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

作者：Seshiru Nakazawa, Federica Pecci, Igor Odintsov, Dimitris Gazgalis, Felix H. Gottlieb, Biagio Ricciuti, Lodovica Zullo, Joao V. Alessi, Alessandro Di Federico, Mihaela Aldea, Edoardo Garbo, Malini Gandhi, Arushi Saini, William W. Feng, Jie Jiang, Simon Baldacci, Francesco Facchinetti, Maisam Makarem, Marie-Anaïs Locquet, Koji Haratani, Danielle Haradon, Benjamin Besse, Antoîne Italiano, Jordi Remón, Pernelle Lavaud, Damien Vasseur, David Planchard, Yusuke Sato, Y. Watanabe, Scott Owen, Alexis B. Cortot, Hoda A. Mahran, Martin Förster, Jiaxin Niu, Pascale Tomasini, Leong Swan Swan, Kevin Tay, Emilio Esteban, Anna Minchom, Sani H. Kizilbash, Marcia Cruz‐Correa, Kin-Hung P. Yu, Xiaoling Zhang, Pan Chen, Mythili Sangem, Jianwei Che, Lynette M. Sholl, Pasi A. Jänne, Mark M. Awad · 发表于：Cancer Discovery · 年份：2025 · DOI：10.1158/2159-8290.cd-24-1726 · 被引用次数：7 · 研究领域：Liver physiology and pathology、Lung Cancer Treatments and Mutations、Cholangiocarcinoma and Gallbladder Cancer Studies

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. In this study, 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 II 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 and 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. SIGNIFICANCE: MET rearrangement-positive cancers are not well-characterized, and optimal treatment strategies are yet to be defined. Through comprehensive genomic analysis, preclinical modeling, and preliminary results of a phase II clinical trial, we demonstrate that MET fusions are a unique molecular subtype of cancers targetable with vebreltinib, a TKI in development.