Enfortumab vedotin plus pembrolizumab led to an objective response rate (ORR) of 73.3% as a first-line combination therapy in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer, according to results of an ongoing phase 1b/2 study.
Christopher Hoimes, DO, PhD, of the Duke Cancer Institute at Duke University and the Seidman Cancer Center at the University Hospitals of Cleveland at Case Western Reserve University, and colleagues conducted the study and published its results in the Journal of Clinical Oncology.
Enfortumab vedotin is a nectin-4-directed antibody and microtubule inhibitor conjugate approved in 2021 by the US Food and Drug Administration for use in cisplatin-ineligible patients who have received at least 1 prior line of therapy. Pembrolizumab is an immune checkpoint inhibitor directed at PD-1.
“Cisplatin-based combination chemotherapy remains the standard of care for locally advanced or metastatic urothelial cancer; however, toxicity is substantial, responses are rarely durable, and many patients [with locally advanced or metastatic urothelial cancer] are ineligible,” Dr. Hoimes and colleagues wrote. “Enfortumab vedotin and pembrolizumab have each shown a survival benefit versus chemotherapy in [urothelial cancer], are not restricted by cisplatin eligibility, and warrant investigation as a first-line combination therapy in patients ineligible for cisplatin.”
The multicenter open-label study included 45 cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. Most patients were male (80%), and the median patient age was 69 years. The patients received enfortumab vedotin 1.25 mg/kg on days 1 and 8 and pembrolizumab 200 mg intravenously on day 1 of each 3-week cycle. The study’s primary end point was safety, with secondary end points including ORR, duration of response (DOR), and overall survival (OS).
The median DOR was 25.6 months. The median progression-free survival was 12.3 months, and the median OS was 26.1 months at a follow-up of 24.9 months. The ORR was 73.3%, with a 15.6% complete response rate after a median of 9 cycles. The disease control rate was 93.3%. The median time to response was 2.1 months, with 87.9% of responses observed at the first tumor assessment.
The most common treatment-related adverse events were peripheral sensory neuropathy (reported in 55.6% of patients), fatigue (51.1%), and alopecia (48.9%). The researchers reported ≥ grade 3 treatment-related adverse events in 29 patients (64.4%). The most common ≥ grade 3 events included increased lipase (17.8%), maculopapular rash (11.1%), and fatigue (11.1%). Investigators classified 1 death as a treatment-related adverse event.
“Enfortumab vedotin plus pembrolizumab showed a manageable safety profile. Most patients experienced tumor shrinkage,” Dr. Hoimes and colleagues concluded. “The median DOR and median OS exceeding 2 years in a cisplatin-ineligible patient population make this a promising combination currently under investigation in a phase 3 study.”
Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol. 2022. doi:10.1200/JCO.22.01643