Phase 3 EV-302 Trial Shows Near Doubling of OS and PFS with Padcev plus Keytruda in Previously Untreated Locally Advanced or Metastatic Urothelial Cancer

▎WuXi

Edited by Kant Content Team

According to detailed data from recently published abstracts ahead of the upcoming European Society for Medical Oncology (ESMO) Congress, the antibody-drug conjugate (ADC) Padcev (enfortumab vedotin), co-developed by Seagen and Astellas, in combination with MSD’s PD-1 inhibitor Keytruda (pembrolizumab), showed outstanding results in the Phase 3 EV-302 clinical trial comparing the treatment to chemotherapy in previously untreated patients with locally advanced or metastatic urothelial cancer (la/mUC).The overall survival (OS) of patients using combination therapy is nearly twice that of the chemotherapy group, reducing the risk of death by 53%!According to the summary conclusion,This positive data shows that the combination therapy of Padcev and Keytruda has the potential to become a first-line standard treatment for untreated metastatic bladder cancer.

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. In addition to 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 patients who undergo surgery will experience disease progression and recurrence within 2-3 years post-operation. Furthermore, approximately 20%-25% of patients with urothelial carcinoma develop metastatic disease, and platinum-based chemotherapy is the standard treatment for la/mUC.

Padcev is an antibody-drug conjugate that targets Nectin-4, a protein located on the cell surface and highly expressed in bladder cancer.Preclinical data suggest that the anticancer activity of this drug is due to its binding to cells expressing Nectin-4, followed by the internalization and release of the antitumor agent MMAE into the cells, leading to cell cycle arrest and programmed cell death (apoptosis).Keytruda 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 anti-tumor effects.In April 2023, the U.S. FDA granted accelerated approval to Padcev in combination with Keytruda for the treatment of 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 la/mUC patients. A total of 886 patients were enrolled. Previously untreated la/mUC patients (regardless of their PD-L1 expression levels) were randomly assigned in a 1:1 ratio. Patients in the combination therapy group (n=442) received Padcev (1.25 mg/kg) on Days 1 and 8 and Keytruda (200 mg) on Day 1, administered every 3 weeks. Patients in the chemotherapy group (n=444) received gemcitabine in combination with either cisplatin or carboplatin. The dual primary endpoints were overall survival (OS) and progression-free survival (PFS), assessed by blinded independent central review (BICR) according to RECIST 1.1. Secondary endpoints included overall response rate (ORR) and safety.

At the time of data cutoff, the median follow-up was 17.2 months.Compared with chemotherapy, the PFS of patients in the combination therapy group was significantly prolonged, and the risk of progression or death was reduced by 55%.(Median PFS was 12.5 months vs 6.3 months; HR=0.45, 95% CI: 0.38-0.54, P

Compared with the chemotherapy group, the OS in the combination therapy group was significantly prolonged, with a 53% reduction in the risk of death (median OS: 31.5 months vs 16.1 months; HR=0.47, 95% CI: 0.38-0.58, P

The confirmed ORR in the combination therapy group and chemotherapy group were 67.7% and 44.4%, respectively (P

In terms of safety, 55.9% of patients in the combination therapy group experienced treatment-related adverse events (TRAE) of Grade ≥3, compared to 69.5% in the chemotherapy group.

According to the abstract conclusion, the combination therapy of Padcev and Keytruda significantly improved the prognosis of previously untreated la/mUC patients, with median PFS and OS nearly doubling compared to chemotherapy. The overall safety was manageable, with no new safety signals.These results support combination therapy as a new first-line standard treatment for la/mUC patients.