MET Expression in Advanced Non-Small-Cell Lung Cancer: Effect on Clinical Outcomes of Chemotherapy, Targeted Therapy, and Immunotherapy

Clin Lung Cancer. 2018 Jul;19(4):e441-e463. doi: 10.1016/j.cllc.2018.03.010. Epub 2018 Mar 17.


Background: The receptor tyrosine kinase MET is implicated in malignant transformation, tumor progression, metastasis, and acquired treatment resistance. We conducted an analysis of the effect of MET expression and MET genomic aberrations on the outcome of patients with advanced or metastatic pulmonary adenocarcinomas prospectively enrolled in an institutional precision oncology program.

Patients and methods: Standardized immunohistochemistry (IHC) analyses of MET and markers of pathway activation were available in 384 patients, and next-generation sequencing-based MET hotspot mutation analyses were available from 892 patients. Clinical data were retrieved with a median follow-up from initial diagnosis of 37 months.

Results: High MET expression, defined as MET IHC 3+ or MET H-Score in the upper quartile, was observed in 102 of 384 patients (26.6%). MET exon 14 mutations were only detected in 7 of 892 patients (0.78%). High MET expression correlated with activation markers of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways only in cases without Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B (BRAF), anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) aberrations. There was no association of MET expression with outcome during chemotherapy. High MET expression negatively affected the outcome during EGFR-targeting therapy but was associated with more favorable results with programmed death 1/programmed death ligand 1 (PD-L1)-directed therapy, independent of smoking history, PD-L1 expression or KRAS mutation. Two patients with MET exon 14 mutation and high PD-L1 expression failed to respond to pembrolizumab.

Conclusion: MET expression affects the outcomes of targeted therapies in non-small-cell lung cancer, thus supporting the development of biomarker-informed combination strategies. The interaction of MET expression and MET mutation with immune checkpoint inhibitor therapy is novel and merits further investigation.

Keywords: EGFR TKI; MET mutation; PD-L1; Pathway activation; Predictive parameter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / analysis
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / therapy
  • Female
  • Humans
  • Immunotherapy / methods
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / therapy
  • Male
  • Middle Aged
  • Molecular Targeted Therapy / methods
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-met / analysis
  • Proto-Oncogene Proteins c-met / biosynthesis*
  • Proto-Oncogene Proteins c-met / genetics
  • Treatment Outcome


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • MET protein, human
  • Proto-Oncogene Proteins c-met