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.
Clinical trial identification
Legal entity responsible for the study
US NIH- Cancer Therapy Evaluation Program supplied entinostat, nivolumab and ipilimumab. V Foundation (Translational Award 2017).
A. Brufsky: Financial Interests, Institutional, Other: Paid consultant for Lilly, Novartis, Pfizer, AstraZeneca, Eisai, Roche, Sanofi. P. Lorusso: Financial Interests, Institutional, Other: Dr. LoRusso reports personal fees from Abbvie, personal fees from Agios, personal fees from Five Prime, personal fees from GenMab, personal fees from Halozyme, personal fees from Roche-Genentech, personal fees from Genentech, personal fees from Cytomx, pe. J.P. Eder: Financial Interests, Institutional, Other: Dr. Eder reports ongoing collaboration with Roche on new approaches to Precision Medicine Tumour Boards. V. Chung: Financial Interests, Institutional, Other: VC COI include Ipsen and Coherus speaker’s bureau; Perthera Consultant; Pfizer Consultant. M.A. Rudek: Financial Interests, Institutional, Other: MAR has received research grants to institution from Celgene Corporation, Cullinan Apollo, and RenovoRx; MAR’s spouse is employed by GlaxoSmithKline. E. Fertig: Non-Financial Interests, Institutional, Other: Viosera Therapeutics, Scientific Advisory Board Member . R.A. Anders: Financial Interests, Institutional, Other: RAA has received research support from Bristol-Myers Squibb, Merck, StandUp2Cancer, FLXbio and is a paid consultant for Bristol-Myers Squibb, Merck, Incyte, AstraZeneca and FLXbio. A. Cimino-Mathews: Financial Interests, Institutional, Other: ACM has received research grants to institution from HeritX, Genentech and Bristol-Myers Squibb and serves as a consultant to Bristol-Myers Squibb. E.M. Jaffee: Financial Interests, Institutional, Other: E.M. Jaffee is a paid consultant for Adaptive Biotech, CSTONE, Achilles, DragonFly, and Genocea. She receives funding from Lustgarten Foundation and Bristol Myer Squibb. She is the Chief Medical Advisor for Lustgarten and SAB advisor to The Parker Institute. V. Stearns: Financial Interests, Institutional, Other: Received research grants to institution from Abbvie, Biocept, Pfizer, Novartis, and Puma Biotechnology. Member, Data Safety Monitoring Board, Immunomedics, Inc. R.M. Connolly: Financial Interests, Institutional, Other: RC has received research grants to institution from Novartis, Puma Biotechnology, Merck, Genentech, Macrogenics; and an unrestricted educational grant from Pfizer. All other authors have declared no conflicts of interest.