Astellas Announces Breakthrough EV-302 Trial Meets Dual Primary Endpoints in First-Line Advanced Bladder Cancer

Recently, Astellas Pharma, Inc. and Seagen, Inc. announced the results of the EV-302 Phase 3 clinical trial (also known as KEYNOTE-A39) comparing enfortumab vedotin-ejfv in combination with pembrolizumab to chemotherapy. The combination therapy improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC), with results showing both statistical and clinical significance. The findings were presented during the Presidential Symposium at the 2023 European Society for Medical Oncology (ESMO) Congress (Abstract #LBA6).

EV-302 Trial Meets Dual Primary Endpoints of Overall Survival and Progression-Free Survival. Compared to platinum-based chemotherapy combined with gemcitabine, patients receiving enfortumab vedotin in combination with pembrolizumab:

• The median overall survival was 31.5 months (95% confidence interval: 25.4-NR), compared to 16.1 months (95% confidence interval: 13.9-18.3) in the chemotherapy group.
  
  

• Compared with chemotherapy, the overall survival was significantly prolonged, and the risk of death was reduced by 53% (Hazard Ratio [HR] = 0.47; 95% Confidence Interval [CI]: 0.38-0.58; P<0.00001).
  
  

• The Independent Data Monitoring Committee determined that the overall survival exceeded the pre-specified efficacy boundary at the interim analysis.
  
  

• The median progression-free survival was 12.5 months (95% confidence interval: 10.4-16.6) compared to 6.3 months (95% confidence interval: 6.2-6.5) in the chemotherapy group.
  
  

• Compared with chemotherapy, the risk of cancer progression or death was reduced by 55% (hazard ratio=0.45; 95% confidence interval: (0.38-0.54); P<0.00001).
  
  

• Including whether cisplatin-tolerant treatment and PD-L1 expression levels, the overall survival results were consistent across all predefined subgroups.
  
  

The most common (≥3%) Grade 3 or higher adverse events (AEs) associated with enfortumab vedotin in combination with pembrolizumab were maculopapular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia. The safety outcomes from the EV-302 clinical study were consistent with previously reported safety results of the EV-103 trial, which evaluated the combination therapy in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (la/mUC). No new safety signals were identified.

In the secondary endpoints, results showed that the objective response rate (ORR) was 68% (95% confidence interval: 63.1-72.1, P<0.00001) for patients receiving enfortumab vedotin in combination with pembrolizumab, compared to 44% (95% confidence interval: 39.7-49.2) for those receiving chemotherapy. In the enfortumab vedotin plus pembrolizumab group, 29.1% of patients achieved complete response and 38.7% had partial response, while in the chemotherapy group, these proportions were 12.5% and 32.0%, respectively. The median duration of response (DOR) was not reached in the enfortumab vedotin plus pembrolizumab group, while it was 7 months in the chemotherapy group (95% confidence interval: 6.2-10.2, P<0.00001).

EV-302 Trial

The EV-302 trial aims to provide the basis for global registration and serves as the confirmatory clinical trial for the accelerated approval of this combination therapy in the United States. In April 2023, the U.S. Food and Drug Administration (FDA) granted accelerated approval for enfortumab vedotin-ejfv in combination with pembrolizumab for the treatment of adult patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin, based on the tumor response rate and durability of response observed in the EV-103 trial. The EV-302 trial is part of a comprehensive program evaluating the efficacy of this combination therapy across multiple stages of treatment for urothelial cancer and other solid tumors. Topline data from the EV-302 trial were announced in September 2023.

About Enfortumab Vedotin

Enfortumab Vedotin is a first-in-class, direct-targeting antibody-drug conjugate that acts on Nectin-4, a protein located on the cell surface that is highly expressed in bladder cancer. Non-clinical data show that the anticancer activity of Enfortumab Vedotin is due to its binding to cells expressing the Nectin-4 protein, followed by the internalization and release of the antitumor agent monomethyl auristatin E (MMAE) into the cells, leading to cell cycle arrest and programmed cell death (apoptosis).

Editor: Muyan

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