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.