Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Hoimes, C. J., Flaig, T. W., Milowsky, M. I., Friedlander, T. W., Bilen, M. A., Gupta, S., Srinivas, S., Merchan, J. R., McKay, R. R., Petrylak, D. P., Sasse, C., Moreno, B. H., Yu, Y., Carret, A. S., Rosenberg, J. E. 2022: 101200JCO2201643


Cisplatin-based combination chemotherapy remains the standard of care for locally advanced or metastatic urothelial cancer (la/mUC); however, toxicity is substantial, responses are rarely durable, and many la/mUC patients are ineligible. Enfortumab vedotin and pembrolizumab have each shown a survival benefit versus chemotherapy in UC, are not restricted by cisplatin eligibility, and warrant investigation as a first-line (1L) combination therapy in patients ineligible for cisplatin.In this ongoing Phase 1b/2, multicenter, open-label study, 1L cisplatin-ineligible patients with la/mUC received enfortumab vedotin 1.25 mg/kg (Days 1 and 8) and pembrolizumab 200 mg (Day 1) intravenously in 3-week cycles. The primary endpoint was safety. Key secondary endpoints included confirmed objective response rate (ORR), duration of response (DOR), and overall survival (OS).Forty-five patients received enfortumab vedotin plus pembrolizumab. The most common treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). Twenty-nine patients (64.4%) had grade 3 or higher TRAEs; the most common were increased lipase (17.8%), maculopapular rash (11.1%), and fatigue (11.1%). One death (2.2%) was classified as a TRAE. Confirmed ORR after a median of 9 cycles was 73.3% with a 15.6% complete response rate. Median DOR and median OS were 25.6 months and 26.1 months, respectively.Enfortumab vedotin plus pembrolizumab showed a manageable safety profile. Most patients experienced tumor shrinkage. 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 (NCT04223856).(Funded by Astellas Pharma US, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Seagen Inc; EV-103/KN-869 ClinicalTrials.gov number NCT03288545).

View details for DOI 10.1200/JCO.22.01643

View details for PubMedID 36041086