On November 21, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) or the subcutaneous formulation pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) in combination with enfortumab vedotin-ejfv (Padcev) as neoadjuvant treatment followed by adjuvant treatment after cystectomy for adults with muscle-invasive bladder cancer who are ineligible for cisplatin.
KEYNOTE-905/EV-303
Efficacy was evaluated in KEYNOTE-905/EV-303 (ClinicalTrials.gov identifier NCT03924895), an open-label, randomized, multicenter, active-controlled trial in 344 patients with previously untreated muscle-invasive bladder cancer who were candidates for radical cystectomy with pelvic lymph node dissection but were ineligible for or declined cisplatin-based chemotherapy. Patients were randomly assigned 1:1 to receive neoadjuvant pembrolizumab and enfortumab vedotin-ejfv followed by surgery followed by adjuvant enfortumab vedotin-ejfv in combination with pembrolizumab followed by pembrolizumab as a single agent, or to undergo immediate surgery alone.
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 event-free and overall survival in patients treated with pembrolizumab and enfortumab vedotin-ejfv before and after radical cystectomy and pelvic lymph node dissection compared with surgery alone. Median event-free survival was not reached (95% confidence interval [CI] = 37.3 months to not reached) in the pembrolizumab and enfortumab vedotin arm and was 15.7 months (95% CI = 10.3–20.5 months) in the surgery alone arm (hazard ratio [HR] = 0.40, 95% CI = 0.28–0.57, P < .0001). Median overall survival was not reached (95% CI = not reached to not reached) and 41.7 months (95% CI = 31.8 months to not reached) in the respective arms (HR = 0.50, 95% CI = 0.33–0.74, P = .0002).
The overall safety profile of enfortumab vedotin-ejfv with pembrolizumab in KEYNOTE-905/EV-303 was similar to that observed in prior trials in advanced urothelial cancer. The pembrolizumab prescribing information includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity. The enfortumab vedotin-ejfv prescribing information 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
The recommended pembrolizumab dose for neoadjuvant treatment is 200 mg intravenously every 3 weeks administered in combination with enfortumab vedotin-ejfv at 1.25 mg/kg (up to a maximum of 125 mg for patients ≥ 100 kg) intravenously on days 1 and 8 of a 21-day cycle for three cycles for a total duration of 9 weeks of neoadjuvant treatment. In the adjuvant phase, enfortumab vedotin-ejfv is continued for six additional cycles every 3 weeks in combination with pembrolizumab, administered either as 200 mg intravenously every 3 weeks for 14 cycles or 400 mg intravenously every 6 weeks for 7 cycles. The duration of the combination of pembrolizumab and enfortumab vedotin-ejfv in the adjuvant setting is 18 weeks, and the overall duration of adjuvant therapy, including pembrolizumab as a single agent, is 42 weeks. Administer pembrolizumab after enfortumab vedotin 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.
Expedited Programs
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, and the United Kingdom’s Medicines and Healthcare products Regulatory Agency. 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 months ahead of the FDA goal date.
This application was granted Priority Review.
