On July 10, the U.S. Food and Drug Administration (FDA) approved the PD-1 inhibitor pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex), each in combination with the NECTIN4-directed antibody-drug conjugate enfortumab vedotin-ejfv (Padcev), as neoadjuvant treatment followed by adjuvant treatment after cystectomy for adults with muscle-invasive bladder cancer (MIBC). This extends the prior approval for the regimen in this setting from patients who are cisplatin-ineligible to all patients with MIBC who are candidates for cystectomy.
KEYNOTE-B15/EV-304
Efficacy was evaluated in KEYNOTE-B15/EV-304 (ClinicalTrials.gov identifier 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 randomly assigned 1:1 to receive neoadjuvant pembrolizumab and enfortumab vedotin followed by surgery followed by adjuvant pembrolizumab and enfortumab vedotin, or to neoadjuvant gemcitabine and cisplatin followed by surgery.
The major efficacy outcome measure was event-free survival assessed by blinded independent central review; overall survival was an additional efficacy outcome. The trial demonstrated statistically significant improvements in both event-free and overall survival in patients treated with perioperative pembrolizumab and enfortumab vedotin compared with neoadjuvant gemcitabine and cisplatin. Median event-free survival was not reached (95% confidence interval [CI] = not reached to not reached) in the pembrolizumab with enfortumab vedotin arm and was 48.5 months (95% CI = 43.3 months to not reached) in the gemcitabine with cisplatin arm (hazard ratio [HR] = 0.53, 95% CI = 0.41–0.70, P < .0001). Median overall survival was not reached in either arm (HR = 0.65, 95% CI = 0.48–0.89, P = .0029).
The overall safety profile of pembrolizumab with enfortumab vedotin 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 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 intravenously (IV) every 3 weeks or 400 mg IV every 6 weeks administered in combination with enfortumab vedotin at 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 four cycles for a total duration of 12 weeks of neoadjuvant treatment. In the adjuvant phase, enfortumab vedotin is continued for five 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 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 when given on the same day.
For dosage and administration information for pembrolizumab and berahyaluronidase alfa given in combination with enfortumab vedotin, refer to the Keytruda Qlex prescribing information.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, Switzerland’s Swissmedic, the United Kingdom’s Medicines and Healthcare products Regulatory Agency, and the Israel Ministry of Health. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 5 weeks ahead of the FDA goal date.
This application was granted Priority Review.
