Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy remains the established standard of care for patients with resectable muscle-invasive bladder cancer (MIBC). This approach has been the historical benchmark against which newer perioperative strategies are assessed.
More recently, combinations of targeted antibody–drug conjugates and immune checkpoint inhibitors have been investigated across the perioperative setting, including in patient populations who are ineligible for or decline cisplatin.
The phase III KEYNOTE-905/EV-303 trial previously evaluated perioperative treatment with the nectin 4–targeted antibody–drug conjugate enfortumab vedotin (EV) plus the anti–PD-1 antibody pembrolizumab in patients who were cisplatin-ineligible or who declined cisplatin-based chemotherapy. That trial showed that these patients could derive substantial benefit from perioperative EV–pembrolizumab, providing a rationale to test the combination in cisplatin-eligible populations.
The KEYNOTE-B15/EV-304 trial enrolled a total of 808 patients with resectable MIBC who were eligible for standard cisplatin-based neoadjuvant chemotherapy. Participants were randomly allocated in a 1:1 ratio to receive either perioperative EV–pembrolizumab or standard neoadjuvant cisplatin–gemcitabine prior to radical cystectomy with pelvic lymph node dissection.
The principal objective of the trial was to compare outcomes between the investigational perioperative combination and the established neoadjuvant chemotherapy approach. The trial authors prespecified event-free survival (EFS) as the primary end point.
Patients assigned to the investigational arm received a perioperative program that began with four cycles of enfortumab vedotin plus pembrolizumab before surgery. After radical cystectomy with pelvic lymph node dissection, the protocol specified adjuvant therapy consisting of five cycles of EV and thirteen cycles of pembrolizumab.
This schedule represents a combined neoadjuvant and adjuvant approach pairing an antibody–drug conjugate directed at nectin 4 with PD-1 blockade, administered across both the preoperative and postoperative periods.
The control arm received four cycles of neoadjuvant cisplatin–gemcitabine prior to radical cystectomy with pelvic lymph node dissection, reflecting the established standard of care for cisplatin-eligible patients.
A protocol amendment allowed patients in the chemotherapy group to receive adjuvant anti–PD-1 therapy with nivolumab when clinically indicated. Despite this allowance, only 7.8% of patients in the chemotherapy arm received adjuvant nivolumab as reported in the source highlight.
The primary end point of KEYNOTE-B15/EV-304 was event-free survival (EFS). According to the research highlight, perioperative EV–pembrolizumab improved the outcomes of cisplatin-eligible patients with MIBC when compared with neoadjuvant cisplatin–gemcitabine.
The highlight does not provide numerical results, hazard ratios, confidence intervals, absolute event rates, or detailed safety and adverse-event data. For comprehensive efficacy and safety metrics, including subgroup analyses and follow-up duration, the original phase III report in the New England Journal of Medicine should be consulted (Galsky et al., N. Engl. J. Med. 2026), which is cited by the highlight.
The reported improvement in outcomes with perioperative enfortumab vedotin–pembrolizumab suggests that this combination may offer a therapeutic alternative to neoadjuvant cisplatin–gemcitabine for patients with resectable MIBC who are eligible for cisplatin. The trial extends prior evidence from cisplatin-ineligible populations to cisplatin-eligible patients.
However, the brief research highlight does not include detailed efficacy magnitudes, comprehensive safety profiles, or long-term survival and quality-of-life data. Clinicians should review the full trial publication and supplementary materials for complete results, adverse-event reporting, duration of follow-up and any stratified outcomes before considering changes to practice patterns. Additional questions that warrant review in the primary report include perioperative morbidity, rates of completion of planned adjuvant therapy, and outcomes in key clinical subgroups.
For definitive interpretation and implementation, multidisciplinary discussion and guideline appraisal will be needed once full results are examined alongside existing standards of care and patient-specific considerations.