Ipilimumab Added to Nivolumab Does Not Improve Outcomes in Refractory Anal Cancer

Key Clinical Takeaways: 

• Design/Population: Part B of the phase 2 NCI9673 trial randomized 100 patients with refractory, incurable anal cancer to receive nivolumab alone or nivolumab plus ipilimumab.
• Key Outcomes: The addition of ipilimumab did not significantly improve progression-free survival, objective response rate, or overall survival compared with nivolumab monotherapy and was associated with a higher rate of grade 3 or higher treatment-related adverse events.
• Clinical Relevance: These findings do not support routine use of dual PD-1 and CTLA-4 blockade in refractory anal cancer and highlight the importance of balancing potential efficacy with added toxicity. Immune biomarker analyses may help guide future combination strategies.

Results from part B of the phase 2 NCI9673 trial showed that adding ipilimumab to nivolumab did not significantly improve survival or response outcomes among patients with refractory, incurable anal cancer.

“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 study, 100 patients were randomized to receive 480 mg of nivolumab once every 4 weeks either alone (n = 52) or in combination with 1 mg/kg of ipilimumab once 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.

At analysis, median PFS was 2.9 months in the nivolumab monotherapy arm and 3.7 months in the nivolumab plus ipilimumab arm (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% in the nivolumab monotherapy arm and 21.5% in the nivolumab plus ipilimumab arm. 

Grade ≥3 treatment-related adverse events occurred in 12% of patients receiving nivolumab monotherapy and 25% of those receiving nivolumab plus ipilimumab. The most frequently reported grade ≥3 or higher events included pneumonitis (n = 4), hyperglycemia (n = 3), hyponatremia (n = 2), and elevated alanine aminotransferase levels (n = 2).

As Dr Morris et al concluded, “No differences in response rate or [PFS] between nivolumab alone or in combination with ipilimumab were observed for treatment of metastatic anal cancer. 

“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