MET aberrations across multiple tumor types: Results of a molecular screening program (MOSCATO 01).

Abstract

e23110 Background: MET gene, encoding the tyrosine kinase receptor for HGF, has been shown to have an oncogenic role in several tumors. We report here the frequency, distribution and clinical characteristics of the patients (pts) found to have MET alterations in a molecular screening trial. Methods: InMOSCATO clinical trial, pts with locally advanced or metastatic solid cancers had an on-purpose tumor biopsy to perform a comprehensive molecular characterization. Results: Among the 844 adult pts who had a successful molecular portrait, 29 (3.4%) had MET aberrations distributed as follows: 18 had abnormalities at the genomic analysis level while 11 had exclusively expression of phosporylated-MET by immunohistochemistry (IHC) and/or a positive fluorescence in situ hybridization (FISH). Only one of the 74 pediatric pts included had a missense mutation. According to the primary tumor, MET alterations were found in 13/170 successfully biopsied pts with lung cancer, 8/197 with digestive tumors, 3/158 with genito-urinary tumors, 2/83 with gynecologic tumors, 2/111 with head and neck cancers, 1/135 with breast cancer and 1 pt with pediatric glioblastoma. Pathogenic variants (PV) were detected in 3 pts by targeted Next Generation Sequencing (NGS), 2 of these PV were exon 14 donor splice site mutations detected also by whole-exome sequencing (WES) in 2 lung tumors. Missense mutations were identified in 3 pts by RNA-sequencing and in one patient by WES. 8 pts had MET amplification identified by comparative genomic hybridization array (CGH) in 5 cases, by FISH in one case and by both FISH and CGH in 2 cases. One patient displayed both amplification and a missense mutation. Ten pts received an anti-MET targeted therapy. One had PV on NGS and missense mutation on WES, 3 had amplification on CGH or FISH and 6 positive IHC. One patient displaying MET exon 14 donor splice site mutation was treated with crizotinib achieving a rapid and sustained partial response. The other 9 pts were treated with SAR125844, a selective MET tyrosine kinase inhibitor, in TED11449 trial (NCT01391533). Conclusions: In this analysis, we saw that MET aberrations are rare in various types of advanced cancers. In selected patients, targeting MET is of clinical interest. Clinical trial information: NCT01566019.