EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors.
Authors: Balar Arjun Vasant , McGregor Bradley Alexander , Rosenberg Jonathan E. , Van Der Heijden Michiel Simon , Park Se Hoon , Lee Jae-Lyun , Harrison Michael Roger , Heath Elisabeth I. , Stein Mark N. , Loriot Yohann , Necchi Andrea , Steinberg Joyce Leta , Liang Shang-Ying , Kim Eric , Trowbridge Janet , Campbell Mary S. , Petrylak Daniel Peter , Yu Evan Y. 
Published: March 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 PD-1/L1 inhibitors (PD-1/L1-i) have a poor prognosis and few treatment (tx) options. Enfortumab vedotin (EV) is an antibody-drug conjugate directed against Nectin-4, an immunoglobulin-like cell adhesion molecule highly expressed in UC. EV-201 (NCT03219333) is a pivotal, single-arm, 2-cohort study of EV in la/mUC; Cohort (C) 1 data led to FDA accelerated approval of EV in adult pts with la/mUC who previously received a PD-1/L1-i and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, la/mUC setting. Here, we present the primary analysis from C2: cis-ineligible pts with prior PD-1/L1-i and no prior platinum for la/mUC. Methods: Pts in this open-label, multicenter, multinational study received 1.25 mg/kg EV on Days 1, 8, and 15 of each 28-day cycle. 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), overall survival (OS), and safety. Results: As of 08 Sep 2020 (data cutoff), 91 pts were enrolled and 89 treated in C2. Pts were elderly (median age: 75 y [range: 49-90]) with comorbidities, including moderate/severe renal impairment. Pts were cis-ineligible at study entry due to CrCl < 60 mL/min (66%), Grade ≥2 hearing loss (15%), or ECOG PS 2 (7%); an additional 12% met ≥1 criterion. The primary tumor site was in upper tract in 43%; 79% had visceral mets, including 24% with liver mets. Median (m) tx duration was 6.0 mo (range: 0.3 – 24.6). Confirmed ORR per BICR was 52% (95% CI: 40.8–62.4), including 20% CR among treated pts. mDOR was 10.9 mo (95% CI: 5.8–NR). mPFS and mOS were 5.8 mo (95% CI 5.0-8.3) and 14.7 mo (95% CI 10.5-18.2), respectively. Most common all-grade tx-related AEs were alopecia (51%), peripheral sensory neuropathy (47%), and fatigue (34%). Tx-related AEs of interest included rash (61% all grade, 17% ≥G3), peripheral neuropathy (54% all grade, 8% ≥G3), and hyperglycemia (10% all grade, 6% ≥G3). Four deaths were reported as tx related by investigators, all in pts ≥75 y with multiple comorbidities: 3 events ≤30 d of first EV dose in pts with BMI ≥30(acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome) and 1 event > 30 d after last dose (pneumonitis). Conclusions: In EV-201 C2, the majority of platinum-naive, cis-ineligible la/mUC pts who progressed on/after PD-1/L1-i achieved durable responses to EV, with 1/5 achieving CR. PFS and OS were encouraging. Safety was consistent with the previously reported AE profile of EV, within the context of a patient population with advanced malignancy and comorbidity. These data show the potential for EV as a non-platinum option following PD-1/L1-i. Clinical trial information: NCT03219333.