NCI9673 (Part B): ETCTN Randomized Phase II Study of Nivolumab With or Without Ipilimumab in Refractory, Metastatic Squamous Cell Carcinoma of the Anal Canal.

PURPOSE: In the previously completed NCI9673 (part A) single-arm study, the antiprogrammed death (PD)-ligand-1 antibody nivolumab demonstrated efficacy for patients with metastatic anal cancer. In NCI9673 (Part B), we evaluated the anticytotoxic T-cell lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in combination with nivolumab for patients with incurable anal cancer. METHODS: In this phase II NCI ETCTN trial, 100 patients with refractory, incurable anal cancer were randomly assigned to receive nivolumab (480 mg IV once every 4 weeks) alone or with ipilimumab (1 mg/kg IV once every 8 weeks). The primary end point was progression-free survival (PFS). Secondary endpoints included radiographic response, overall survival (OS), and grade ≥3 adverse events. A log-rank test was used to compare survival between arms, with a one-sided alpha of 0.1 and power of 90%. Immune biomarkers were analyzed from baseline and on treatment tissue and blood collections. RESULTS: The median PFS for nivolumab versus nivolumab plus ipilimumab were 2.9 months (90% CI, 1.9 to 3.8) and 3.7 months (90% CI, 2.0 to 5.6), respectively (hazard ratio [HR], 0.86 [95% CI, 0.60 to 1.23]; P = .25). Response rates were similar for nivolumab (17.4%) and nivolumab plus ipilimumab (21.5%; P = .89). The median OS was 15.9 months for nivolumab and 20.0 months for nivolumab plus ipilimumab (HR, 0.98 [90% CI, 0.63 to 1.51]). Grade ≥3 treatment-related AEs occurred in 6 patients (12%) receiving nivolumab alone and in 12 patients (25%) receiving nivolumab plus ipilimumab. At week 9, circulating TIGIT+ CD8+ cells (P < .001) increased with nivolumab plus ipilimumab treatment relative to baseline. CONCLUSION: The addition of ipilimumab to nivolumab did not statistically improve overall response rate, PFS, or OS but may harbor increased toxicity. Paired blood samples identified TIGIT expression on peripheral T cells as a compensatory change unique to dual PD-1 plus CTLA-4 blockade.