Neoadjuvant Nivolumab with or without Ipilimumab for Cisplatin-Ineligible Patients with Muscle-Invasive Bladder Cancer

Clinical Snapshot

Key Findings

• P Value: Not reported for primary comparison

• Effect Size: Pathologic complete response: 13% nivolumab vs 7% combination

• Primary Outcome: Cystectomy eligibility ≤60 days: 12/15 (80%) nivolumab vs 8/15 (53%) combination

• Nnt Or Sensitivity: Number needed to treat for pCR approximately 8 with nivolumab alone

• Confidence Interval: 12-month RFS: 79% (95% CI 61-100%) nivolumab vs 61% (95% CI 39-95%) combination

Clinical Application

Limited by low response rates and potential for treatment delays, particularly with combination therapy Nivolumab available on PBS for melanoma and lung cancer; bladder cancer indication would require TGA approval and PBS listing. Current Australian guidelines favor immediate cystectomy for cisplatin-ineligible patients Cisplatin-ineligible patients with muscle-invasive bladder cancer considering neoadjuvant therapy

Abstract

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.

References

1. 1.Guercio, B. J., Pietzak, E. J., Ravichandran, V., Chen, J.-F., Shah, R. H., Peters, V., Regazzi, A. M., Niglio, S. A., Aggen, D. H., Funt, S. A., Donahue, T. F., Goh, A. C., Cha, E. K., Wong, P., Richards, A. L., Cobbs, C. C., Donat, S. M., Dalbagni, G., Bochner, B. H., Iyer, G., Donoghue, M. T. A., Ostrovnaya, I., Al-Ahmadie, H. A., Rosenberg, J. E., & Teo, M. Y. (2026). Neoadjuvant Nivolumab with or without Ipilimumab for Cisplatin-Ineligible Patients with Muscle-Invasive Bladder Cancer. Clinical Cancer Research, 32(8). https://doi.org/10.1158/1078-0432.CCR-25-3771