Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Br J Cancer. 2019 Jun;120(12):1105-1112. doi: 10.1038/s41416-019-0473-y. Epub 2019 May 17.
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.
人表皮生长因子 2（HER2）是乳腺癌的有效治疗靶点；然而，对曲妥珠单抗和拉帕替尼等抗 HER2 药物的耐药性会发展。在临床前模型中，组蛋白去乙酰化酶抑制剂通过表观遗传逆转了癌细胞对曲妥珠单抗的耐药性，并显示与拉帕替尼联合使用时抑制曲妥珠单抗耐药 HER2 阳性（HER2+）乳腺癌的生长具有协同作用。
进行了一项 1b 期、剂量递增研究，以评估最大耐受剂量、安全性/毒性、临床疗效，并探索与来普汀联合拉帕替尼联合或不联合曲妥珠单抗的反应的药效学生物标志物。
联合用药安全。最大耐受剂量为：拉帕替尼，每日 1000mg；来普汀，每两周 12mg；曲妥珠单抗，初始剂量 8mg/kg，随后每 3 周 6mg/kg。不良事件包括腹泻（89%）、中性粒细胞减少（31%）和血小板减少（23%）。中性粒细胞减少症、血小板减少症和低钾血症。药效学评估未得出明确结果。在 35 名可评估反应的患者中，3 名患者观察到 PR，3 名患者观察到 CR，1 名患者持续 SD 超过 6 个月。
这项研究确定了来普汀、拉帕替尼和曲妥珠单抗联合用药的最大耐受剂量，为 HER2+转移性乳腺癌的大量预处理患者提供了可接受的耐受性和抗肿瘤活性，支持进行确证性试验。
