ONCOGENIC SIGNALING

The MET pathway

MET signaling is critical in normal biological processes. It activates downstream signaling pathways, including RAS/ERK/MAPK, PI3K/AKT, and JAK/STAT, which drive cell proliferation, motility, and apoptosis. Dysregulation of the MET pathway (for example, MET mutations and amplifications) can drive cancer cell proliferation, survival, invasion, and metastasis.1

Tepotinib – MET kinase inhibitor

Description and Mechanism of Action:

Tepotinib is an investigational small molecule inhibitor of the MET receptor tyrosine kinase. Alterations of the MET signaling pathway are found in various cancer types and are thought to correlate with aggressive tumor behavior and poor clinical prognosis.1,2

In vitro, tepotinib inhibited tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent tumor cells. In mice implanted with tumor cell lines with oncogenic activation of MET, including METex14 skipping alterations, tepotinib inhibited tumor growth, led to sustained inhibition of MET phosphorylation, and, in one model, decreased the formation of metastases.2

The MET Pathway

Areas of Interest:

TRIALS

VISION3 (NCT02864992)

A phase II, single-arm, multi-cohort clinical trial investigating tepotinib in patients with advanced non-small cell lung cancer (NSCLC) harboring MET alterations

INSIGHT 24 (NCT03940703)

A phase II clinical trial to investigate tepotinib combined with osimertinib in patients with osimertinib-resistant, MET-amplified, EGFR-mutant NSCLC

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TARGETING MET clinical trials now enrolling

Targeting MET

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Pathways Under Investigation

EGFR/MUC1

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Abbreviations:
AKT, protein kinase B; EGFR/MUC1, epidermal growth factor receptor/mucin 1; ERK, extracellular signal regulated kinase; IAP, inhibitor of apoptosis; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MET, mesenchymal epithelial transition factor; METex14, MET exon 14; PI3K, phosphatidylinositol 3 kinase; RAS, rat sarcoma; STAT, signal transducers and activators of transcription.

References:

  1. Wu Y-L, Soo RA, Locatelli G, Stammberger U, Scagliotti G, Park K. Does c-Met remain a rational target for therapy in patients with EGFR TKI-resistant non-small cell lung cancer? Cancer Treat Rev. 2017;61:70-81.
  2. TEPMETKO. Prescribing information. Merck KGaA; 2021.
  3. Tepotinib phase II in NSCLC harboring MET alterations (VISION). ClincalTrials.gov identifier: NCT02864992. Updated September 22, 2021. Accessed November 4, 2021. https://www.clinicaltrials.gov/ct2/show/NCT02864992
  4. A study of tepotinib plus osimertinib in osimertinib relapsed MET amplified NSCLC (INSIGHT 2). ClincalTrials.gov identifier: NCT03940703. Updated November 2, 2021. Accessed November 4, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03940703

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