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.
Arjun Vasant Balar, Bradley A. McGregor, Jonathan E. Rosenberg, Michiel Simon Van Der Heijden, Se Hoon Park, Jae‐Lyun Lee, Michael R. Harrison, Elisabeth I. Heath, Mark N. Stein, Yohann Loriot, Andrea Necchi, Joyce Steinberg, Shang-Ying Liang, Eric H. Kim, Janet Trowbridge, Mary S. Campbell, Daniel P. Petrylak, Evan Y. Yu
Abstract
394 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.