KEYNOTE-B15 is a phase III study of neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab and cystectomy versus neoadjuvant gemcitabine, cisplatin and cystectomy in patients with muscle-invasive bladder cancer who are cystectomy candidates and who are cisplatin eligible. The standard of care for patients with muscle-invasive bladder cancer for the past almost 25 years has been neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. There has been a paucity of advances to such treatment since that time. Enfortumab vedotin plus pembrolizumab is now a standard treatment for patients with metastatic urothelial cancer and was recently shown to improve outcomes when given as neoadjuvant and adjuvant treatment with radical cystectomy for patients with muscle-invasive bladder cancer who are cisplatin ineligible. So KEYNOTE-B15 is now testing this regimen against the former standard of care, neoadjuvant gemcitabine and cisplatin followed by cystectomy, in patients who are cisplatin eligible.

What was the study design?

The design of the study involved a 1:1 randomisation in cisplatin eligible patients with muscle-invasive bladder cancer who were eligible for cisplatin and eligible for radical cystectomy. Patients were randomised to the enfortumab vedotin plus pembrolizumab arm, which consisted of four cycles of neoadjuvant enfortumab vedotin plus pembrolizumab followed by radical cystectomy followed by 13 cycles of adjuvant pembrolizumab, the first five of which were administered with enfortumab vedotin. The gemcitabine and cisplatin arm involved four cycles of neoadjuvant gemcitabine and cisplatin followed by radical cystectomy followed by observation. The primary endpoint of the study was event free survival as determined by blinded independent central review; secondary endpoints included overall survival and pathological complete response rate.

What were the key findings?

808 patients were randomised on study. The primary endpoint of the study was event free survival and event free survival was defined from the time of randomisation until the first occurrence of any of the following events: disease progression precluding cystectomy, muscle-invasive bladder cancer that was biopsy confirmed in patients who didn’t undergo radical cystectomy, incomplete surgical resection, distant or local recurrence as determined by central review or biopsy proven, or death from any cause. Enfortumab vedotin was associated with a significant improvement in event free survival compared to the gemcitabine plus cisplatin arm. The median event free survival was not reached on the EV/pembro arm, it was 48.5 months on the GemCis arm. The hazard ratio for event free survival favouring enfortumab vedotin plus pembrolizumab was 0.53.

Overall survival was also significantly improved with the EV/pembro arm versus the GemCis arm; the median overall survival was not reached in either arm at the time of this interim analysis number one, however the hazard ratio for overall survival was 0.65 favouring enfortumab vedotin plus pembrolizumab. Pathological complete response rate was also significantly improved with EV/pembro versus GemCis – the pathCR rate with GemCis was 32.5% and was 55.8% with enfortumab vedotin plus pembrolizumab.

What could be the clinical implications of these results?

Enfortumab vedotin plus pembrolizumab in the neoadjuvant and adjuvant setting with cystectomy is now a standard of care for patients with muscle-invasive bladder cancer who are cisplatin ineligible. These two independent studies, KEYNOTE-905 and KEYNOTE-B15, together really reinforce the reproducibility and generalisability of outcomes with this treatment regimen. So neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab and cystectomy can now really be considered a standard for patients with muscle-invasive bladder cancer, regardless of cisplatin eligibility.