Is Mobotinib/Mobotinib a treatment for HER2 mutated diseases?

There are currently no targeted therapies approved for patients with lung adenocarcinoma with HER2 exon 20 insertion mutations. Mobocertinib 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 effect of mobosetinib on HER2 exon 20 insertion mutant lung cancer remains unclear.

Systematic characterization of preclinical models is currently being conducted to understand the activity profile of mobosertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion mutation cell lines, the IC50 of mobosetinib is higher than that of poziotinib, and is comparable to or slightly lower than afatinib, neratinib and pyrotinib. Mobosetinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobosetinib displays the best selectivity profile in these models. Furthermore, moboxetinib demonstrated potent inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776VC lung tumors showed sustained complete responses to moboxetinib, whereas HER2 exon 20YVMA tumors showed only partial and transient responses.

Using a second antibody-drug conjugate (ADC) directed against HER2, ado-trastuzumab emtansine (T-DM1) in combination with moboxetinibHER2 exon 20YVMA tumors. In addition to tumor cell autonomous effects, sustained tumor growth control results from M1 macrophage infiltration and CD4+ T cell activation. These findings support the ongoing clinical development of mobosertinib and provide a theoretical basis for future clinical evaluation of T-DM1 combination therapy in patients with lung adenocarcinoma with HER2 exon 20YVMA insertion mutations.

Reference materials:https://pmc.ncbi.nlm.nih.gov/articles/PMC8530969/