Targeting HER2 Exon 20 Insertion-Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Cancer Res. 2021 Oct 15;81(20):5311-5324. doi: 10.1158/0008-5472.CAN-21-1526. Epub 2021 Aug 11.


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) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / drug therapy*
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / pathology
  • Ado-Trastuzumab Emtansine / administration & dosage
  • Animals
  • Antibodies, Bispecific / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis
  • Cell Proliferation
  • Exons*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • INDEL Mutation*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Receptor, ErbB-2 / genetics*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antibodies, Bispecific
  • amivantamab-vmjw
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Ado-Trastuzumab Emtansine

Associated data