Antitumor activity of vebreltinib and characterization of clinicogenomic features in solid tumors with MET rearrangements

Abstract Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement-positive cancers are limited. Here, in a pan-cancer analysis of >46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ~0.04% of cancers. Preliminary analysis from a phase 2 clinical trial of the type I MET tyrosine kinase inhibitor (TKI) vebreltinib in MET fusion-positive solid tumors demonstrated an objective response rate of 50% and disease control rate of 79%, with antitumor activity seen in diverse cancer types including lung adenocarcinoma, intrahepatic cholangiocarcinoma, among others. Similar to MET exon 14-altered lung cancer, secondary mutations in the kinase domain can confer resistance to MET TKIs in MET fusion-positive cancers. Overall, these data categorize MET rearrangements as actionable targets in solid tumors.