Network meta-analysis ranks neoadjuvant options in cisplatin-eligible MIBC

A network meta-analysis comparing neoadjuvant treatment strategies for cisplatin-eligible muscle-invasive bladder cancer found that enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) was associated with the strongest improvements in event-free survival, overall survival, and pathologic complete response rate relative to gemcitabine-cisplatin alone,¹ although the perioperative design of the key trials introduces interpretive nuance, according to Chiara Mercinelli, MD.

The analysis was motivated by a rapidly changing treatment landscape. For decades, gemcitabine plus cisplatin was the only established neoadjuvant option for cisplatin-eligible MIBC. Recent years brought the NIAGARA trial (NCT06960577), KEYNOTE-B15/EV-304 (NCT04700124), KEYNOTE-905 (NCT03924856), and the earlier VESPER trial (NCT01812369)—each offering a different regimen, but without direct head-to-head randomized comparisons between them.

"We went from only one treatment available to different options to offer to our patients, and not always comparison between them," Mercinelli said. The meta-analysis used indirect comparison methodology to evaluate which strategy showed the strongest association with improved outcomes vs the legacy standard.

All evaluated regimens outperformed gemcitabine-cisplatin alone on event-free survival, overall survival, and pathologic complete response. But enfortumab vedotin plus pembrolizumab emerged at the top of the ranking across all 3 end points. The combination was associated with an HR of approximately 0.53 for event-free survival and 0.65 for overall survival—results Mercinelli described as substantial. It also achieved the highest pathologic complete response rate among the regimens evaluated.

A key interpretive consideration is that both EV plus pembrolizumab and the VESPER regimen were studied in perioperative rather than purely neoadjuvant designs, meaning the adjuvant treatment phase may be contributing to the survival endpoint results. Mercinelli acknowledged this directly: "We need to take into consideration that both VESPER and KEYNOTE had a perioperative strategy, so there's also an impact of the adjuvant phase on these specific survival end points."

However, she noted that EV plus pembrolizumab's pathologic complete response advantage—which is measured before surgery and therefore captures only the neoadjuvant phase—argues that at least part of its superiority reflects the neoadjuvant contribution alone.

"The PCR results itself says that maybe the results wouldn't be that much lower without the adjuvant phase," she said.

The findings are indirect comparisons and carry the inherent limitations of network meta-analysis, including differences in trial populations, design, and follow-up—a distinction Mercinelli emphasized. Nonetheless, the consistency of EV plus pembrolizumab's performance across all three endpoints strengthens the signal.

REFERENCE

1. Mercinelli C, Scilipoti P, Cigliola A, et al. Defining the optimal therapeutic approach in muscle-invasive bladder cancer: A systematic review and meta-analysis of novel strategies versus gemcitabine-cisplatin. JCO Oncol Adv 3, e2600058(2026). doi:10.1200/OA-26-00058