Gonzalvez Francois, Vincent Sylvie, Baker Theresa E, Gould Alexandra E, Li Shuai, Wardwell Scott D, Nadworny Sara, Ning Yaoyu, Zhang Sen, Huang Wei-Sheng, Hu Yongbo, Li Feng, Greenfield Matthew T, Zech Stephan G, Das Biplab, Narasimhan Narayana I, Clackson Tim, Dalgarno David, Shakespeare William C, Fitzgerald Michael, Chouitar Johara, Griffin Robert J, Liu Shengwu, Wong Kwok-Kin, Zhu Xiaotian, Rivera Victor M
ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Cancer Discov. 2021 Jul;11(7):1672-1687. doi: 10.1158/2159-8290.CD-20-1683. Epub 2021 Feb 25.
Most exon 20 insertion (ex20ins) driver mutations in non-small cell lung cancer (NSCLC) are insensitive to approved EGFR tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting -mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating ex20ins mutations with selectivity over wild-type EGFR. The and activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse ex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of ex20ins-mutated NSCLC. SIGNIFICANCE: No oral EGFR-targeted therapies are approved for exon 20 insertion (ex20ins) mutation-driven NSCLC. Mobocertinib is a novel small-molecule EGFR inhibitor specifically designed to target EGFRex20ins mutants. Preclinical data reported here support the clinical development of mobocertinib in patients with NSCLC with exon 20 insertion mutations...
非小细胞肺癌（NSCLC）中大多数外显子20插入（ex20ins）驱动突变对已获批的表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）不敏感。为解决现有针对EGFR突变型NSCLC疗法的局限性，莫博赛替尼（TAK-788），一种新型不可逆EGFR TKI，被专门设计用于有效抑制含有激活型ex20ins突变的致癌变体，且对野生型EGFR具有选择性。在携带多种ex20ins突变的工程化模型和患者来源模型中评估了莫博赛替尼的活性和疗效。莫博赛替尼比已获批的EGFR TKI更有效地抑制了各种EGFR ex20ins驱动的细胞系的活力，并在患者来源的异种移植模型和小鼠原位模型中显示出抗肿瘤疗效。这些发现支持了莫博赛替尼用于治疗ex20ins突变型NSCLC的正在进行的临床开发。意义：尚无口服EGFR靶向疗法获批用于外显子20插入（ex20ins）突变驱动的NSCLC。莫博赛替尼是一种专门设计用于靶向EGFR ex20ins突变体的新型小分子EGFR抑制剂。此处报告的临床前数据支持莫博赛替尼在具有外显子20插入突变的NSCLC患者中的临床开发……
