Targeting <i>HER2</i> Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Abstract

No targeted treatments are currently approved for <i>HER2</i> 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 (<i>HER2/ERBB2</i>) exon 20 insertion mutations. However, the function of mobocertinib on <i>HER2</i> 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 <i>HER2</i> exon 20 insertions. In <i>HER2</i> 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 <i>HER2</i> exon 20^YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, <i>HER2</i> exon 20^G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas <i>HER2</i> exon 20^YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against <i>HER2</i>, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in <i>HER2</i> exon 20^YVMA 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) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in <i>HER2</i> exon 20^YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against <i>HER2</i> exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.