Tepotinib Efficacy in a Patient with Non-Small Cell Lung Cancer with Brain Metastasis Harboring an HLA-DRB1-MET Gene Fusion

Abstract

Alterations in c‐MET, a tyrosine kinase receptor encoded by the MET gene, have been reported in approximately 3% of non‐small cell lung cancer (NSCLC) cases and carry important treatment implications. The best studied genetic alterations are exon 14 skipping and gene amplification; however, gene rearrangement has also been described, and multiple fusion partners have been reported. Recently, in METex14‐mutated NSCLC, multitarget tyrosine kinase inhibitors (TKIs), such as crizotinib and cabozantinib, as well as MET‐selective TKIs, such as tepotinib and capmatinib, have demonstrated durable responses. In this study, we present the case of a 41‐year‐old woman with advanced NSCLC harboring an HLA‐DRB1‐MET gene fusion. The patient was offered successively two different MET multikinase inhibitors, crizotinib and cabozantinib, and the selective inhibitor tepotinib. Each time, including under tepotinib, the patient experienced rapid and complete responses associated with a tremendous improvement in her physical function. Key Points To our knowledge, this is the first report of a patient with non‐small cell lung cancer harboring an HLA‐DRB1‐MET gene fusion demonstrating a clinical response to multiple MET inhibitors, including tepotinib. This finding illustrates the efficacy and rationale to targeting MET regardless of fusion partner and gives insight to pooling of patients with different MET fusion products in trials assessing safety and efficacy of novel molecules.

Case Report: Patient With Lung Adenocarcinoma With ALK-HLA-DRB1 Rearrangement Shows Impressive Progression-Free Survival After Sequential Crizotinib and Ceritinib Treatment

“…Human leukocyte antigen (HLA), located on chromosome 6, encodes genes that are crucial in the immune response to pathogens (15). There have been 4 described cases of HLA-DRB1-MET gene rearrangement in lung adenocarcinoma (16)(17)(18)(19). Davies et al reported the first case of HLA-DRB1-MET gene rearrangement who was detected a previously undescribed fusion of HLA-DRB1 exon 5 (NM_002124) to MET exon 15 (NM_000245) (18).…”

Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

“…A meta-analysis showed that c-Met overexpression correlated to distant metastasis, large tumour size and high histologic grade in breast cancer ( Zhao et al, 2017 ). MET gene fusions have been primarily identified in lung cancer such as the HLA-DRB1-MET ( Davies et al, 2017 ; Blanc-Durand et al, 2020 ), KIF5B-MET ( Gow et al, 2018 ), MET-UBE2H ( Zhu et al, 2018a ), and MET-ATXN7L1 ( Zhu et al, 2018b ). The first case of HLA-DRB1-MET fusion was reported, however further studies are required to elucidate the specific mechanisms of the fusion gene ( Davies et al, 2017 ).…”

“…Meanwhile, it was also proposed that the MET-UBE2H fusion protein could be a novel resistance mechanism against EGFR-TKI treatment ( Zhu et al, 2018a ). MET fusions that occur at exon 15 and contain the 3’ MET kinase domain are thought to become activated due to constitutive dimerization of MET ( Blanc-Durand et al, 2020 ).…”

Targeted Treatment of Non-Small Cell Lung Cancer: Focus on Capmatinib with Companion Diagnostics

“…The VISION and INSIGHT trials, along with three separately published case reports, have also indicated that tepotinib has intracranial activity. [56][57][58][59][60] These findings prompted FDA accelerated approval for tepotinib for METex14 skipping NSCLC in February 2021. 61 Future studies evaluating genomic or other clinical determinants of response may help better differentiate the two promising drugs.…”