Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer

Abstract

Purpose: Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting.

Patients and methods: In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms.

Results: The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%).

Conclusion: EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.

Trial registration: ClinicalTrials.gov NCT03288545.

FIG 1.

CONSORT diagram. Screening, allocation, follow-up, and analyses. A patient is considered discontinued from the treatment only if both agents are discontinued, including patients who discontinued both agents because of AE(s) or discontinued the latter of the two agents because of an AE (the other agent may be discontinued because of a non-AE at an earlier time). AE, adverse event; EV, enfortumab vedotin; PD, progressive disease; Pembro, pembrolizumab.

FIG 2.

(A) Best overall response by BICR. (B) Antitumor activity of EV + Pembro, waterfall plot of percentage reduction of tumor size from baseline of target lesions by BICR per RECIST v1.1. BICR, blinded independent central review; CPS, combined positive score; CR, complete response; EV, enfortumab vedotin; ORR, objective response rate; PD, progressive disease; Pembro, pembrolizumab; PR, partial response.

FIG 3.

(A) Durations of response per BICR by RECIST v1.1. (B) Kaplan-Meier estimate of durations of response per BICR, EV + Pembro treatment arm. (C) Kaplan-Meier estimate of durations of response per BICR, EV monotherapy treatment arm. This study was not designed with statistical comparison between the two treatment arms; direct comparisons should not be made. BICR, blinded independent central review; DOR, duration of response; EV, enfortumab vedotin; mDOR, median duration of response; mono, monotherapy; PD, progressive disease; Pembro, pembrolizumab; v1.1, version 1.1.

FIG 4.

EV + Pembro. (A) PFS per BICR, by RECIST v1.1, OS, and median follow-up time. (B) Kaplan-Meier estimate of PFS per BICR by RECIST v1.1. (C) Kaplan-Meier estimate of OS. Preliminary mPFS and mOS are reported here and are expected to evolve over time. At the time of data cutoff, 54 (of 76) patients remain on study for OS follow-up. BICR, blinded independent central review; EV, enfortumab vedotin; mOS, median overall survival; mPFS, median progression-free survival; OS, overall survival; Pembro, pembrolizumab; PFS, progression-free survival; v1.1, version 1.1.

FIG 5.

EV monotherapy. (A) PFS per BICR by RECIST v1.1, OS, and median follow-up time. (B) Kaplan-Meier estimates of PFS per BICR by RECIST v1.1. (C) Kaplan-Meier estimates of OS. Preliminary mPFS and mOS are reported here and are expected to evolve over time. At the time of data cutoff, 46 (of 73) patients remain on study for OS follow-up. BICR, blinded independent central review; EV, enfortumab vedotin; mOS, median overall survival; mPFS, median progression-free survival; OS, overall survival; PFS, progression-free survival; v1.1, version 1.1.

FIG A1.

Antitumor activity of EV monotherapy. Waterfall plot of percentage reduction of tumor size from baseline of target lesions by blinded independent central review per RECIST version 1.1. CR, complete response; EV, enfortumab vedotin; PR, partial response.

FIG A2.

Subgroup analysis of ORR in patients treated with EV + Pembro and patients treated with EV monotherapy. ^aOne patient had primary disease at both bladder and ureter. CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; EV, enfortumab vedotin; ORR, objective response rate; Pembro, pembrolizumab.

FIG A3.

H-score of nectin-4 expression at baseline by best overall response by blinded independent central review in responders and nonresponders. (A) EV + pembrolizumab. (B) EV monotherapy. EV, enfortumab vedotin; MAX, maximum; MIN, minimum; Q1, 1st quartile; Q3, 3rd quartile; SD, standard deviation.