Paradigm Shift in the Management of Advanced Urothelial Cancer

Platinum-based chemotherapy has long been the standard of care for metastatic urothelial cancer, with cisplatin eligibility determined based on clinical and laboratory features. Recently, both pembrolizumab, a PD-1 inhibitor, and enfortumab vedotin, an antibody–drug conjugate directed against nectin-4, demonstrated improved overall survival (OS) compared with a variety of chemotherapeutic agents in phase 3 studies, and the combination of enfortumab vedotin and pembrolizumab (EVP) demonstrated provocative antitumor activity in a phase 2 study. Now, in an industry-funded, global, phase 3, randomized trial, investigators compared platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin) against EVP.

Eligible patients had unresectable or metastatic urothelial cancer with adequate organ function and performance status (ECOG score ≤2); perioperative chemotherapy was permitted if recurrence occurred more than 1 year after completion of therapy. Of 886 patients, median age was 69 and most were male (77%) and white (68%); <2% were African-American.

At a median follow-up of 17.2 months, the two primary outcomes — progression-free survival (PFS) and OS — were longer in the EVP group than the chemotherapy group (median PFS, 12.5 vs. 6.3 months; hazard ratio, 0.45; P< 0.001; and median OS, 31.5 vs. 16.1 months; HR, 0.47; P< 0.001). Any grade neuropathy occurred in 50.0% of patients in the EVP group and led to discontinuation of treatment in 10.7%. Grade 3 or higher treatment-related adverse events occurred in 55.9% of the EVP group and 69.5% of the chemotherapy group, most commonly maculopapular rash (7.7%), hyperglycemia (5.0%), and neutropenia (4.8%) with EVP and anemia (31.4%), neutropenia (30.0%), and thrombocytopenia (19.4%) with chemotherapy.