964MO Entinostat, nivolumab and ipilimumab in advanced HER2-negative breast cancer (ETCTN-9844)

Abstract

In murine models of breast cancer the histone deacetylase inhibitor entinostat increases CD8+ effector: FoxP3+ regulatory T-cell ratios (CD8/FoxP3), and improves the efficacy of immune checkpoint inhibitors. We identified a recommended phase II dose (RP2D) for the combination of entinostat, nivolumab and ipilimumab (ETCTN-9884, manuscript submitted). We report combined safety and efficacy results of participants with HER2-negative breast cancer treated in dose escalation (n=6) and expansion cohorts treated at the RP2D (n=18). Participants received entinostat PO 5mg weekly x 2 (run-in), then 3-5mg weekly entinostat PO, 3mg/kg q2 weeks nivolumab, and 1mg/kg q6 weeks ipilimumab IV (max 4 doses ipi, RP2D). Primary endpoint: Safety (CTCAE v5). Secondary endpoints: Change in tumor CD8/FoxP3 ratio (integrated biomarker); Objective response rate (ORR). We obtained tissue samples at baseline, after 2 week run-in, and after 8 weeks of combination therapy and completed immunohistochemical staining for CD8, FoxP3 and PD-L1. Blood samples at each timepoint were obtained and Luminex analysis for global changes in plasma cytokine expression was performed. Amongst 24 participants [12 hormone receptor-positive (HR+), 12 triple-negative (TNBC)], median age was 54.5 years (range 38-77) and median prior therapies 6.5 (range 1-13). Median cycles received was 2 (range 1-17). Grade 3/4 AEs included anemia (N=4, 17%), decreased neutrophil count (N=3, 13%), and increased lipase (N=2, 8%). Most common immune-related (ir) AEs included rash (N =7, 29%), hypothyroidism (N =5, 21%), and pneumonitis (N=2, 8%). ORR by RECIST (v1.1) was 30% (6/20 evaluable), and by irRECIST was 20% (4/20 evaluable), including a complete response in a participant with TNBC. The combination of entinostat, nivolumab and ipilimumab at the RP2D was associated with expected (ir) AEs in advanced HER2-negative breast cancer. An ORR of 30% suggests this combination should be evaluated further. Correlative analyses from serial biospecimens pre- and post-therapy to evaluate the immune response and landscape will be presented.