Neoadjuvant nivolumab with or without ipilimumab for cisplatin-ineligible patients with muscle-invasive bladder cancer

Purpose: Many patients with muscle-invasive bladder cancer (MIBC) are ineligible for cisplatin-based therapy. We conducted a phase II trial of neoadjuvant nivolumab±ipilimumab for cisplatin-ineligible patients. Patients and Methods: Patients with MIBC enrolled in two consecutive cohorts: (1) nivolumab alone; (2) ipilimumab/nivolumab. A third cohort with alternative dosing was planned. The primary endpoint was eligibility for cystectomy ≤60 days after last treatment. Correlative analyses were performed, with the PURE-01 trial used as an independent dataset. Results: Fifteen patients enrolled onto each cohort. In cohorts 1 and 2, 12/15 and 8/15 were eligible for cystectomy within 60 days, respectively. Due to cohort 2's failure to meet the primary endpoint, cohort 3 was not initiated. With nivolumab alone, 4 patients achieved <ypT2ypN0 (26%), with 2 pathologic complete responses (pCRs) (13%). With ipilimumab/nivolumab, 3 achieved <ypT2ypN0 (20%), with 1 pCR (7%). One patient after nivolumab and 2 after ipilimumab/nivolumab had durable clinical CRs without cystectomy. 12-month recurrence-free survival (RFS) was 79% with nivolumab (95% confidence interval [CI], 61-100) and 61% with ipilimumab/nivolumab (95% CI, 39-95). Sequencing suggested NCOR1 alterations may associate with favorable outcomes. Gene expression profiling indicated potential association between tumor-infiltrating immune cells and longer RFS (log-rank p = 0.18); this was also observed in PURE-01 (p = 0.022). Conclusions: Among cisplatin-ineligible patients with MIBC, nivolumab alone was well tolerated. Ipilimumab/nivolumab caused toxicity that delayed cystectomy. Cases of progression before cystectomy indicated insufficient efficacy of pure neoadjuvant immunotherapy for unselected patients. Despite low response rates, some patients experienced sustained clinical CRs without cystectomy.