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人类表皮生长因子二（HER2）是乳腺癌的有效治疗靶点。不过，抗HER2药物例如曲妥珠单抗和拉帕替尼可能发生耐药。根据临床前模型研究，组蛋白脱乙酰酶（HDAC）抑制剂恩替诺特可以通过表观遗传，逆转癌细胞对曲妥珠单抗的耐药，并且与拉帕替尼对于抑制曲妥珠单抗耐药HER2阳性乳腺癌生长具有协同作用。 2019年5月17日，英国癌症研究基金会、英国《自然》旗下《英国癌症杂志》在线发表美国德克萨斯大学MD安德森癌症中心、休斯敦卫理公会医院、东南地区医疗中心、国家癌症研究所的1B期剂量递增研究报告，探讨了恩替诺特＋拉帕替尼±曲妥珠单抗治疗HER2阳性转移性乳腺癌曲妥珠单抗耐药患者的最大耐受剂量、安全性、毒性、临床疗效、药效动力学生物标志。 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) 结果，最大耐受剂量为拉帕替尼每天1000毫克、恩替诺特每2周12毫克、曲妥珠单抗每公斤体重首次8毫克随后每3周6毫克。不良事件包括腹泻、中性粒细胞减少、血小板减少（89%、31%、23%）。严重不良事件包括中性粒细胞减少、血小板减少、低血钾。药效动力学评定尚未得出确切结果。对于35例可评估疗效患者，其中3例完全缓解、3例部分缓解、1例保持疾病稳定超过6个月。 因此，该研究结果表明，恩替诺特＋拉帕替尼＋曲妥珠单抗安全有效，对于难治型HER2阳性转移性乳腺癌患者，耐受性和抗肿瘤活性可接受，值得开展下一步研究进行确认。 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
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