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.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

DISCUSSION:

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.

• Authors: Bora Lim, Rashmi K Murthy, Jangsoon Lee, Summer A Jackson, Toshiaki Iwase, Darren W Davis, Jie S Willey, Jimin Wu, Yu Shen, Debu Tripathy, Ricardo Alvarez, Nuhad K Ibrahim, Abenaa M Brewster, Carlos H Barcenas, Powel H Brown, Sharon H Giordano, Stacy L Moulder, Daniel J Booser, Jeffrey A Moscow, Richard Piekarz, Vicente Valero, Naoto T Ueno
• Journal: British journal of cancer (Br J Cancer) Vol. 120 Issue 12 Pg. 1105-1112 (06 2019) ISSN: 1532-1827 [Electronic] England
• PMID: 31097774 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Pyridines
• Lapatinib
• entinostat
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Benzamides (administration & dosage, adverse effects)
• Breast Neoplasms (drug therapy, enzymology)
• Breast Neoplasms, Male (drug therapy, enzymology)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Drug Synergism
• Female
• Humans
• Lapatinib (adverse effects)
• Male
• Middle Aged
• Neoplasm Metastasis
• Pyridines (administration & dosage, adverse effects)
• Receptor, ErbB-2 (metabolism)
• Survival Rate
• Trastuzumab (administration & dosage, adverse effects)