0.65 (95% CI 0.48-0.89).

"For muscle-invasive bladder cancer, a comprehensive treatment approach is important; the neoadjuvant phase can help shrink the tumor and target undetectable cancer cells early before surgery, while the adjuvant phase can be critical in eliminating residual, undetectable cancer cells following surgery," said Christopher Hoimes, a physician at Duke Cancer Institute. "These data from [KEYNOTE-B15/EV-304] and this approval show that by delivering this regimen across both the neoadjuvant and adjuvant phases, without platinum-based chemotherapy, we can significantly reduce the risk of recurrence and improve overall survival -- offering a potential new standard of care for adult patients with muscle-invasive bladder cancer."

The overall safety profile observed in KEYNOTE-B15/EV-304 for pembrolizumab and enfortumab vedotin aligned with previous trials of this combination in bladder cancer. The prescribing information for pembrolizumab includes warnings for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity. Enfortumab vedotin's prescribing information includes warnings regarding skin reactions, hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.

Why It Matters

This expanded FDA approval means a treatment combination previously accessible only to cisplatin-ineligible patients is now available to a broader adult population with muscle-invasive bladder cancer who are candidates for surgery. The KEYNOTE-B15/EV-304 trial findings, which supported this approval, documented improvements in event-free survival and overall survival rates with the combination therapy compared to standard chemotherapy.