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. 2025 Nov 18:64:1544-1553.
doi: 10.2340/1651-226X.2025.44344.

Prevalence, molecular characterization, and prognosis of c-Met protein overexpression in a real-world cohort of patients with non-squamous non-small cell lung cancer

Jair Bar  1 , Mona H Cai  2 , Yookyung Christy Choi  2 , Shobhit Baijal  3 , Weilong Zhao  2 , Alexander Liede  2 , Athan Vasilopoulos  2 , Lisa Roberts-Rapp  2 , Fang Jiang  2 , Archana Simmons  2 , Christine Ratajczak  2 , Shun Lu  4 , Peter J Ansell  2 , D Ross Camidge  5
Affiliations

Prevalence, molecular characterization, and prognosis of c-Met protein overexpression in a real-world cohort of patients with non-squamous non-small cell lung cancer

Jair Bar et al. Acta Oncol. .

Abstract

Background and purpose: c-Met (also known as MET) protein is encoded by the MET proto-oncogene. In non-small cell lung cancer (NSCLC), c-Met protein overexpression (OE) drives tumorigenesis and is a therapeutic target, given recent US Food and Drug Administration approval of telisotuzumab vedotin-tllv. This retrospective analysis of tumor samples and clinical data from real-world patients with non-squamous NSCLC characterized the prevalence of c-Met protein OE, its association with messenger ribonucleic acid (mRNA) expression, MET gene amplification, programmed-death ligand 1 (PD-L1) expression, and its impact on prognosis.

Patients and methods: A patient cohort was selected for manual abstraction of clinical data from electronic health records. Patients were selected based on the availability of sufficient remnant tissue for biomarker analyses, including c-Met immunohistochemistry (IHC). Comparative assessments were conducted for c-Met protein expression by IHC, MET gene amplification, mRNA expression, and PD-L1 expression levels by IHC.

Results: In total, 305 and 84 patients were included in the biomarker prevalence and outcome analyses, respectively. Overall, c-Met protein OE was detected in 25% of tissue samples. Of the 212 samples with fluorescence in situ hybridization data, MET amplification was seen in 9%. Concordance of c-Met protein OE with MET mRNA levels was observed with area under the concentration-time curve values of 0.738 and 0.736 in MET OE or MET high OE, respectively, using Receiver Operating Characteristic analysis. c-Met protein OE was associated with poor prognosis (unadjusted hazard ratio for death of 2.04).

Interpretation: These data suggest that c-Met protein OE is associated with MET mRNA expression, shows limited overlap with other MET aberrations, and may be linked to poor prognosis in NSCLC.

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Conflict of interest statement

J. Bar: Advisory role: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Janssen, MSD, Merck Serono, Medison, Roche, Takeda; Writing/speaker engagement: BMS, Medison, Pfizer. Research funding: Immunai, OncoHost, MSD, AstraZeneca, Roche, AbbVie (institutional).

S. Baijal: Honoraria received from: AbbVie, Agilent, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, FoundationOne, Gilead, GlaxoSmithKline, Janssen, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, Roche, Servier, Sanofi, and Takeda.

D.R. Camidge: Honoraria: AbbVie, Amgen, Astellas Pharma, AnHeart Therapeutics, Apollomics, AstraZeneca, BeiGene, Bio-Thera Solutions, Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, EMD Serono, GlaxoSmithKline, Helsinn Therapeutics, Hengrui Pharmaceuticals, Janssen, Kestrel Labs, Lilly, Mersana, Nuvalent, Inc, OnKure, Pfizer, Puma Biotechnology, Qilu Pharmaceutical, Ribon Therapeutics, Roche, Sanofi, Seagen, Takeda, Turning Point Therapeutics; research funding: Inivata (Inst).

S. Lu: This author reports there are no competing interests to declare.

M. H. Cai, Y.C. Choi, W. Zhao, A. Vasilopoulos, M. Li, A. Liede, L. Roberts-Rapp, F. Jiang, A. Simmons, C. Ratajczak, P.J. Ansell: Employed by AbbVie and may own stocks or options.

Figures

Figure 1
Figure 1
Summary of patient attrition. The index data is the earliest date of metastasis (or diagnosis date for patients diagnosed at stage 4). aExcluded first-line targeted therapy class include EGFR inhibitor (n = 34), ALK inhibitor (n = 9), KRAS inhibitor (n = 1), BRAF inhibitor (n = 1). ALK: anaplastic lymphoma kinase; BRAF: B-Raf proto-oncogene, serine/threonine kinase; EGFR: epidermal growth factor receptor; KRAS: Kirsten rat sarcoma viral oncogene homolog; NSCLC: non-small cell lung cancer.
Figure 2
Figure 2
MET mRNA levels in c-Met protein overexpression-positive and -negative tumor specimens among patients with non-squamous NSCLC. ROC analysis was used to associate MET mRNA levels with c-Met protein OE. Left: ROC analysis evaluating MET mRNA expression vs c-Met protein overexpression by IHC in which c-Met protein OE positive is defined as ≥ 25% tumor cells with 3+ intensity. Right: ROC analysis evaluating MET mRNA expression vs high c-Met protein overexpression by IHC in which c-Met protein OE positive is defined as ≥ 50% tumor cells with 3+ intensity. ROC: Receiver Operating Characteristic; auROC: area under the ROC curve; NSCLC: non-small cell lung cancer; OE: overexpression; IHC: immunohistochemistry; mRNA: messenger ribonucleic acid..
Figure 3
Figure 3
Examples of c-Met protein overexpression and PD-L1 staining categories for tumor specimens among patients with non-squamous NSCLC. PD-L1 high: ≥ 50% cells expressing PD-L1; PD-L1 low: 1–49% cells expressing PD-L1; PD-L1 negative: ≤ 1% cells expressing PD-L1. C-Met protein OE positive is defined as ≥ 25% tumor cells with 3+ intensity. NSCLC: non-small cell lung cancer; OE: overexpression; PD-L1: programmed-death ligand 1.
Figure 4
Figure 4
c-Met overexpression and PD-L1 levels among patients with non-squamous NSCLCa. aPatients receiving targeted therapy as first-line treatment including tyrosine kinase inhibitors were excluded. Overall, EGFR status was unknown for 65 patients. PD-L1 high: ≥ 50% cells expressing PD-L1, PD-L1 low: 1–49% cells expressing PD-L1, PD-L1 negative: ≤ 1% cells expressing PD-L1. C-Met protein OE positive is defined as ≥ 25% tumor cells with 3+ intensity; high OE as ≥ 50% tumor cells with 3+ staining intensity, intermediate OE as ≥ 25 to < 50% tumor cells with 3+ staining intensity. EGFR: epidermal growth factor receptor; IHC: immunohistochemistry; NSCLC: non-small cell lung cancer; OE: overexpression; PD-L1: programmed-death ligand 1; Unk: unknown; WT: wild-type.
Figure 5
Figure 5
c-Met protein overexpression and survival probability in real-world patients. aPatients receiving targeted therapy as first-line treatment including tyrosine kinase inhibitors were excluded. bPatients were censored at clinical trial enrollment, last follow-up, or development of a new primary lung cancer, whichever occurred first. c-Met protein OE positive is defined as ≥ 25% tumor cells with 3+ intensity. OE: overexpression.
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References

    1. Blumenschein GR Jr, Mills GB, Gonzalez-Angulo AM. Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol. 2012;30:3287–96. 10.1200/JCO.2011.40.3774 - DOI - PMC - PubMed
    1. Rosário M, Birchmeier W. How to make tubes: signaling by the Met receptor tyrosine kinase. Trends Cell Biol. 2003;13:328–35. https://doi.org/0.1016/s0962-8924(03)00104-1 - PubMed
    1. Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011;3:S7–19. 10.1177/1758834011422556 - DOI - PMC - PubMed
    1. Gentile A, Trusolino L, Comoglio PM. The Met tyrosine kinase receptor in development and cancer. Cancer Metast Rev. 2008;27:85–94. 10.1007/s10555-007-9107-6 - DOI - PubMed
    1. Zhang YW, Su YL, Volpert OV, Vande Woude GF. Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation. Proc Natl Acad Sci U S A. 2003;100:12718–23. https://doi.org/0.1073/pnas.2135113100 - PMC - PubMed

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