China's National Medical Products Administration (NMPA) has approved Padcev (enfortumab vedotin), in combination with Keytruda (pembrolizumab), for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC). This approval marks a significant advancement, providing a new therapeutic option for patients in China and an alternative to platinum-containing chemotherapy, which has been the standard of care for nearly 40 years. The decision is based on the Phase 3 EV-302 trial, demonstrating superior overall survival (OS) and progression-free survival (PFS) with the combination therapy.
Clinical Efficacy and Trial Data
The approval is supported by data from the pivotal Phase 3 EV-302 trial (also known as KEYNOTE-A39), which evaluated enfortumab vedotin plus pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated la/mUC. The trial enrolled 886 patients eligible for cisplatin- or carboplatin-containing chemotherapy, irrespective of PD-L1 status.
The results demonstrated a statistically significant and clinically meaningful improvement in both OS and PFS. The combination therapy achieved a median OS of 31.5 months (95% CI: 25.4-NR) compared to 16.1 months (95% CI: 13.9-18.3) with platinum-containing chemotherapy, representing a 53% reduction in the risk of death (HR=0.47; 95% CI: 0.38-0.58; P<0.00001). Median PFS was 12.5 months (95% CI: 10.4-16.6) with the combination versus 6.3 months (95% CI: 6.2-6.5) with chemotherapy, indicating a 55% reduction in the risk of cancer progression or death (HR=0.45; 95% CI: 0.38-0.54; P<0.00001).
Expert Commentary
Professor Guo Jun, Lead Primary Investigator of the EV-302 trial in China, stated, "The NMPA approval of enfortumab vedotin in combination with pembrolizumab is the first non-platinum treatment for Chinese patients with advanced urothelial cancer that can be used in the first-line setting... I believe that this new treatment regimen will change the clinical treatment landscape of urothelial carcinoma in China and bring hope of longer survival to more Chinese patients with advanced urothelial carcinoma."
Professor Huang Jian, another Lead Primary Investigator, added, "The current first-line treatment strategy for advanced urothelial carcinoma in China is platinum-based chemotherapy, with very limited clinical options available. The approval of enfortumab vedotin in combination with pembrolizumab represents the first treatment regimen in the past 20-30 years that has shown superiority over platinum-based chemotherapy in the entire population. We hope that this combination could become the future standard of care treatment."
Safety Profile
The safety profile of the combination was consistent with previously reported data. Common adverse events (≥3% Grade 3 or higher) included maculo-papular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia. No new safety concerns were identified.
Disease Burden and Current Treatment Landscape
Urothelial cancer accounts for 90% of all bladder cancers. In China, bladder cancer is a significant health concern, with over 92,000 new cases diagnosed in 2022 and approximately 41,000 deaths reported. When diagnosed at a late stage, survival rates are poor, highlighting the urgent need for new treatment strategies.
About Enfortumab Vedotin
Enfortumab vedotin is a first-in-class antibody-drug conjugate (ADC) targeting Nectin-4, a protein highly expressed in bladder cancer. Nonclinical data suggest its anticancer activity stems from binding to Nectin-4-expressing cells, followed by internalization and release of monomethyl auristatin E (MMAE), leading to cell cycle arrest and apoptosis.
Ongoing Clinical Trials
The combination is being investigated in multiple ongoing trials, including EV-304 (NCT04700124) and EV-303 (NCT03924895) in muscle-invasive bladder cancer (MIBC), and EV-104 (NCT05014139) in non-muscle invasive bladder cancer (NMIBC).
