New Standard of Care: EV/Pembro Significantly Improves Survival in Previously Untreated la/mUC

Results of the global, phase 3, open-label, randomized EV-302/KEYNOTE-A39 study showed nearly double the median progression-free survival (PFS) and overall survival (OS) benefit in patients with previously untreated locally advanced metastatic urothelial carcinoma (la/mUC) after enfortumab vedotin (EV) plus pembrolizumab versus chemotherapy.

Thomas B. Powles, MBBS, MRCP, MD, of the Barts Cancer Centre at St. Bartholomew’s Hospital, presented the results as a late-breaking abstract at the European Society for Medical Oncology Congress 2023.

Platinum-based chemotherapy is considered standard of care in patients with la/mUC. However, long-term outcomes in this population are poor.

In EV-302/KEYNOTE-A39, a total of 886 patients who were eligible for cisplatin- or carboplatin-containing chemotherapy were randomized (1:1) to receive 3-week cycles of EV (1.25 mg/kg intravenously) on days 1 and 8 and pembrolizumab (200 mg intravenously) on day 1 (n=442) or gemcitabine with cisplatin or carboplatin (n=444).

The dual primary end points were PFS (per Response Evaluation Criteria in Solid Tumours version 1.1 by blinded independent central review) and OS. Secondary end points included overall response rate (ORR) and safety.

At the data cutoff, median follow-up was 17.2 months. Dr. Powles reported that PFS was significantly prolonged in the experimental arm, reducing the risk of progression or death by 55% (median PFS, 12.5 vs 6.3 months, respectively; hazard ratio [HR], 0.45; 95% CI, 0.38-0.54; P<.00001). Similarly, OS was significantly prolonged in the experimental arm, reducing the risk of death by 53% (median OS, 31.5 vs 16.1 months, respectively; HR, 0.47; 95% CI, 0.38-0.58; P<.00001).

Additionally, he shared that the confirmed ORR was 67.7% and 44.4%, respectively (P<.00001).

Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 55.9% and 69.5% of patients, respectively; the most common TRAEs were maculopapular rash (7.7%), hyperglycemia (5.0%), and neutropenia (4.8%) in the experimental arm and anemia (31.4%), neutropenia (30.0%), and thrombocytopenia (19.4%) in the chemotherapy arm. The most common grade 3 or higher TRAEs of special interest for EV included skin reactions (15.5%), peripheral neuropathy (6.8%), and hyperglycemia (6.1%), while skin reactions (11.8%) were the most common TRAE of special interest for pembrolizumab.

With the significant improvement in PFS and OS associated with EV plus pembrolizumab, along with the “generally manageable” safety profile of this combination, Dr. Powles and colleagues believe that EV plus pembrolizumab should be considered a new standard of care for first-line la/mUC.