Comprehensive analysis of MET mutations in NSCLC patients in a real-world setting

Xinghao Ai; Yongfeng Yu; Jun Zhao; Wang Sheng; Jing Bai; Zaiwen Fan; Xuemei Liu; Wenxiang Ji; Rongrong Chen; Shun Lu

doi:10.1177/17588359221112474

Comprehensive analysis of MET mutations in NSCLC patients in a real-world setting

Ther Adv Med Oncol. 2022 Jul 16:14:17588359221112474. doi: 10.1177/17588359221112474. eCollection 2022.

Authors

Xinghao Ai¹, Yongfeng Yu¹, Jun Zhao², Wang Sheng³, Jing Bai⁴, Zaiwen Fan⁵, Xuemei Liu⁶, Wenxiang Ji¹, Rongrong Chen⁷, Shun Lu⁸

Affiliations

¹ Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
² Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department I of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
³ Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
⁴ Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Guangxi Medical University, Nanning, China.
⁵ Department of Medical Oncology, Air Force Medical Center, PLA, Beijing, China.
⁶ Department of Radiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
⁷ Geneplus-Beijing, Floor 9, Building 6, Medical Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
⁸ Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, No.241, Huaihai West Road, Shanghai 200032, China.

Abstract

Background: Aberrant mesenchymal-epithelial transition/hepatocyte growth factor (MET/HGF) regulation presented in a wide variety of human cancers. MET exon 14 skipping, copy number gain (CNG), and kinase domain mutations/arrangements were associated with increased MET activity, and considered to be oncogenic drivers of non-small cell lung cancers (NSCLCs).

Methods: We retrospectively analyzed 564 patients with MET alterations. MET alterations were classified into structural mutations or small mutations. MET CNG, exon 14 skipping, gain of function (GOF) mutations, and kinase domain rearrangement were defined as actionable mutations.

Results: Six hundred thirty-two MET mutations were identified including 199 CNG, 117 exon 14 skipping, 12 GOF mutations, and 2 actionable fusions. Higher percentage of MET structural alterations (CNG + fusion) were detected in advanced NSCLC patients. Moreover, MET CNG was enriched while exon 14 skipping was rare in epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI)-treated advanced NSCLC patients. Ten of the 12 MET GOF mutations were also in EGFR-TKI-treated patients. Fifteen (68.1%) of the 22 patients treated with crizotinib or savolitinib had a partial response. Interestingly, one patient had a great response to savolitinib with a novel MET exon 14 skipping mutation identified after failure of immune-checkpoint inhibitor.

Conclusions: Half of the MET alterations were actionable mutations. MET CNG, exon 14 skipping and GOF mutations had different distribution in different clinical scenario but all defined a molecular subgroup of NSCLCs for which MET inhibition was active.

Keywords: MET mutation; MET-TKI; actionable mutations; genetics; non-small cell lung cancer.