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The latest findings released from the Phase III EV-302/KEYNOTE-A39 (NCT04223856) trial show that the combination of Padcev (enfortumab vedotin-ejfv) plus Keytruda (pembrolizumab) produced sustained benefits in overall survival (OS) and progression-free survival (PFS) compared to chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC).1,2 The FDA approved the combination for la/mUC in December 2023 based on results from the EV-302 trial.3
“Patients with bladder cancer can face a poor prognosis, particularly in the advanced stages, and until recently had few available treatment options,” Roger Dansey, MD, chief oncology officer, Pfizer, said in a press release. “The updated EV-302 results show sustained long-term efficacy in a broad population that includes both cisplatin eligible and ineligible patients and reinforce this combination’s ability to reshape the urothelial cancer treatment landscape.”1
Keytruda is an anti-programed death receptor-1 (PD-1) therapy that improves the immune system’s ability to detect and fight tumor cells. The humanized monoclonal antibody blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which leads to the activation of T lymphocytes that could affect tumor and healthy cells.
Padcev is a first-in-class antibody-drug conjugate (ADC) directed against Nectin-4 with a microtubule disrupter, monomethyl auristatin. The FDA approved Padcev on December 18, 2019, for patients with previously treated la/mUC. In April 2023, the FDA granted accelerated approval to the Keytruda plus Padcev combination for the treatment of patients with la/mUC who are ineligible for cisplatin-containing chemotherapy.4
The FDA granted the accelerated approval based on tumor response rate and durability of response, with continued approval contingent upon verification and description of clinical benefit in confirmatory trials. The approval was the first for an anti-PD-1 therapy plus an ADC in the United States for this indication.
Trial Design
The open-label, randomized EV-302/Keynote-A39 trial enrolled 886 patients with la/mUC who received no prior systemic therapy for advanced disease. Patients were randomly assigned in a 1:1 ratio to receive either Padcev with Keytruda or platinum-based chemotherapy consisting of gemcitabine with either cisplatin or carboplatin. The trial’s primary efficacy outcomes were OS and PFS as assessed by blinded independent central review (BICR) per RECIST v1.1, with secondary endpoints that included objective response rate per RECIST v1.1 by BICR, duration of response per RECIST v1.1 by BICR, and safety.
The latest results demonstrated sustained OS and PFS benefits in patients administered Padcev plus Keytruda that were consistent with findings from the primary analysis after an additional 12 months of follow-up, with a median follow-up of 29.1 months.
The combination was found to lower the risk of death by 49% compared to chemotherapy (hazard ratio [HR] = 0.51, 95% confidence interval [CI], 0.43-0.61). Median OS was 33.8 months benefits in patients administered Padcev plus Keytruda compared to 15.9 months in patients administered chemotherapy.
This benefit was demonstrated across all prespecified subgroups, including in those eligible and ineligible for cisplatin. Further, Padcev plus Keytruda was found to lower the risk of disease progression or death by 52% compared to chemotherapy (HR = 0.48, 95% CI, 0.41-0.57). Median PFS was 12.5 months in the Padcev plus Keytruda cohort compared to 6.3 months in the chemotherapy cohort. In terms of safety, the profile was consistent with prior reports and no new safety signals were identified.
The most common adverse effects (AEs) reported in at least 20% of patients administered Padcev plus Keytruda included laboratory abnormalities, increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, and diarrhea. Other common AEs observed in the trial were alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection, and decreased platelets.3
“These latest findings from the EV-302 trial reaffirm the primary results, which demonstrated survival improvements for patients treated with enfortumab vedotin and pembrolizumab that were previously unprecedented in locally advanced or metastatic urothelial cancer,” trial primary investigator Thomas Powles, MRCP, MD, professor of Genitourinary Oncology at Queen Mary University of London; Director, Barts Cancer Center, London, said in a press release. “These data show that the potential survival benefit has become even more robust with extended follow up and further solidify the combination as standard of care.”1
References
1. Pfizer and Astellas’ PADCEV® (enfortumab vedotin-ejfv) plus KEYTRUDA® (pembrolizumab) Shows Long-Term Efficacy in First-Line Treatment of Locally Advanced or Metastatic Urothelial Cancer (la/mUC). News release. Pfizer. February 10, 2025. Accessed February 11, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-astellas-padcevr-enfortumab-vedotin-ejfv-plus-0
2. Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer (EV-302). ClinicalTrials.gov. Updated September 27, 2024. https://clinicaltrials.gov/study/NCT04223856. Accessed February 11, 2025. https://clinicaltrials.gov/study/NCT04223856
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. News release. December 15, 2023. Accessed February 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
4. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) in Combination With Padcev® (enfortumab vedotin-ejfv) for First-Line Treatment of Certain Patients With Locally Advanced or Metastatic Urothelial Cancer. Merck. News release. April 3, 2023. Accessed February 11, 2025. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-in-combination-with-padcev-enfortumab-vedotin-ejfv-for-first-line-treatment-of-certain-patients-with-locally-advanced-or-metastatic/