Mobocertinib (TAK-788): A Targeted Inhibitor of <i>EGFR</i> Exon 20 Insertion Mutants in Non–Small Cell Lung Cancer

Abstract

Most <i>EGFR</i> exon 20 insertion (<i>EGFR</i>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 <i>EGFR</i>-mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating <i>EGFR</i>ex20ins mutations with selectivity over wild-type EGFR. The <i>in vitro</i> and <i>in vivo</i> activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse <i>EGFR</i>ex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated <i>in vivo</i> antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of <i>EGFR</i>ex20ins-mutated NSCLC. SIGNIFICANCE: No oral EGFR-targeted therapies are approved for <i>EGFR</i> exon 20 insertion (<i>EGFR</i>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 <i>EGFR</i> exon 20 insertion mutations.<i>See related commentary by Pacheco, p. 1617</i>.<i>This article is highlighted in the In This Issue feature, p. 1601</i>.