Antitumor Activity of Vebreltinib and Characterization of Clinicogenomic Features in Solid Tumors with MET...

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Oncogenic translocations involving the MET gene are implicated in various cancers.
• Clinicogenomic characterization of MET rearrangement-positive cancers remains limited.
• Prospective clinical trials for MET inhibitors in these cancers are scarce.

Purpose of the Study:

• To characterize MET rearrangement-positive cancers through pan-cancer genomic profiling.
• To evaluate the antitumor activity of the MET tyrosine kinase inhibitor (TKI) vebreltinib in a phase II clinical trial.
• To identify potential resistance mechanisms to MET TKIs.

Main Methods:

• Pan-cancer analysis of over 46,000 solid tumors using comprehensive genomic profiling.
• Preliminary analysis of a phase II clinical trial of vebreltinib in MET fusion-positive solid tumors.
• Identification of secondary mutations conferring resistance to MET TKIs.

Main Results:

• Oncogenic MET rearrangements were identified in approximately 0.04% of all solid tumors.
• Vebreltinib demonstrated an objective response rate of 50% and a disease control rate of 79% in MET fusion-positive solid tumors.
• Antitumor activity was observed across diverse cancer types, including lung adenocarcinoma and intrahepatic cholangiocarcinoma.
• Secondary mutations in the kinase domain were found to confer resistance to MET TKIs, similar to MET exon 14-altered lung cancer.

Conclusions:

• MET rearrangements represent actionable molecular targets in solid tumors.
• MET fusions define a unique, targetable molecular subtype of cancer.
• Vebreltinib shows significant therapeutic potential in MET fusion-positive cancers.