Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors: An updated analysis of EV-201 Cohort 2.
Authors: McGregor Bradley Alexander , Balar Arjun Vasant , Rosenberg Jonathan E. , Van Der Heijden Michiel Simon , Park Se Hoon , Lee Jae-Lyun , Kojima Takahiro , Harrison Michael Roger , Heath Elisabeth I. , Stein Mark N. , Loriot Yohann , Necchi Andrea , Steinberg Joyce Leta , Liang Shang-Ying , Trowbridge Janet , Petrylak Daniel P. , Yu Evan Y. 
Published: June 2021

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Background: Cisplatin (cis)-ineligible, platinum-naive patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) who progress on/after anti-PD-1/L1 treatment (tx) have a poor prognosis and few tx options. Enfortumab vedotin (EV), a Nectin-4-directed antibody-drug conjugate, demonstrated overall survival (OS) benefit in pts with la/mUC who previously received anti-PD-1/L1 tx and platinum-containing chemotherapy (EV-301). EV-201 (NCT03219333) is a pivotal, single-arm, 2-cohort (C) study. C2 enrolled cis-ineligible pts with prior anti PD-1/L1 tx and no prior platinum for la/mUC. Results of the C2 primary analysis were previously presented. In this updated analysis, with 3 additional mo of follow-up (f/u), all responders were followed for ≥6 mo after onset of response. Methods: Pts received 1.25 mg/kg EV on Days 1, 8, and 15 of each 28-day cycle. The primary endpoint was confirmed objective response rate (ORR) per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints were duration of response (DOR), progression-free survival (PFS), OS, and safety. Results: 91 pts were enrolled and 89 treated in C2. Median (m) age was 75 y (range: 49-90). Pts were cis-ineligible at baseline, primarily due to CrCl < 60 mL/min (78%). Primary tumor site was upper tract in 43%, and 79% had visceral mets, including 24% with liver mets. As of 04 Dec 2020 (data cut-off), m f/u was 16.0 mo and m tx duration was 6.0 mo (range: 0.3-24.6). Confirmed ORR per BICR was 51% (95% confidence interval [CI] 39.8-61.3), including 22% complete response (CR) among treated pts. mDOR was 13.8 mo (95% CI 6.4-not reached). mPFS and mOS were 6.7 mo (95% CI 5.0-8.3) and 16.1 mo (95% CI 11.3-24.1), respectively. All-grade and grade (G) ≥3 tx-related adverse events (TRAEs) were reported in 97% and 55% of pts, respectively. Most common all-grade TRAEs were alopecia (51%), peripheral sensory neuropathy (49%), and fatigue (34%). For TRAEs ≥G3, each preferred term occurred in < 10% pts. TRAEs of interest included skin reactions (61% all grade, 17% ≥G3), peripheral neuropathy (56% all grade, 8% ≥G3), and hyperglycemia (10% all grade, 6% ≥G3). Four deaths were previously reported as tx related by investigators: 3 events ≤30 d of first EV dose (acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome) and 1 > 30 d of last EV dose (pneumonitis). Conclusions: Efficacy and safety in this updated analysis of EV-201 C2 are consistent with the primary analysis. The majority of platinum-naive, cis-ineligible la/mUC pts who progressed on/after anti-PD-1/L1 tx responded to EV, with 22% achieving CR and mDOR exceeding a year. PFS and OS continue to be encouraging in this elderly population, with no new safety signals. These data show the potential for EV as a non-platinum option for cis-ineligible pts following anti-PD-1/L1 tx. Clinical trial information: NCT03219333.