ASCO 2019: Preliminary Data from Cohort 1, EV-201: Prior Checkpoint Inhibitor and Platinum-containing Chemotherapy Treated with Enfortumab Vedotin Monotherapy for Locally Advanced or Metastatic Urothelial Cancer

Chicago, IL ( Locally advanced or metastatic urothelial cancer remains a lethal disease with limited treatment options for patients who progress on or after platinum and/or checkpoint inhibitor therapy. Response rates to second-line PD-1/L1 inhibitors are 13-21%, with few options once patients progress. Furthermore, single-agent chemotherapy post-platinum and post-PD-1/L1 inhibitors show very limited activity (ORR 11%).1  Enfortumab vedotin is an antibody-drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma, showing an objective response rate (ORR) of 45% in a phase I study of patients receiving prior PD-1/L1 inhibitors. The primary mechanism of enfortumab vedotin is a molecule that disrupts microtubules. Dr. Daniel Petrylak and colleagues presented results of EV-201 as a late-breaking abstract: A phase II study assessing enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors.

EV-201 enrolled patients in this open-label, multicenter study to receive 1.25 mg/kg enfortumab vedotin on Days 1, 8, and 15 of each 28-day cycle. The primary endpoint was confirmed ORR per RECIST 1.1 by blinded independent central review. Secondary endpoints are the duration of response, PFS, OS, safety/tolerability. Key eligibility criteria included (i) histologically documented urothelial carcinoma, including squamous differentiation and mixed cell types, (ii) metastatic disease or locally advanced disease deemed unresectable, (iii) previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor, (iv) progression during or following most recent treatment, (v) measurable disease by RECISTv1.1, (vi) no ongoing sensory or motor neuropathy >= Grade 2, (vii) no active CNS metastases, and (viii) no uncontrolled diabetes mellitus. The trial schema for EV-201 is as follows:

ASCO 2019 EV 201 pivotal phase 2 trial

Between October 2017 and July 2018, EV-201 enrolled 128 patients with locally advanced or metastatic urothelial cancer who were previously treated with platinum and a checkpoint inhibitor therapy; 125 were treated with enfortumab vedotin. Patients were 70% male, the median age was 69 years (range 40–84), 34% of patients had primary upper tract urothelial carcinoma, and a median of two prior systemic therapies were received. Nectin expression was detected in all patients tested. At the data cutoff of March 1, 2019, the median time on treatment was 4.6 months (range 0.5-15.6 months). The confirmed ORR was 44% (95% CI 35.1%–53.2%), with a 12% complete response (CR) rate. Furthermore, 84% of patients had a change in tumor measurement based on a blinded central review. The median duration of response was 7.6 months (range 0.95-11.30). The ORR in checkpoint inhibitor non-responders was 41% (95% CI 31.3%–51.3%), and 38% (95% CI 24.7%–52.8%) in patients with liver metastases. The complete subgroup analysis is as follows:

ASCO 2019 EV 201 subgroup analysis

The median progression free survival (PFS) was 5.8 months (95% CI 4.9-7.5; 81 events) and the median OS was 11.7 months (95% CI 9.1 – not reached; 54 events):

ASCO 2019 EV PFS graph

The most common treatment-related adverse events, as determined by investigators, included fatigue (50%), alopecia (49%), and decreased appetite (44%). Treatment-related adverse events led to discontinuation of therapy in only 12% of cases, with peripheral sensory neuropathy as the most common reason (6%). There was one treatment-related death (interstitial lung disease).

Dr. Petrylak concluded this exciting presentation of EV-201 with several take-home messages:

  • There is an unmet need for patients with advanced and metastatic urothelial carcinoma
  • Enfortumab vedotin is the first novel therapeutic to demonstrate substantial clinical activity in patients who progressed after platinum chemotherapy and a PD-1/L1 inhibitor, with a 44% response rate (12% complete response) and 7.6-month median duration of response
  • Responses were observed across all subgroups and irrespective of response to prior PD-1/L1 inhibitor or presence of liver metastases
  • Enfortumab vedotin had a manageable safety profile, and results are highly consistent with the phase 1 EV-101 trial in the same patient population
  • These data support submission to the FDA for accelerated approval – if approved, enfortumab vedotin may have the potential to become a new standard of care in patients who have progressed after platinum and PD-1/L1 inhibitors
Clinical trial information:  NCT03219333

Presented by: Daniel P. Petrylak, MD, Yale School of Medicine, New Haven, CT

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

  1. Petrylak DP, de Wit R, Chi KN, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): A randomized, double-blind, phase 3 trial. Lancet 2017;390(10109):2266-2277.