Abstract
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.
Original language | English (US) |
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Pages (from-to) | 5311-5324 |
Number of pages | 14 |
Journal | Cancer Research |
Volume | 81 |
Issue number | 20 |
DOIs | |
State | Published - Oct 15 2021 |
Funding
T.E. Baker reports personal fees from Takeda, personal fees from Amathus Therapeutics, and personal fees from MOMA Therapeutics outside the submitted work. V.M. Rivera reports other support from ARIAD Pharmaceuticals and other support from Theseus Pharmaceuticals outside the submitted work. S. Vincent reports other support from Takeda during the conduct of the study. K.K. Wong reports grants from Takeda during the conduct of the study and grants from Bristol Myers Squibb, grants from Mirati, grants from Merus, grants from Alkermes, grants from Ansun, grants from Tvardi, grants from Delfi, grants from Dracen, other support from Recursion Pharmaceuticals, other support from Prelude, grants and other support from Rentals, and grants and other support from Janssen outside the submitted work. K.K. Wong is a founder and equity holder of G1 Therapeutics. No disclosures were reported by the other authors. This study is supported by NIH grants CA154303 and CA098101 as well as by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
ASJC Scopus subject areas
- Oncology
- Cancer Research