EV-302: Subanalysis of Cisplatin-Eligible Population

A recent subanalysis of the cisplatin-eligible population from the EV-302/KEYNOTE-A39 trial confirms that the combination of enfortumab vedotin (EV) and pembrolizumab significantly improves clinical outcomes for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). This combination therapy demonstrated superior progression-free survival (PFS) and overall survival (OS) compared with traditional platinum-based chemotherapy (PBC). The results will be presented at the 2024 American Society of Clinical Oncology Annual Meeting by lead author Jens Bedke, MD, of the Department of Urology and Eva Mayr-Stihl Cancer Center, Klinikum Stuttgart, in Germany.

The phase 3 EV-302/KEYNOTE-A39 trial is a global, randomized, open-label study designed to compare EV combined with pembrolizumab against PBC as first-line treatment for patients with la/mUC, irrespective of their eligibility for cisplatin. The trial’s previous findings indicated a statistically significant and clinically meaningful benefit of EV plus pembrolizumab over PBC for the dual primary end points of PFS and OS, leading to US Food and Drug Administration approval of EV plus pembrolizumab for adults with la/mUC in December 2023.

In this study, patients with previously untreated la/mUC were randomized in a 1:1 ratio to receive either EV (1.25 mg/kg IV on days 1 and 8) and pembrolizumab (200 mg IV on day 1) in 3-week cycles, or PBC (gemcitabine with cisplatin or carboplatin). The analysis focused on the subset of patients eligible for cisplatin, as determined by protocol-defined criteria. Key secondary end points included confirmed objective response rate (ORR), duration of response (DOR), and safety.

Out of 478 cisplatin-eligible patients, 244 received EV plus pembrolizumab and 234 received PBC. In the PBC arm, 94% of patients received cisplatin at cycle 1. The median PFS was significantly longer for the EV plus pembrolizumab group (14.6 months) compared with the PBC group (6.5 months; hazard ratio [HR], 0.48; 95% CI, 0.38-0.62). Similarly, the median OS was 31.5 months for EV plus pembrolizumab and 18.4 months for PBC (HR, 0.53; 95% CI, 0.39-0.72).

The ORR for the EV plus pembrolizumab group was 70.8%, including a 32.5% complete response rate. In contrast, the ORR for the PBC group was 53.0%, with a 15.5% complete response rate. The median DOR was not reached for the EV plus pembrolizumab group, while it was 8.3 months for the PBC group.

Regarding safety, grade ≥3 treatment-related adverse events (TRAEs) were observed in 53.9% of patients receiving EV plus pembrolizumab and 62.7% of those receiving PBC. Common severe TRAEs for EV included skin reactions (14.8%), hyperglycemia (7.8%), and peripheral neuropathy (5.8%). For pembrolizumab, the most frequent severe TRAEs were skin reactions (9.5%), pneumonitis (4.9%), and colitis (2.9%).

The findings from the EV-302/KEYNOTE-A39 trial indicate that the combination of EV and pembrolizumab significantly improves clinical outcomes for cisplatin-eligible patients with previously untreated la/mUC. “The results of EV-302 support EV [plus pembrolizumab] as a new standard of care for la/mUC, including patients who are eligible for cisplatin,” the study authors stated. The safety profile of EV plus pembrolizumab was manageable, with no new safety concerns, making it a viable option for first-line treatment in this patient population.