NCI9673 (Part B): A multi-institutional ETCTN randomized phase II study of nivolumab with or without ipilimumab in refractory, metastatic squamous cell carcinoma of the anal canal

The proportion of patients (pts) with squamous cell carcinoma of the anus (SCCA) who develop incurable distant metastases continues to increase. Previously, in the single-arm study, NCI9673 (Part A), the anti-PD-L1 antibody nivolumab (N) demonstrated clinical efficacy for pts with unresectable or metastatic SCCA. In NCI9673 (Part B), we evaluated the role of the anti-CTLA-4 antibody ipilimumab (I) in combination with N for pts with refractory, incurable SCCA. In this phase II NCI ETCTN trial (NCI9673 Part B), pts with previously treated, unresectable or metastatic SCCA naïve to immunotherapy were randomized 1:1 to receive N (480 mg IV every 4 weeks) alone or in combination with I (1 mg/kg IV) every 8 weeks. Radiographic response was evaluated every 8 weeks (RECIST 1.1). The primary endpoint was progression-free survival (PFS). Secondary endpoints included radiographic response rate (RR), overall survival (OS), and grade ≥3 adverse events (AE’s; CTCAE version 5). A log-rank test was used to compare median PFS between treatment arms, with a one-sided alpha of 0.1 and power of 90%. A Cox proportional hazard ratio was used to estimate hazard ratio (HR). After a median follow-up of 21.8 months, 100 pts were enrolled (52 to N alone; 48 to N + I). Mean age was 60 years, and 77% participants were female. Improvement in PFS with the addition of I to N was not statistically significant (HR .80, 95% confidence interval (CI) .51 – 1.24), with a median PFS of 2.9 months (95% CI, 1.91-3.98) for N alone vs. 3.7 months (95% CI, 2.0-7.1) for N+I (p=0.16). The RR was 17.4% vs. 21.5% (p=.89); disease-control rate was 43.5% vs. 47.7%; and median OS was 15.4 months (95% CI, 11.1-NA) vs. 20.0 months (95% CI, 13.5-23.6; HR .86, 95% CI .51-1.47, p= .59) for N vs. N+I, respectively. Grade ≥3 treatment-related AEs occurred in 6 pts receiving N alone, and in 12 pts receiving N+I [grade 5 pneumonitis (N=1) and grade 4 hyperglycemia (N=2)]. The most common grades ≥3 treatment-related AEs were pneumonitis (6%), hyponatremia (5%), and hyperglycemia (4%). The addition of I to N trended in favor for PFS and OS but was not statistically significant in refractory, unresectable or metastatic SCCA pts, resulting in increased toxicity. Ongoing correlative studies for NCI9673 to characterize responses to single vs. combined immunotherapy in this population seek to provide rationale for the design of future studies.