Adding Ipilimumab to Nivolumab Does Not Improve Outcomes in Refractory Anal Cancer
Clinical Summary:
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Design/Population: Part B of the randomized phase 2 NCI9673 trial compared nivolumab alone with nivolumab plus ipilimumab in patients with refractory, incurable anal cancer.
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Key Outcomes: Adding ipilimumab to nivolumab did not improve progression-free survival, objective response rate, or overall survival compared with nivolumab alone and was associated with a higher incidence of grade 3 or higher treatment-related adverse events.
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Clinical Relevance: These findings do not support routine dual PD-1 and CTLA-4 blockade for refractory anal cancer and highlight the need for more effective immunotherapy combinations guided by predictive biomarkers.
Results from part B of the phase 2 NCI9673 trial demonstrated that adding ipilimumab to nivolumab did not improve efficacy compared with nivolumab alone in patients with refractory, incurable anal cancer and resulted in higher rates of treatment-related toxicity.
“In the previously completed NCI9673 (part A) single-arm study, the [PD-L1] antibody nivolumab demonstrated efficacy for patients with metastatic anal cancer,” stated Van Morris, MD, MD Anderson Cancer Center, Houston, Texas, and coauthors. “In NCI9673 (part B), we evaluated the [CTLA-4] antibody ipilimumab in combination with nivolumab for patients with incurable anal cancer.”
In this trial, 100 patients with refractory, incurable anal cancer were randomized to receive either 480 mg of nivolumab every 4 weeks (n = 52) or nivolumab plus 1 mg/kg of ipilimumab every 8 weeks (n = 48). The primary end point was progression-free survival (PFS). Key secondary end points included objective response rate (ORR), overall survival (OS), and safety.
Median PFS was 2.9 months with nivolumab alone and 3.7 months with nivolumab plus ipilimumab (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.60 to 1.23; P = .25). Median OS was 15.9 months and 20 months, respectively. The ORR was 17.4% with nivolumab monotherapy and 21.5% with the combination.
Grade ≥3 treatment-related adverse events occurred in 12% of patients receiving nivolumab alone compared with 25% of those receiving nivolumab plus ipilimumab. The most common grade ≥3 events included pneumonitis, hyperglycemia, hyponatremia, and elevated alanine aminotransferase levels.
“No differences in response rate or [PFS] between nivolumab alone or in combination with ipilimumab were observed for treatment of metastatic anal cancer," concluded Dr Morris et al.
“New immunomodulatory and/or other therapeutic directions are needed in this rare malignancy,” added Journal of Clinical Oncology associate editor Eileen O’Reilly, MD, Memorial Sloan Kettering Cancer Center, New York, New York.
Source:
Morris VK, Ciombor KK, Xiao L, et al. NCI9673 (Part B): ETCTN randomized phase II study of nivolumab with or without ipilimumab in refractory, metastatic squamous cell carcinoma of the anal canal. J Clin Oncol. Published online January 7, 2026. doi:10.1200/JCO-25-00929
