Protein tyrosine kinases of the human epidermal growth factor receptor family, including EGFR and HER2, have emerged as important therapeutic targets in non-small-cell lung, breast and gastroesophageal cancers, and are of relevance for the treatment of various other malignancies (particularly colorectal cancer). Classic activating EGFR exon 19 deletions and exon 21 mutations, and HER2 amplification and/or overexpression, are predictive of response to matched molecularly targeted therapies, translating into favourable objective response rates and survival outcomes. By comparison, cancers with insertion mutations in exon 20 of either EGFR or HER2 are considerably less sensitive to the currently available tyrosine kinase inhibitors and antibodies targeting these receptors. These exon 20 insertions are structurally distinct from other EGFR and HER2 mutations, providing an explanation for this lack of sensitivity. In this Review, we first discuss the prevalence and pan-cancer distribution of EGFR and HER2 exon 20 insertions, their biology and detection, and associated responses to current molecularly targeted therapies and immunotherapies. We then focus on novel approaches that are being developed to more effectively target tumours driven by these non-classic EGFR and HER2 alterations.

人表皮生长因子受体家族的蛋白酪氨酸激酶，包括 EGFR 和 HER2，已成为非小细胞肺癌、乳腺癌和胃食管癌的重要治疗靶点，并且与其他各种恶性肿瘤（尤其是结直肠癌）的治疗相关癌症）。典型的活化EGFR外显子 19 缺失和外显子 21 突变，以及HER2扩增和/或过表达，可预测对匹配的分子靶向治疗的反应，转化为有利的客观反应率和生存结果。相比之下，在EGFR或HER2的外显子 20 中具有插入突变的癌症对目前可用的酪氨酸激酶抑制剂和靶向这些受体的抗体的敏感性要低得多。这些外显子 20 插入在结构上不同于其他EGFR和HER2突变，为这种缺乏敏感性提供了解释。在这篇综述中，我们首先讨论了EGFR和HER2外显子 20 插入的患病率和泛癌分布、它们的生物学和检测，以及对当前分子靶向疗法和免疫疗法的相关反应。然后，我们专注于正在开发的新方法，以更有效地靶向由这些非经典EGFR和HER2改变驱动的肿瘤。