E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group

Abstract

Purpose: Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

Patients and methods: E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15.

Results: Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients.

Conclusion: The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.

Trial registration: ClinicalTrials.gov NCT02115282.

Conflict of interest statement

Roisin M. ConnollyOther Relationship: Pfizer Kathy D. MillerConsulting or Advisory Role: Merck, Genentech/Roche, Athenex, AstraZeneca, Bristol Myers Squibb/CelgeneResearch Funding: Taiho Pharmaceutical, Novartis, Seattle Genetics, Pfizer, Astex Pharmaceuticals, British Biotech, CytomX Therapeutics, Alphamab Karen L. SmithStock and Other Ownership Interests: AbbVie, Abbott LaboratoriesHonoraria: ASiM CMEResearch Funding: Pfizer Ursa A. Brown-GlabermanConsulting or Advisory Role: Novartis, Biotheranostics, Eisai, Seattle Genetics, Taiho OncologyResearch Funding: Seattle Genetics Bryan A. FallerConsulting or Advisory Role: L.E.K. ConsultingTravel, Accommodations, Expenses: Genentech, Novartis, EB SQUIBB, Celgene, Boehringer Ingelheim, Eisai, AstraZeneca, Lilly, Amgen, Merck, TakedaOpen Payments Link: https://openpaymentsdata.cms.gov/physician/127090 Adedayo A. OnitiloConsulting or Advisory Role: Kite, a Gilead Company, Envision CommunicationsSpeakers' Bureau: GlaxoSmithKline, Puma Biotechnology, Kite/Gilead, AbbVie Mark E. BurkardConsulting or Advisory Role: Pointcare Genomics, Strata Oncology, NovartisResearch Funding: AbbVie, Strata Oncology, Puma Biotechnology, Loxo, Merck, Arcus, Apollomics, Elevation Oncology, GenentechPatents, Royalties, Other Intellectual Property: I have a patent for implantable or localized drug delivery device that can sample the tumor microenvironment and deliver drug. I have a patent for a method to detect recombination events with CRISPR-mediated editing. I have a patent for conducting expansion microscopy without specialized equipment George T. BuddHonoraria: DecipheraConsulting or Advisory Role: Deciphera, Epic SciencesSpeakers' Bureau: DecipheraResearch Funding: Genentech/Roche, TRACON Pharma, Daiichi Sankyo/Lilly, AmbrxOpen Payments Link: https://openpaymentsdata.cms.gov/physician/774695/summary Ellis G. LevineResearch Funding: Oncolytic BiotechPatents, Royalties, Other Intellectual Property: UpToDate Peter A. KaufmanStock and Other Ownership Interests: AmgenHonoraria: LillyConsulting or Advisory Role: Polyphor, Roche/Genentech, Lilly, Eisai, Macrogenics, Pfizer, Merck, AstraZenecaSpeakers' Bureau: LillyResearch Funding: Eisai, Polyphor, Roche/Genentech, Lilly, Novartis, Macrogenics, Pfizer, SanofiTravel, Accommodations, Expenses: Lilly, Polyphor, Macrogenics Alexandra ThomasStock and Other Ownership Interests: Johnson & Johnson, Gilead Sciences, Bristol Myers Squibb, PfizerConsulting or Advisory Role: BeyondSpring Pharmaceuticals, LillyResearch Funding: SanofiPatents, Royalties, Other Intellectual Property: UpToDate RoyaltiesTravel, Accommodations, Expenses: Genentech Jane B. TrepelResearch Funding: Syndax, EpicentRX, AstraZeneca Antonio C. WolffConsulting or Advisory Role: Ionis PharmaceuticalsPatents, Royalties, Other Intellectual Property: Antonio Wolff has been named as inventor on one or more issued patents or pending patent applications relating to methylation in breast cancer and has assigned his rights to JHU and participates in a royalty-sharing agreement with JHUOpen Payments Link: https://openpaymentsdata.cms.gov/physician/357301/summary Joseph A. SparanoStock and Other Ownership Interests: MetastatConsulting or Advisory Role: Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, Merrimack, Adgero Biopharmaceuticals, Cardinal Health, GlaxoSmithKline, CStone Pharmaceuticals, Epic Sciences, Daiichi Sankyo, BMSiSpeakers' Bureau: Eisai, CertaraResearch Funding: Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, Merrimack, Radius Health, Olema PharmaceuticalsTravel, Accommodations, Expenses: Menarini Silicon Biosystems, Roche/Genentech, Adgero Biopharmaceuticals, Myriad Genetics, Pfizer, AstraZeneca, Rhenium MedicalNo other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram. AEs, adverse events; AI, aromatase inhibitor.

FIG 2.

Kaplan-Meier estimates of (A) PFS and (B) OS by treatment arm. EE, exemestane and entinostat; EP, exemestane and placebo; OS, overall survival; PFS, progression-free survival.

FIG 3.

Median fold change in lysine acetylation in peripheral blood mononuclear cells by treatment arm.