Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.
The Medical Department, 3D Medicines Inc., Shanghai, China.
Cancer Res Treat. 2023 Apr;55(2):626-635. doi: 10.4143/crt.2022.1058. Epub 2022 Dec 23.
The human epidermal growth factor receptor 2 (HER2) is an established therapeutic target for various kinds of solid tumors. HER2 amplification occurs in approximately 1% to 6% of colorectal cancer. In this study, we aimed to assess the efficacy and safety of trastuzumab in combination with chemotherapy in HER2-positive metastatic colorectal cancer (mCRC).
An open-label, phase II trial (Clinicaltrials.gov: NCT03185988) was designed to evaluate the antitumor activity of trastuzumab and chemotherapy in HER2-positive digestive cancers excluding gastric cancer in 2017. Patients from this trial with HER2-positive, KRAS/BRAF wild-type, unresectable mCRC were analyzed in this manuscript. Eligible patients were treated with trastuzumab (8 mg/kg loading dose and then 6 mg/kg every 3 weeks) and irinotecan (120 mg/m2 days 1 and 8 every 3 weeks). The primary endpoint was the objective response rate.
Twenty-one HER2-positive mCRC patients were enrolled in this study. Seven patients (33.3%) achieved an objective res-ponse, and 11 patients (52.4%) had stable disease as their best response. The median progression-free survival (PFS) was 4.3 months (95% confidence interval, 2.7 to 5.9). Four of the 21 patients (19.0%) had grade 3 adverse events, including leukopenia, neutropenia, urinary tract infection, and diarrhea. No treatment-related death was reported. Exploratory analyses revealed that high tumor tissue HER2 copy number was associated with better therapeutic response and PFS. Alterations in the mitogen-activated protein kinase pathway, HER2 gene, phosphoinositide 3-kinase/AKT pathway, and cell cycle control genes were potential drivers of trastuzumab resistance in mCRC.
Trastuzumab combined with chemotherapy is a potentially effective and well-tolerated therapeutic regimen in mCRC with a high HER2 copy number.
人表皮生长因子受体 2（HER2）是各种实体瘤的既定治疗靶点。HER2 扩增发生在约 1%至 6%的结直肠癌中。在这项研究中，我们旨在评估曲妥珠单抗联合化疗治疗 HER2 阳性转移性结直肠癌（mCRC）的疗效和安全性。
一项开放标签、二期临床试验（Clinicaltrials.gov：NCT03185988）于 2017 年设计，旨在评估曲妥珠单抗和化疗在除胃癌以外的 HER2 阳性消化系统癌症中的抗肿瘤活性。本研究分析了该试验中 HER2 阳性、KRAS/BRAF 野生型、不可切除的 mCRC 患者。符合条件的患者接受曲妥珠单抗（8 mg/kg 负荷剂量，然后每 3 周 6 mg/kg）和伊立替康（120 mg/m2 天 1 和 8 每 3 周）治疗。主要终点是客观缓解率。
本研究共纳入 21 例 HER2 阳性 mCRC 患者。7 例患者（33.3%）达到客观缓解，11 例患者（52.4%）最佳缓解为疾病稳定。中位无进展生存期（PFS）为 4.3 个月（95%置信区间，2.7 至 5.9）。21 例患者中有 4 例（19.0%）发生 3 级不良事件，包括白细胞减少、中性粒细胞减少、尿路感染和腹泻。无治疗相关死亡报告。探索性分析表明，高肿瘤组织 HER2 拷贝数与更好的治疗反应和 PFS 相关。MAPK 通路、HER2 基因、PI3K/AKT 通路和细胞周期控制基因的改变是 mCRC 曲妥珠单抗耐药的潜在驱动因素。
曲妥珠单抗联合化疗是一种潜在有效的、耐受性良好的治疗方案，适用于高 HER2 拷贝数的 mCRC。
