FDA Expands Perioperative Treatment Approval for Muscle-Invasive Bladder Cancer

Efficacy and Safety

Efficacy was evaluated in KEYNOTE-B15/EV-304 (NCT04700124), an open-label, randomized, active-controlled, multicenter trial in 808 patients with previously untreated MIBC who were candidates for radical cystectomy with pelvic lymph node dissection and were eligible for cisplatin-based chemotherapy. Patients were randomized (1:1) to receive neoadjuvant pembrolizumab and enfortumab vedotin-ejfv followed by surgery followed by adjuvant pembrolizumab and enfortumab vedotin-ejfv or to neoadjuvant gemcitabine and cisplatin followed by surgery.

The major efficacy outcome measure was event-free survival (EFS) assessed by blinded independent central review. Overall survival (OS) was an additional efficacy outcome. The trial demonstrated statistically significant improvements in EFS and OS in patients treated with perioperative pembrolizumab and enfortumab vedotin-ejfv compared with neoadjuvant gemcitabine and cisplatin. Median EFS was not reached (NR) (95% CI: NR, NR) in the pembrolizumab with enfortumab vedotin-ejfv arm and was 48.5 months (95% CI: 43.3, NR) in the gemcitabine with cisplatin arm (hazard ratio 0.53 [95% CI: 0.41, 0.70]; p-value <0.0001). Median OS was not reached in either arm (hazard ratio 0.65 [95% CI: 0.48, 0.89]; p-value 0.0029).

The overall safety profile of pembrolizumab with enfortumab vedotin-ejfv in KEYNOTE-B15/EV-304 was similar to that observed in prior trials of this combination in urothelial cancer. The prescribing information for pembrolizumab includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity. The prescribing information for enfortumab vedotin-ejfv includes warnings and precautions for skin reactions, hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity.

Recommended Dosage

For patients who are cisplatin-eligible, the recommended pembrolizumab dose for neoadjuvant treatment is 200 mg IV every 3 weeks or 400 mg IV every 6 weeks administered in combination with enfortumab vedotin-ejfv 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 4 cycles for a total duration of 12 weeks of neoadjuvant treatment. In the adjuvant phase, enfortumab vedotin-ejfv is continued for 5 additional cycles, every 3 weeks in combination with pembrolizumab, administered either as 200 mg IV every 3 weeks for 13 cycles or 400 mg IV every 6 weeks for 7 cycles. The duration of the combination of pembrolizumab and enfortumab vedotin-ejfv in the adjuvant setting is 15 weeks and the overall duration of adjuvant therapy, including pembrolizumab as a single agent, is 39 weeks. Administer pembrolizumab after enfortumab vedotin-ejfv when given on the same day.

For dosage and administration information for pembrolizumab and berahyaluronidase alfa-pmph given in combination with enfortumab vedotin-ejfv, refer to the Keytruda Qlex prescribing information.