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Severe Psychiatric Symptoms in a Patient With EGFR Exon-20 Insertion Mutation Receiving Mobocertinib: A Case Report

ABSTRACT: Tyrosine kinase inhibitor therapy is an established standard of care for patients with NSCLC with EGFR mutations, but a worse prognosis has been observed in patients with specific EGFR exon-20 insertion mutations. Mobocertinib (TAK-788) is a novel tyrosine kinase inhibitor developed to target EGFR exon-20 insertion and has exhibited promising response rates and acceptable safety in phase 1 and 2 trials. We report a case of a 59-year-old woman with metastatic NSCLC and EGFR exon-20 mutation responsive to mobocertinib therapy, who developed severe depression and catatonia approximately 4 months after mobocertinib initiation, ultimately necessitating its permanent discontinuation. Given the observed severe depression in this case report, we recommend that, for patients on mobocertinib who develop neuropsychiatric adverse effects, strong consideration should be given for dose interruption or discontinuation.

SUBMITTER: Kamel J

PROVIDER: S-EPMC8571787 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Severe Psychiatric Symptoms in a Patient With EGFR Exon-20 Insertion Mutation Receiving Mobocertinib: A Case Report

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