ASCO 2024: Enfortumab Vedotin with Pembrolizumab Versus Chemotherapy in Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma: Analysis of Cisplatin-Eligible Population from EV-302/KEYNOTE-A39

( The 2024 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between May 31 and June 4 was host to the Poster Session: Genitourinary Cancer: Kidney and Bladder. Dr. Jens Bedke presented their poster titled: Enfortumab vedotin (EV) with pembrolizumab (P) versus chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): Analysis of cisplatin (cis)-eligible population from EV-302/KEYNOTE-A39.

Dr. Bedke began by discussing that EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, randomized, open-label, global study comparing EV+P with platinum-based chemotherapy for first-line treatment of patients with locally advanced/metastatic urothelial carcinoma (la/mUC) regardless of cisplatin eligibility (1). In the EV-302 trial, EV+P demonstrated a significant clinically meaningful benefit compared with chemotherapy for the dual primary endpoints of progression-free survival (PFS) (hazard ratio [HR]: 0.45; P<0.00001) and overall survival (OS) (HR: 0.47; P<0.00001) in the overall patient population. This led the FDA to approve EV+P in December 2023 for the treatment of adults with la/mUC. For this presentation, the researchers focused on patients in the EV-302 trial who were eligible for cisplatin at randomization.

In EV-302, patients with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg IV; Days 1 and 8) and pembrolizumab (200 mg IV; Day 1) or platinum-based chemotherapy (gemcitabine with cisplatin or carboplatin). Patients were deemed eligible/ineligible for cisplatin by the protocol’s defined criteria:

  • Glomerular filtration rate (GFR) of 30 to less than 60 ml per minute per 1.73 m2 of body-surface area.
  • Hearing loss of grade 2 or higher
  • Eastern Cooperative Oncology Group performance-status (ECOG-PS) score of 2
  • New York Heart Association (NYHA) class III heart failure at enrollment 

The study design is outlined in the figure below.

Dr. Bedke reported that a total of 478 patients were cisplatin-eligible at randomization, with 244 in the EV+P arm and 234 in the chemotherapy arm. Ninety-four percent of the patients in the chemotherapy arm received at least one cycle of platinum-based chemotherapy. Baseline characteristics were well balanced; however, he noted that liver metastasis was more pronounced in the EV + P arm (20.5% vs. 19.7%). The rest of the baseline characteristics are shown in the table below.EV-302/KEYNOTE-A39 key demographics and baseline characteristics
In the cis-eligible cohort, the median PFS was 14.6 months for EV+P compared to 6.5 months for chemotherapy, with a 52% reduction in the risk of progression (HR: 0.48, 95% CI: 0.38, 0.62).
EV-302/KEYNOTE-A39 pfs per BICR
The median OS was 31.5 months for EV+P vs. 18.4 months for chemotherapy, showing a 47% reduction in the risk of death (HR: 0.53, 95% CI: 0.39, 0.72).EV-302/KEYNOTE-A39 overall survival
For the cis-eligible population, the overall response rate (ORR) for EV+P was 70.8%, with 32.5% achieving a complete response. The ORR for chemotherapy was 53%, with a 15.5% complete response rate. The time to OR was similar between both arms (median 2.1 months).EV-302/KEYNOTE-A39 best overall response
For the EV+P arm, the median duration of response was not reached (95% CI: 18.2 months, NR) compared to a median duration of response for the chemotherapy arm of 8.3 months (95% CI: 5.9, 10.9).
EV-302/KEYNOTE-A39 duration of objective response
In the cis-eligible population, 34% of patients in the EV+P arm remained on treatment at the data cutoff, and 34.8% received subsequent therapy. Seventy-two patients (29.5%) received platinum-based therapy as their first subsequent therapy, with 17.6% receiving cisplatin. In the chemotherapy arm, all patients were off-study treatment at the time of data cutoff. 62.4% received any program death-1 or program death ligand-1 (PD-1/L1) therapy following chemotherapy. Eighty-three patients received maintenance avelumab, and 59 patients received PD-1/L1 therapy as second-line treatment.

Treatment-related adverse events (TRAEs) Grade ≥3 occurred in 53.9% of patients in the EV+P arm and 62.7% of patients in the chemotherapy arm in the cis-eligible population. The most common grade ≥3 TRAEs of special interest for EV were skin reactions (14.8%), hyperglycemia (7.8%), and peripheral neuropathy (5.8%). The most common grade ≥3 treatment-emergent adverse events of special interest for platinum-based chemotherapy were severe skin reactions (9.5%), pneumonitis (4.9%), and colitis (2.9%). TRAEs are depicted in the figure below.EV-302/KEYNOTE-A39 trae
Dr. Bedke wrapped up his presentation concluding that in the cisplatinum-eligible population of the EV-302/KEYNOTE-A39 trial:

  • EV+P improved clinical outcomes, reducing the risk of death by 47% and the risk of progression by 52% compared with platinum-based chemotherapy.
  • EV+P showed a significant ORR of 70.8%, with 32.5% of patients achieving a complete response
  • The Results of this cisplatin-eligible population analysis were consistent with the overall population.
  • The results of EV-302 support EV+P as a new SOC for la/mUC, including patients who are eligible for cisplatin.

Presented by: Jens Bedke, MD, Professor, Urologic Oncology, Vice-Chairman of the Department of Urology, University of Tubingen, Germany.

Written by: Julian Chavarriaga, MD – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @chavarriagaj on Twitter during the 2024 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between May 31st and June 4th.


  1. Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. doi: 10.1056/NEJMoa2312117. PMID: 38446675.