Phase 3 EV-302 Trial of ADC Combination Therapy Meets Dual Primary Endpoints in First-Line Treatment of Advanced Bladder Cancer

▎WuXi

Edited by Kant Content Team

Astellas and Seagen announced today,Seagen and Astellas' drug Padcev (enfortumab vedotin) in combination with PD-1 inhibitor Keytruda (pembrolizumab) achieved dual primary endpoints in the Phase 3 EV-302 clinical trial, comparing chemotherapy for the first-line treatment of locally advanced or metastatic urothelial carcinoma (la/mUC).The EV-302 trial is designed to serve as the confirmatory trial for the U.S. FDA’s accelerated approval of the combination therapy and as the basis for submitting global regulatory applications.

Bladder cancer is the 10th most common cancer globally, with more than 573,000 new cases diagnosed annually. Urothelial carcinoma most commonly originates from the cells lining the inside of the bladder and accounts for approximately 90% of bladder cancer cases. Besides the bladder, urothelial carcinoma can occur in other parts of the urinary tract, including the ureters and renal pelvis. Most patients with urothelial carcinoma are diagnosed at an early stage, but about 50% of those undergoing surgery will experience disease progression and recurrence within 2-3 years post-operation. Additionally, approximately 20%-25% of patients with urothelial carcinoma develop metastatic disease.

Padcev is an antibody-drug conjugate (ADC) that targets Nectin-4, a protein located on the cell surface and highly expressed in bladder cancer.Nonclinical data suggest that the anticancer activity of this drug is due to its binding to cells expressing Nectin-4, followed by internalization and release of the antitumor agent MMAE into the cell, leading to cell cycle arrest and programmed cell death (apoptosis). Pembrolizumab is a PD-1 monoclonal antibody that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2, thereby activating T lymphocytes to exert antitumor efficacy.In April 2023, the U.S. FDA granted accelerated approval to Padcev in combination with Keytruda for adult patients with la/mUC who are not eligible for cisplatin-containing chemotherapy, based on the results of the EV-103 trial.

EV-302 (also known as KEYNOTE-A39) is an open-label, randomized, controlled Phase 3 study evaluating the efficacy and safety of Padcev in combination with Keytruda versus chemotherapy in previously untreated patients with la/mUC. In this study, patients were randomly assigned to receive either the combination therapy or chemotherapy. The dual primary endpoints of the trial are overall survival (OS) and progression-free survival (PFS), as assessed by blinded independent central review (BICR) according to RECIST v1.1.

The analysis shows,Compared with chemotherapy, this combination therapy achieved the dual primary endpoints of OS and PFS. The independent data monitoring committee determined that OS exceeded the predefined efficacy threshold at the interim analysis.The safety results of the combination therapy were consistent with the previously reported safety results in la/mUC patients who were ineligible for cisplatin treatment.

[1] PADCEV® (enfortumab vedotin-ejfv) and KEYTRUDA®(pembrolizumab) Significantly Improve Overall Survival and Progression-FreeSurvival in Patients With Previously Untreated Advanced Bladder Cancer inPivotal Phase 3 EV-302 Trial. Retrieved September 22, 2023 from https://newsroom.astellas.us/2023-09-22-PADCEV-R-enfortumab-vedotin-ejfv-and-KEYTRUDA-R-pembrolizumab-Significantly-Improve-Overall-Survival-and-Progression-Free-Survival-in-Patients-With-Previously-Untreated-Advanced-Bladder-Cancer-in-Pivotal-Phase-3-EV-302-Trial