The FDA has approved enfortumab vedotin (Padcev, Astellas Pharma) in combination with pembrolizumab (Keytruda, Merck) or subcutaneous pembrolizumab (Keytruda Qlex, Merck) for the neoadjuvant and adjuvant treatment of muscle-invasive bladder cancer (MIBC) that is ineligible for cisplatin chemotherapy.

The approval was based on the open-label KEYNOTE-905/EV-303 trial in 344 previously untreated patients undergoing radical cystectomy with pelvic lymph node dissection who were ineligible for or who declined cisplatin-based chemotherapy.

Patients were randomly assigned equally to either immediate surgery or a treatment regimen that included neoadjuvant pembrolizumab with enfortumab vedotin, surgery, and then adjuvant pembrolizumab with enfortumab vedotin followed by pembrolizumab alone.

Median event-free survival with surgery alone was 15.7 months but was not reached in the pembrolizumab or enfortumab vedotin arm (hazard ratio [HR], 0.40; P < .0001). Median overall survival was 41.7 months in the surgery-alone group but not reached with pembrolizumab or enfortumab vedotin (HR, 0.50; P = .0002).

The probability of remaining event-free was 74.7% for patients who received the combination and 39.4% for patients treated with surgery only. The probability of survival at 2 years was 79.7% for the combination vs 63.1% for surgery alone, according to an Astellas press release.

Safety was consistent with previously reported findings for the combination, according to the company.

The most common (≥ 20%) adverse events were increased glucose, decreased hemoglobin, increased aspartate aminotransferase, rash, increased alanine aminotransferase, fatigue, pruritus, increased creatinine, decreased sodium, decreased lymphocytes, peripheral neuropathy, increased potassium, alopecia, dysgeusia, diarrhea, decreased appetite, constipation, nausea, decreased phosphate, urinary tract infection, dry eye, and decreased weight.

Grade 3 or worse adverse events occurred in 71.3% of patients treated with the combination vs 45.9% in the surgery-alone arm.

Pembrolizumab’s label includes warnings and precautions 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 and precautions for skin reactions, hyperglycemia, pneumonitis or interstitial lung disease, peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.

The recommended neoadjuvant pembrolizumab dose is 200 mg intravenous (IV) every 3 weeks administered in combination with enfortumab vedotin 1.25 mg/kg (up to a maximum of 125 mg for patients ≥ 100 kg) IV on days 1 and 8 of a 21-day cycle for three cycles, with a total duration of 9 weeks of neoadjuvant treatment.

In the adjuvant phase, enfortumab vedotin is continued for six additional cycles every 3 weeks in combination with pembrolizumab, administered either as 200 mg IV every 3 weeks for 14 cycles or 400 mg IV every 6 weeks for seven cycles. The duration of adjuvant pembrolizumab or enfortumab vedotin is 18 weeks with pembrolizumab, continuing alone another 24 weeks.

Pembrolizumab should be administered after enfortumab vedotin when given on the same day.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com