Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer

Abstract

Purpose: 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 patients with la/mUC are ineligible. Each enfortumab vedotin and pembrolizumab have 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.

Methods: In this ongoing phase Ib/II, multicenter, open-label study, 1L cisplatin-ineligible patients with la/mUC received enfortumab vedotin 1.25 mg/kg once daily on days 1 and 8 and pembrolizumab 200 mg (day 1) intravenously once daily in 3-week cycles. The primary end point was safety. Key secondary end points included confirmed objective response rate, duration of response (DOR), and overall survival (OS).

Results: 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. The confirmed objective response rate after a median of nine cycles was 73.3% with a complete response rate of 15.6%. The median DOR and median OS were 25.6 months and 26.1 months, respectively.

Conclusion: 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 III study (ClinicalTrials.gov identifier: NCT04223856).

Trial registration: ClinicalTrials.gov NCT03288545 NCT04223856.

FIG 1.

Screening, allocation, follow-up, and analyses. 2L, second-line; EV, enfortumab vedotin; pembro, pembrolizumab.

FIG 2.

Change in target lesions from baseline. (A) Waterfall plot of change from baseline in the sum of the diameters of target lesions by investigator per RECIST v1.1. (B) Change from baseline of the sum of diameters of target lesions (the dotted horizontal line indicates threshold for partial response (–30%) but is not necessarily indicative of response) and (C) Swimmer plot of time to response and duration of response in patients achieving confirmed objective response per RECIST v1.1. PD-L1 expression status was assessed using the combined positive score (low, < 10; high ≥ 10) with a validated PD-L1 IHC assay using the 22C3 antibody. Two patients did not have any post-baseline response assessments before the end of the study and did not have change from baseline in sum of the diameters of target lesions. CPS, combined positive score; CR, complete response; IHC, immunohistochemistry; PR, partial response.

FIG 3.

(A) DOR, (B) PFS, and (C) OS by the investigator per RECIST v1.1. DOR, duration of response; EV, enfortumab vedotin; OS, overall survival; PD, progressive disease; pembro, pembrolizumab; PFS, progression-free survival.