Targeted treatment strategies are available for human epidermal growth factor receptor 2 (HER2)–positive (amplified and/or overexpressed) metastatic colorectal cancer (mCRC), and HER2 testing is indicated in patients with mCRC. At present, standard of care first-line treatment for those with HER2-positive mCRC remains chemotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors or bevacizumab, depending on RAS/BRAF mutational status and tumor sidedness. HER2-targeted agents should be considered for those with RAS/BRAF wild-type disease in subsequent-line treatment and in first-line treatment for patients not appropriate for intensive therapy. While the choice of anti-HER2 therapy is empiric given lack of head-to-head comparisons, the combination of trastuzumab plus tucatinib has received FDA accelerated approval for use in this setting and is generally the authors’ preference. Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, and trastuzumab deruxtecan (T-DXd) also have evidence of efficacy in this setting. As T-DXd has demonstrated activity following treatment with other HER2-targeted regimens and carries an increased risk of high-grade toxicities, the authors favor reserving it for use after progression on prior anti-HER2 therapy. HER2-targeted therapies that inhibit signal transduction appear to have limited activity in those with RAS mutations, including trastuzumab-containing regimens. However, the antibody drug conjugate T-DXd has some data showing efficacy in this setting, and the authors would consider T-DXd in subsequent-line therapy for HER2-positive, RAS-mutated mCRC. Several areas of uncertainty remain regarding how to best utilize HER2-targeted therapies in mCRC. These include the optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies, the optimal combination partners for anti-HER2 therapies, and the incorporation of predictive biomarkers to guide use of anti-HER2 therapies. Results of ongoing studies may thus alter the treatment paradigm above in the coming years.

靶向治疗策略可用于人表皮生长因子受体 2 (HER2) 阳性（扩增和/或过度表达）的转移性结直肠癌 (mCRC)，并且 HER2 检测适用于 mCRC 患者。目前，HER2 阳性转移性结直肠癌患者的一线治疗标准仍然是化疗联合表皮生长因子受体 (EGFR) 抑制剂或贝伐珠单抗，具体取决于RAS / BRAF突变状态和肿瘤侧面。对于RAS/BRAF野生型疾病患者，应考虑在后续治疗中使用 HER2 靶向药物，对于不适合强化治疗的患者，应在一线治疗中考虑使用 HER2 靶向药物。虽然由于缺乏头对头比较，抗 HER2 疗法的选择是经验性的，但曲妥珠单抗加图卡替尼的组合已获得 FDA 加速批准用于这种情况，并且通常是作者的首选。曲妥珠单抗加拉帕替尼、曲妥珠单抗加帕妥珠单抗和曲妥珠单抗德鲁替康 (T-DXd) 也有证据表明在此情况下有效。由于 T-DXd 在其他 HER2 靶向治疗方案治疗后已表现出活性，并且具有较高毒性的风险增加，因此作者倾向于保留其在先前的抗 HER2 治疗出现进展后使用。抑制信号转导的 HER2 靶向疗法似乎对RAS突变患者的活性有限，包括含曲妥珠单抗的治疗方案。然而，抗体药物偶联物 T-DXd 有一些数据显示在此情况下的功效，作者将考虑在 HER2 阳性、RAS突变 mCRC 的后续一线治疗中使用 T-DXd。关于如何在转移性结直肠癌中最好地利用 HER2 靶向疗法，仍然存在一些不确定性。其中包括抗 HER2 疗法与化疗和抗 EGFR 疗法的最佳顺序、抗 HER2 疗法的最佳组合伙伴，以及纳入预测性生物标志物以指导抗 HER2 疗法的使用。因此，正在进行的研究结果可能会在未来几年改变上述治疗模式。