人類表皮生長因子二（HER2）是乳腺癌的有效治療靶點。不過，抗HER2藥物例如曲妥珠單抗和拉帕替尼可能發(fā)生耐藥。根據(jù)臨床前模型研究，組蛋白脫乙酰酶（HDAC）抑制劑恩替諾特可以通過表觀遺傳，逆轉(zhuǎn)癌細胞對曲妥珠單抗的耐藥，并且與拉帕替尼對于抑制曲妥珠單抗耐藥HER2陽性乳腺癌生長具有協(xié)同作用。
2019年5月17日，英國癌癥研究基金會、英國《自然》旗下《英國癌癥雜志》在線發(fā)表美國德克薩斯大學MD安德森癌癥中心、休斯敦衛(wèi)理公會醫(yī)院、東南地區(qū)醫(yī)療中心、國家癌癥研究所的1B期劑量遞增研究報告，探討了恩替諾特＋拉帕替尼±曲妥珠單抗治療HER2陽性轉(zhuǎn)移性乳腺癌曲妥珠單抗耐藥患者的最大耐受劑量、安全性、毒性、臨床療效、藥效動力學生物標志。
NCT01434303: Entinostat, Lapatinib Ditosylate and Trastuzumab in Treating Patients With Locally Recurrent or Distant Relapsed Metastatic Breast Cancer Previously Treated With Trastuzumab Only (Phase I and Phase I Trastuzumab Cohort Study of Entinostat, Lapatinib and Trastuzumab in Patients With HER2-Positive Metastatic Breast Cancer in Whom Trastuzumab Has Failed)
結(jié)果，最大耐受劑量為拉帕替尼每天1000毫克、恩替諾特每2周12毫克、曲妥珠單抗每公斤體重首次8毫克隨后每3周6毫克。不良事件包括腹瀉、中性粒細胞減少、血小板減少（89%、31%、23%）。嚴重不良事件包括中性粒細胞減少、血小板減少、低血鉀。藥效動力學評定尚未得出確切結(jié)果。對于35例可評估療效患者，其中3例完全緩解、3例部分緩解、1例保持疾病穩(wěn)定超過6個月。
因此，該研究結(jié)果表明，恩替諾特＋拉帕替尼＋曲妥珠單抗安全有效，對于難治型HER2陽性轉(zhuǎn)移性乳腺癌患者，耐受性和抗腫瘤活性可接受，值得開展下一步研究進行確認。
Br J Cancer. 2019 May 17. [Epub ahead of print]
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.
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.
The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Methodist Hospital, Houston, TX, USA; ApoCell, Houston, TX, USA; Southeastern Regional Medical Center, Newnan, GA, USA; National Cancer Institute, Rockville, MD, USA.
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, 1000mg daily; entinostat, 12mg every other week; trastuzumab, 8mg/kg followed by 6mg/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.
DOI: 10.1038/s41416-019-0473-y
