ASCO 2021: Study EV-103: Update on Durability Results and Long Term Outcome of Enfortumab Vedotin + Pembrolizumab in First Line Locally Advanced or Metastatic Urothelial Carcinoma

( Significant unmet need remains for people with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma. In the first-line setting, carboplatin-based regimens have demonstrated poor tolerability, modest objective response rate, and limited durability. PD-1/PD-L1 inhibitors demonstrate durable responses, however, only a minority of patients achieve a response (ORR 24-29%). Enfortumab vedotin is an antibody-drug conjugate delivering the microtubule-disrupting agent monomethyl auristatin E (MMAE) to targeted tumor cells expressing Nectin-4. Enfortumab vedotin has shown an overall survival benefit versus chemotherapy in previously treated locally advanced or metastatic urothelial carcinoma.1 Preclinical studies show that antibody drug conjugates utilizing MMAE can induce immunogenic cell death and may enhance antitumor immunity. Clinical data suggests the combination of enfortumab vedotin + pembrolizumab may have the potential to induce greater antitumor activity compared to either agent alone. Preliminary data on enfortumab vedotin + pembrolizumab was previously presented, and the FDA granted breakthrough therapy designation to enfortumab vedotin + pembrolizumab for the treatment of patients with first-line cisplatin-ineligible locally advanced or metastatic urothelial carcinoma in February 2020. At the 2021 American Society of Clinical Oncology (ASCO) 2021 Annual Meeting, Dr. Terence Friedlander and colleagues reported updated data from the EV-103 clinical trial.

The multi-cohort EV-103 study evaluates the safety/activity of enfortumab vedotin + pembrolizumab (Dose Escalation/Cohort A). For this study, Dr. Friedlander highlighted first-line cisplatin-ineligible patients treated with 3-week cycles of enfortumab vedotin 1.25 mg/kg (Days 1, 8) and pembrolizumab (Day 1). Endpoints include safety/tolerability, investigator response per RECIST v1.1, duration of response, progression-free survival, and OS.

As of October 13, 2020, the median follow-up for the 45 first-line locally advanced or metastatic urothelial carcinoma patients was 24.9 months. The median number cycles of enfortumab vedotin + pembrolizumab was 9 (range 1-34). Confirmed objective response rate was 73.3% (95% CI: 58.1, 85.4) including 17.8% complete response and an objective response rate of 57.1% (8/14) in patients with liver metastasis. The best overall response by investigator is as follows, noting 93% of assessable patients had tumor reduction:


The median duration of response was 25.6 months (95% CI: 8.3 to not reached). Fifty-three percent of the responders had duration of response at 24 months. Additionally, the disease control rate is 93.3%, the median progression free survival is 12.3 months (95% CI: 8.0 – not reached), and the median OS is 26.1 months. The OS rate at 24 months is 56.3% (95% CI: 39.8, 69.9):


The most common treatment-related adverse events were peripheral sensory neuropathy (56%, 4% ≥ grade 3), fatigue (51%, 11% ≥ grade 3), and alopecia (49%). There was one death reported as possibly related to study treatment (multiple organ dysfunction syndrome) per investigator assessment.

Dr. Friedlander concluded his presentation of the update EV-103 study with the following conclusions:
  • Enfortumab vedotin + pembrolizumab, a platinum-free option, continues to demonstrate promising activity with a durable response profile in first-line cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma
  • The safety profile is manageable and stable over time with no new safety signals
  • Cohort K of EV-103 in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma is actively randomizing patients to enfortumab vedotin monotherapy or enfortumab vedotin + pembrolizumab to evaluate the contribution of each agent
  • The phase 3 trial EV-302 is currently enrolling enfortumab vedotin in combination with pembrolizumab versus chemotherapy in patients with locally advanced or metastatic urothelial carcinoma in the first-line setting

Clinical trial information: NCT03288545     

Presented by: Terence W. Friedlander, MD, University of California San Francisco Medical Center, San Francisco, CA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021


  1. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 2021 Mar 25;384(12):1125-1135.