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.

Figure 1

Thoracic computed tomography scans. (A): December 2016: diagnosis of locally advanced (stage IIIA) NSCLC. (B): September 2017: multiple millimeter‐sized lung metastases. (C): November 2017: complete resolution of the lung lesions. (D): May 2019: new secondary lesion in right lung (yellow arrow). (E): August 2019: complete disappearance of the lung metastases.

Figure 2

Molecular analysis of the tumor. (A): Screenshot of the Integrative Genomics Viewer from the next‐generation sequencing fusion assay showing abundant supporting RNA reads with sequences starting from HLA‐DRB1 exon 4 and continuing to MET exon 15, indicating the presence of the HLA‐DRB1‐MET gene fusion. (B): Break‐apart fluorescence in situ hybridization assay showing the separation of MET 5' green probes from 3' red probes, confirming MET translocation. (C): Schematic of intron‐exon structures of the HLA‐DRB1 and MET genes and the HLA‐DRB1‐MET gene fusion. Abbreviation: Ig, immunoglobulin.

Figure 3

Brain magnetic resonance imaging scans. (A): August 2017: multiple disseminated brain metastases. (B): November 2017: complete resolution of the brain metastases. (C): May 2018: new secondary brain lesions (yellow arrow). (D): September 2018: complete resolution of the brain metastases.

Figure 4

Timeline of the successive treatments. Note that the patient received whole brain radiation therapy with dexamethasone following relapse in May 2018 and prior to initiation of tepotinib in July 2018. The patient had not progressed on cabozantinib as of November 2019. Abbreviation: RCT, radiochemotherapy.