Neoadjuvant nivolumab alone or with ipilimumab in cisplatin-ineligible 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 were enrolled in two consecutive cohorts: (i) nivolumab alone and (ii) 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 of 15 and eight of 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, four patients achieved <ypT2ypN0 (26%), with two pathologic complete responses (pCR; 13%). With ipilimumab/nivolumab, three achieved <ypT2ypN0 (20%), with one pCR (7%). One patient after nivolumab and two after ipilimumab/nivolumab had durable clinical complete responses (CR) without cystectomy. Twelve-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 analyses suggest that NCOR1 alterations may be associated with improved clinical outcomes. Gene expression profiling indicated a 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 CR without cystectomy.