FDA Reviewing New Combination Therapy for Patients with MIBC

Muscle-invasive bladder cancer, representing approximately 25% of all bladder cancer cases, is typically managed with radical cystectomy combined with cisplatin-based chemotherapy.

However, a significant number of patients are ineligible for cisplatin due to issues like kidney impairment, hearing loss, or poor performance status.

The FDA has accepted for priority review a supplemental Biologics License Application (sBLA) for a combination therapy for patients with muscle-invasive bladder cancer (MIBC), Astellas Pharma Inc. announced in October.

The sBLA is based on results from the Phase 3 EV-303 clinical trial, which were presented at the European Society for Medical Oncology (ESMO) 2025 Congress.

Christina Quicquaro, Pharm.D., M.S.H.I., executive medical affairs director and head of enfortumab vedotin, Medical Affairs US for Astellas, explained to Managed Healthcare Executive that Seagen and Astellas first entered a clinical collaboration agreement with Merck to evaluate Padcev (enfortumab vedotin) in combination with Merck’s Keytruda (pembrolizumab) in patients with previously untreated locally advanced or metastatic urothelial cancer, a more advanced stage of bladder cancer.

“The collaboration was motivated by the potential to combine two different mechanisms of action, a nectin-4-directed antibody-drug conjugate and a PD-1 inhibitor, to further improve outcomes for patients,” she said. “In preclinical studies, the combination of Padcev with a PD-1 inhibitor resulted in upregulation of immune function and increased antitumor activity in tumor models expressing nectin-4.” Nectin-4 is a transmembrane receptor that research has identified as implicated in migration, adhesion and proliferation of tumor cells.

The combination of Padcev and Keytruda offers a potential alternative for these patients, potentially revolutionizing the approach to treatment in the perioperative setting.

Results from the pivotal Phase 3 EV-303 trial demonstrated that, when used before (neoadjuvant) and after (adjuvant) surgery, Padcev in combination with Keytruda reduced the risk of cancer recurrence, progression, or death by 60% and the risk of death by 50% compared to surgery alone in cisplatin-ineligible patients with MIBC.

“Consistent event-free survival (EFS) and overall survival (OS) benefits were seen across all predefined subgroups, including age, gender, smoking status and PD-L1 status as well as protocol-defined stratification groups based on cisplatin ineligibility (ineligible vs. eligible but declined), clinical stage, and geographic region,” Quicquaro said.

The use of Padcev and Keytruda, before and after surgery, in cisplatin-ineligible patients with MIBC, is currently under review and is not approved by the FDA.

“The standard treatment for patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery, which has been shown to prolong survival,” Quicquaro said. “However, up to half of patients with MIBC are not eligible to receive cisplatin and face limited treatment options, typically undergoing surgery without any systemic treatment, and will have their cancer return within two years.”

The EV-303 results have the potential to establish a new efficacy benchmark in cisplatin-ineligible MIBC, showing for the first time that a systemic treatment approach used as neoadjuvant and adjuvant therapy combined with surgery has improved survival outcomes over standard surgery alone.

In the EV-303 trial, the most common adverse events reported in the neoadjuvant and adjuvant Padcev-Keytruda plus pembrolizumab arm were pruritus (itching), alopecia, diarrhea, fatigue and anemia. Serious side effects (Grade 3 or higher) due to any cause occurred in 71.3% of patients treated with the combination compared with 45.9% of patients who received surgery only.

Padcev is already approved in combination with Keytruda for the treatment of adults with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy. The new sBLA seeks to expand its use into earlier-stage, muscle-invasive disease, offering potential benefits for patients undergoing curative-intent surgery.

Quicquaro noted if approved, the Padcev-Keytruda combination would become the first and only antibody-drug conjugate and PD-1 regimen available for cisplatin-ineligible patients with MIBC.