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MET inhibitors in combination with other therapies in non-small cell lung cancer.

ABSTRACT: MET and its ligand hepatocyte growth factor/scatter factor (HGF) influence cell motility and lead to tumor growth, invasion, and angiogenesis. Alterations in MET have been observed in non-small cell lung cancer (NSCLC) tumors, with increased expression associated with more aggressive cancer, as well as acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). MET inhibitors act via two basic mechanisms. Small molecule inhibitors antagonize ATP in the intracellular tyrosine kinase domain of MET, with studies on the following agents reviewed here: tivantinib (ARQ-197), cabozantinib (XL-184), crizotinib (PF-02341066), amuvatinib (MP470), MGCD265, foretinib (EXEL-2880), MK2461, SGX523, PHA665752, JNJ-38877605, SU11274, and K252A. The monoclonal monovalent antibody fragment onartuzumab (MetMAb) is also discussed here, which binds to and prevents the extracellular activation of the receptor by ligand. MET inhibition may both overcome the negative prognostic effect of MET tumor expression as well as antagonize MET-dependent acquired resistance to EGFR inhibitors. Here we discuss MET inhibitors in combination with other therapies in lung cancer.

SUBMITTER: Padda S

PROVIDER: S-EPMC4367550 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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MET inhibitors in combination with other therapies in non-small cell lung cancer.

Padda Sukhmani S Neal Joel W JW Wakelee Heather A HA

Translational lung cancer research 20121201 4

MET and its ligand hepatocyte growth factor/scatter factor (HGF) influence cell motility and lead to tumor growth, invasion, and angiogenesis. Alterations in MET have been observed in non-small cell lung cancer (NSCLC) tumors, with increased expression associated with more aggressive cancer, as well as acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). MET inhibitors act via two basic mechanisms. Small molecule inhibitors antagonize ATP in the intrac ...[more]

PMID: 25806189

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Project description:BackgroundDysregulation of the mesenchymal epithelial transition (MET) pathway contributes to poor clinical outcomes in patients with non-small cell lung cancer (NSCLC). Numerous clinical trials are currently investigating several therapies based on modulation of the MET pathway.ObjectivesThis study aimed to systematically evaluate the activity and safety of MET inhibitors in patients with NSCLC.MethodsWe searched PubMed, Embase, and the Cochrane Library from inception to June 02, 2022. The objective response rate (ORR) and disease control rate (DCR) were extracted as the main outcomes and pooled using the weighted mean proportion with fixed- or random-effects models in cases of significant heterogeneity (I 2>50%). Safety analysis was performed based on adverse events reported in all studies.ResultsEleven studies (882 patients) were included in the meta-analysis. The pooled ORR was 28.1% (95% confidence interval [CI], 0.223-0.354), while the pooled DCR was 69.1% (95% CI, 0.631-0.756). ORRs were higher for tepotinib (44.7% [95% CI, 0.365-0.530]) and savolitinib (42.9% [95% CI, 0.311-0.553]) than for other types of MET inhibitors. Patients with NSCLC with exon 14 skipping exhibited higher ORRs (39.3% (95% CI, 0.296-0.522)) and DCRs (77.8% (95% CI, 0.714-0.847)) than those with MET protein overexpression or amplification. Intracranial response rate and intracranial disease control rates were 40.1% (95% CI, 0.289-0.556) and 95.4% (95% CI, 0.892-0.100), respectively. Adverse events were mild (grade 1 to 2) in 87.2% of patients. Common adverse events above grade 3 included lower extremity edema (3.5% [95% CI, 0.027-0.044]), alanine aminotransferase (ALT) elevation (2.4% [95% CI, 0.014-0.033]), and lipase elevation (2.2% [95% CI, 0.016-0.031]).ConclusionMET inhibitors, which exhibited a satisfactory safety profile in the current study, may become a new standard of care for addressing MET dysregulation in patients with advanced or metastatic NSCLC, and even in those with brain metastases, particularly tepotinib, savolitinib and capmatinib. Further randomized trials are required to establish standard predictive biomarkers for MET therapies and to compare the effects of different MET inhibitors in NSCLC with MET dysregulation.

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MET inhibitors in combination with other therapies in non-small cell lung cancer.

Publications

MET inhibitors in combination with other therapies in non-small cell lung cancer.

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