Dr Vulsteke on the Rationale for Evaluating Perioperative Enfortumab Vedotin Plus Pembrolizumab in Cisplatin-Ineligible MIBC

“Two years ago, we presented also at ESMO, transformative results of the combination of EV/pembrolizumab in the metastatic urothelial carcinoma setting. In that setting, there was a doubling of the overall survival. It went up from [approximately] 16 months to 35 months. Thirty percent of patients [achieved] a CR.”

Christof Vulsteke, MD, PhD, head of the Integrated Cancer Center Ghent, outlined the biological and clinical rationale for evaluating perioperative enfortumab vedotin-ejfv (EV; Padcev) plus pembrolizumab (Keytruda) in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin, as investigated in the phase 3 KEYNOTE-905/EV-303 trial (NCT03924895).

Vulsteke explained that the conceptual foundation for KEYNOTE-905 was built on highly compelling efficacy data previously observed with the EV/pembrolizumab in the metastatic urothelial carcinoma setting in the phase 3 EV-302 trial (NCT04223856). Results from the study demonstrated that the combination produced substantial survival improvements in patients with advanced disease, with median overall survival extending from approximately 16 months with historical standards to approximately 35 months with EV plus pembrolizumab. In that metastatic population, complete responses (CRs) were observed in approximately 30% of patients, and notably, long-term durability was evident, with approximately 75% of those patients remaining in CR at 2 years. These outcomes were achieved in patients with visceral metastatic involvement, including liver and lung metastases, underscoring the depth and persistence of antitumor activity.

Given these previously established results, Vulsteke emphasized that it was biologically and clinically reasonable to explore whether similar benefits could be realized earlier in the disease course. Patients with MIBC who are cisplatin-ineligible represent a particularly high-risk population with limited curative options.

KEYNOTE-905 was therefore designed to test whether introducing a highly active antibody-drug conjugate combined with immune checkpoint blockade in the perioperative setting could improve long-term outcomes in this underserved population. Vulsteke noted that the rationale extends beyond simple efficacy extrapolation; EV delivers a potent cytotoxic payload directly to nectin-4–expressing tumor cells and pembrolizumab enhances antitumor immune responses through PD-1 inhibition.

By moving EV/pembrolizumab into the perioperative setting, KEYNOTE-905 aims to determine whether deep responses, durable disease control, and potentially curative outcomes can be achieved for cisplatin-ineligible patients. Vulsteke underscored that this strategy reflects a broader shift in urothelial cancer management, leveraging transformative metastatic data to rationally redefine standards of care earlier in the disease continuum.