Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.

中文翻译：

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EGFR 和 HER2 外显子 20 选择性激酶抑制剂治疗非小细胞肺癌的机制和临床活性。


尽管表皮生长因子受体 (EGFR) 突变型非小细胞肺癌 (NSCLC) 的大多数激活突变对可用的 EGFR 酪氨酸激酶抑制剂 (TKI) 敏感，但 EGFR 和 HER2 外显子 20 发生改变的子集具有内在耐药性，并且缺乏有效的治疗方法。我们使用计算机、体外和体内测试来模拟由外显子 20 突变引起的结构改变并鉴定有效的抑制剂。 3D 建模表明改变限制了药物结合袋的大小，从而限制了大的刚性抑制剂的结合。我们发现，poziotinib 由于其体积小且具有灵活性，可以规避这些空间变化，并且是最常见的 EGFR 和 HER2 外显子 20 突变体的有效抑制剂。在体外、患者衍生的 EGFR 或 HER2 外显子 20 突变 NSCLC 异种移植模型以及 NSCLC 基因工程小鼠模型中，Poziotinib 表现出比已批准的 EGFR TKI 更高的活性。在一项 2 期试验中，首批 11 名 EGFR 外显子 20 突变的 NSCLC 患者接受 poziotinib 治疗后，经证实客观缓解率为 64%。这些数据表明 Poziotinib 是一种有效的、具有临床活性的 EGFR 和 HER2 外显子 20 突变抑制剂，并阐明了 TKI 的分子特征，可以规避这些突变引起的空间变化。