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Ref Type Journal Article
PMID (31097774)
Authors Lim B, Murthy RK, Lee J, Jackson SA, Iwase T, Davis DW, Willey JS, Wu J, Shen Y, Tripathy D, Alvarez R, Ibrahim NK, Brewster AM, Barcenas CH, Brown PH, Giordano SH, Moulder SL, Booser DJ, Moscow JA, Piekarz R, Valero V, Ueno NT
Title A phase Ib study of entinostat plus lapatinib with or without trastuzumab in patients with HER2-positive metastatic breast cancer that progressed during trastuzumab treatment.
Journal Vol Issue Date Pages Journal Short Title
British journal of cancer 120 12 2019 06 1105-1112 Br J Cancer
URL
Abstract Text Human epidermal growth factor 2 (HER2) is an effective therapeutic target in breast cancer; however, resistance to anti-HER2 agents such as trastuzumab and lapatinib develops. In a preclinical model, an HDAC inhibitor epigenetically reversed the resistance of cancer cells to trastuzumab and showed synergistic efficacy with lapatinib in inhibiting growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer.A phase 1b, dose escalation study was performed to assess maximum tolerated dose, safety/toxicity, clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab.The combination was safe. The MTD was lapatinib, 1000 mg daily; entinostat, 12 mg every other week; trastuzumab, 8 mg/kg followed by 6 mg/kg every 3 weeks. Adverse events included diarrhoea (89%), neutropenia (31%), and thrombocytopenia (23%). Neutropenia, thrombocytopenia and hypokalaemia were noted. Pharmacodynamic assessment did not yield conclusive results. Among 35 patients with evaluable response, PR was observed in 3 patients and CR in 3 patients, 1 maintained SD for over 6 months.This study identified the MTD of the entinostat, lapatinib, and trastuzumab combination that provided acceptable tolerability and anti-tumour activity in heavily pre-treated patients with HER2+ metastatic breast cancer, supporting a confirmatory trial.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References