The US FDA approved both Keytruda (pembrolizumab) and Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph), each combined with Padcev (enfortumab vedotin-ejfv), as perioperative therapy for adults with muscle-invasive bladder cancer (MIBC), regardless of cisplatin eligibility. The decision extends a prior approval — based on the KEYNOTE-905 trial for cisplatin-ineligible patients, as previously reported — to a substantially broader population, and establishes the combination as the first PD-1 inhibitor plus antibody-drug conjugate (ADC) regimen approved for MIBC irrespective of cisplatin eligibility.
The approval covers neoadjuvant use followed by adjuvant continuation post-cystectomy. Keytruda is administered intravenously at 200 mg on Day 1 of each 21-day cycle; Keytruda Qlex, a fixed-dose subcutaneous formulation co-formulated with berahyaluronidase alfa to facilitate dermal dispersion, is administered as a one-minute subcutaneous injection every three weeks. Padcev is dosed at 1.25 mg/kg intravenously on Days 1 and 8 of each 21-day cycle. The regimen is delivered for four neoadjuvant cycles prior to surgery, with adjuvant Keytruda continuing for up to 13 cycles and adjuvant Padcev for five cycles.
The new approval is supported by the Phase III KEYNOTE-B15 trial (also known as EV-304; NCT04700124), an open-label, randomized, active-controlled study enrolling 808 patients with previously untreated, cisplatin-eligible MIBC. Conducted in collaboration with Pfizer and Astellas, the trial compared perioperative Keytruda plus Padcev against neoadjuvant gemcitabine plus cisplatin followed by observation. The primary endpoint was event-free survival (EFS) as assessed by blinded independent central review. Keytruda plus Padcev demonstrated a statistically significant 47% reduction in the risk of EFS events compared with chemotherapy (HR=0.53 [95% CI, 0.41–0.70]; p<0.0001), with a pathological complete response rate of 44% versus 12% in the chemotherapy arm.
Keytruda blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2, restoring T-cell-mediated anti-tumor activity. Padcev targets Nectin-4, a cell adhesion molecule overexpressed in urothelial tumors, delivering the cytotoxic payload monomethyl auristatin E (MMAE) directly to tumor cells. The mechanistic complementarity — immune checkpoint disinhibition combined with targeted cytotoxic delivery — provides a rationale for the combination that does not depend on cisplatin sensitivity.