Ipilimumab and nivolumab followed by chemoradiotherapy as bladder-sparing treatment in muscle-invasive bladder cancer: a phase 2 trial

Radical cystectomy is the most commonly used definitive local treatment for muscle-invasive bladder cancer (MIBC), yet it carries substantial perioperative complication risk, alongside major changes in urinary and sexual function. Chemoradiotherapy (CRT) is used as a bladder-sparing alternative but is usually reserved for small, solitary tumors. Highly active systemic induction therapy could enable bladder preservation for patients with more advanced tumors and reduce recurrence risk. We previously demonstrated high activity of preoperative ipilimumab (3 mg kg -1) plus nivolumab in patients with stage III MIBC. Given this high activity, the single-arm, multicenter phase 2 INDIBLADE trial aimed to provide effective bladder-sparing treatment to patients with stage II/III (cT2-4aN0-2, n = 50) MIBC, using induction ipilimumab (3 mg kg -1) plus nivolumab followed by CRT. After a median follow-up of 28.7 months, the primary endpoint of estimated 2-year bladder-intact event-free survival (BI-EFS) was met at 78% (95% confidence interval (CI): 0.67-0.9, P < 0.001). Secondary endpoints included overall survival, safety and the predictive value of circulating tumor DNA (ctDNA). Two-year overall survival was 96% (95% CI: 0.91-1). Grade 3-4 immune-related adverse events occurred in 24% of patients; grade 3-4 CRT-related adverse events occurred in 7% of patients. Absence of detectable ctDNA after induction immunotherapy was associated with BI-EFS (hazard ratio 8.3, 95% CI: 1.38-50.36, P = 0.02). In conclusion, our results show that induction combination immunotherapy followed by CRT is an effective bladder-sparing treatment in MIBC, and response can be monitored by ctDNA. ClinicalTrials.gov identifier: NCT05200988 .