No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 ( HER2/ERBB2 ) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2 , ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib ([NCT02716116][1]) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients. Significance: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02716116&atom=%2Fcanres%2F81%2F20%2F5311.atom

中文翻译：

---

使用新型酪氨酸激酶抑制剂 Mobocertinib 靶向 HER2 外显子 20 插入突变型肺腺癌

目前尚无靶向治疗获批用于 HER2 外显子 20 插入突变型肺腺癌患者。Mobocertinib (TAK-788) 是一种有效的不可逆酪氨酸激酶抑制剂 (TKI)，旨在靶向人表皮生长因子受体 2 (HER2/ERBB2) 外显子 20 插入突变。然而，mobocertinib 对 HER2 外显子 20 插入突变肺癌的作用仍不清楚。在这里，我们对临床前模型进行了系统表征，以了解 mobocertinib 针对 HER2 外显子 20 插入的活性概况。在 HER2 外显子 20 插入突变细胞系中，mobocertinib 的 IC50 高于 poziotinib，与阿法替尼、来那替尼和吡咯替尼相当或略低。Mobocertinib 具有最低的 HER2 外显子 20 插入 IC50/野生型 (WT) EGFR I​​C50 比率，表明 mobocertinib 在这些模型中显示出最佳选择性。此外，mobocertinib 在 HER2 外显子 20YVMA 同种异体移植和患者来源的异种移植模型中显示出强烈的抑制活性。在基因工程小鼠模型中，HER2 外显子 20G776>VC 肺肿瘤对 mobocertinib 表现出持续的完全反应，而 HER2 外显子 20YVMA 肿瘤仅表现出部分和瞬时反应。在 HER2 外显子 20YVMA 肿瘤中，与 HER2 ado-trastuzumab emtansine (T-DM1) 的二抗-药物偶联物 (ADC) 联合治疗，与 mobocertinib 协同作用。除了肿瘤细胞自主效应外，持续的肿瘤生长控制源自 M1 巨噬细胞浸润和 CD4+ T 细胞活化。这些发现支持正在进行的 mobocertinib ([NCT02716116][1]) 临床开发，并为未来在 HER2 外显子 20YVMA 插入突变肺腺癌患者中进行 T-DM1 联合治疗的临床评估提供了依据。意义：本研究阐明了 mobocertinib 对 HER2 外显子 20 插入突变型肺癌的有效抑制活性以及联合 mobocertinib 和 T-DM1 的协同作用，为临床研究提供了强有力的理论依据。[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02716116&atom=%2Fcanres%2F81%2F20%2F5311.atom 本研究阐明了 mobocertinib 对 HER2 外显子 20 插入突变型肺癌的有效抑制活性以及联合 mobocertinib 和 T-DM1 的协同作用，为临床研究提供了强有力的理论依据。[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02716116&atom=%2Fcanres%2F81%2F20%2F5311.atom 本研究阐明了 mobocertinib 对 HER2 外显子 20 插入突变型肺癌的有效抑制活性以及联合 mobocertinib 和 T-DM1 的协同作用，为临床研究提供了强有力的理论依据。[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02716116&atom=%2Fcanres%2F81%2F20%2F5311.atom