c-Met, also known as MET or HGFR (Hepatocyte Growth Factor Receptor), is a receptor tyrosine kinase in the MET family that is expressed on the surface of various cell types. Hepatocyte Growth Factor (HGF) is currently the only known natural ligand with high affinity for c-Met. The binding of HGF to c-Met activates a cascade of intracellular signaling pathways involved in normal embryonic development and wound healing.

However, in cancer cells, abnormal activation of the HGF/c-Met axis—often driven by mutations, overexpression, or amplification of the c-Met gene—is closely linked to tumor initiation and progression. This occurs through the stimulation of several signaling pathways, including PI3K/AKT, Ras/MAPK, JAK/STAT, SRC, and Wnt/β-catenin.

Abnormal regulation of c-Met has been observed in various tumor types, including gastrointestinal (GI) cancers, hepatocellular carcinoma (HCC), and non-small cell lung cancer (NSCLC). Such dysregulation often results from c-Met overexpression, genomic rearrangements (such as translocations, amplifications, or mutations), and other alterations. Additionally, the HGF/c-Met pathway can significantly interact with other receptor tyrosine kinase (RTK) signaling pathways, contributing to tumor progression and resistance to targeted therapies. As a result, c-Met is widely recognized as a promising therapeutic target for the treatment of multiple cancers.

Current Status of c-Met Inhibitor Research

Various types of c-Met inhibitors have been developed, including small molecule inhibitors, monoclonal antibodies, bispecific antibodies, and antibody-drug conjugates (ADCs).

Table 1. FDA-Approved c-Met Targeted Therapies

c-Met Targeted Antibody-Drug Conjugate (ADC)

EMRELIS (telisotuzumab vedotin-tllv) is the first ADC targeting c-Met, comprising of a c-Met-specific antibody, a cleavable linker, and the cytotoxic agent MMAE (monomethyl auristatin E). It is designed to kill cancer cells that overexpress c-Met.

On May 14, 2025, the U.S. FDA granted accelerated approval for EMRELIS to treat adults with locally advanced or metastatic non-squamous NSCLC who have high c-Met protein overexpression (defined as ≥50% of tumor cells showing strong [3+] staining), as confirmed by an FDA-approved test, and who have previously received systemic therapy.

This approval was based on results from the Phase 2 LUMINOSITY study (NCT03539536), which evaluated the drug’s safety and effectiveness in advanced NSCLC patients with high c-Met expression. Among 84 patients, EMRELIS achieved a 35% overall response rate (ORR) (95% CI: 24–46), with a median duration of response (DOR) of 7.2 months (95% CI: 4.2–12).

C-met Targeted Bispecific Antibody 

Amivantamab (Rybrevant) is a bispecific antibody developed by Johnson & Johnson that targets both the EGFR and MET receptors, inhibiting their signaling pathways and engaging immune cells to attack tumors with relevant EGFR/MET alterations.

In May 2021, the U.S. FDA granted accelerated approval for Amivantamab for the treatment of advanced NSCLC with EGFR exon 20 insertion mutations whose disease has progressed after platinum-based chemotherapy.

In March 2024, the FDA granted full approval for Amivantamab in combination with chemotherapy as a first-line treatment for patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations.

In August 2024, the FDA approved Amivantamab in combination with lazertinib as a first-line treatment for adult patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations. Notably, this combination demonstrated a median overall survival improvement of over one year.

Small Molecule c-Met Inhibitors

(1) Multi-Target c-Met Inhibitors

Crizotinib and Cabozantinib are multi-kinase inhibitors that target c-Met among other kinases. These agents exhibit stronger activity against VEGFR than c-Met, making them less effective in selectively targeting oncogenic c-Met mutations.

Crizotinib (Xalkori)

• • Targets: ALK, c-Met (HGFR), ROS1, and RON
• • Indications: ALK- or ROS1-positive non-small cell lung cancer (NSCLC), ALK-positive anaplastic large cell lymphoma (ALCL), and ALK-positive inflammatory myofibroblastic tumors (IMTs)

Developed by Pfizer, Crizotinib is a multi-targeted tyrosine kinase inhibitor of ALK, MST1R, ROS1, and c-Met. It was the first ALK inhibitor approved globally and received FDA approval on August 26, 2011, for the treatment of ALK-positive NSCLC. In March 2016, it was further approved for ROS1-positive NSCLC, marking the first FDA-approved therapy for this indication.

Cabozantinib (Cometriq, Cabometyx)

• • Targets: MET, VEGFR1/2/3, ROS1, RET, AXL, NTRK, KIT
• • Approved Indications: Thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, neuroendocrine tumors

Cabozantinib is a broad-spectrum, multi-target tyrosine kinase inhibitor developed by Exelixis Inc. It inhibits at least nine key oncogenic targets, including MET, VEGFR1/2/3, RET, KIT, FLT3, AXL, NTRK, and ROS1. Due to its ability to target multiple critical pathways, Cabozantinib has demonstrated significant therapeutic efficacy across a wide range of cancers, including renal cell carcinoma, thyroid cancer, hepatocellular carcinoma, soft tissue sarcoma, non-small cell lung cancer, prostate cancer, breast cancer, ovarian cancer, and colorectal cancer.

(2) Selective c-Met Inhibitors

Selective c-Met inhibitors are designed to bind to the unique hinge region of the MET kinase domain, allowing for highly specific inhibition of c-Met activity. Due to concerns about off-target effects and safety profiles associated with multi-kinase inhibitors, current research and development efforts have increasingly focused on the development of selective c-Met inhibitors.

Capmatinib (Tabrecta®)

• • Target: MET exon 14 (METex14)
• • Indication: Treatment of metastatic non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutations

Capmatinib is an oral, highly selective MET tyrosine kinase inhibitor developed by Novartis. It inhibits MET phosphorylation and downstream signaling pathways, thereby suppressing the proliferation and migration of MET-dependent tumor cells and inducing apoptosis. On May 6, 2020, the U.S. FDA approved Capmatinib as the first targeted therapy for patients with locally advanced or metastatic NSCLC harboring MET exon 14 skipping mutations.

Tepotinib (Tepmetko®)

• • Target: MET exon 14 (METex14)
• • Indication: Treatment of metastatic non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutations

Tepotinib, developed by Merck, is an oral MET kinase inhibitor specifically targeting MET exon 14 skipping mutations. It blocks MET phosphorylation and downstream signaling, thereby inhibiting tumor growth, anchorage-independent proliferation, and migration of MET-dependent cancer cells. In February 2021, the U.S. FDA granted accelerated approval for Tepotinib (Tepmetko) for the treatment of adult patients with metastatic NSCLC harboring MET exon 14 skipping mutations.

References:
[1] Bradley CA, Salto-Tellez M, Laurent-Puig P, et al. Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nat Rev Clin Oncol. Published online January 23, 2018. doi:10.1038/nrclinonc.2018.13
[2] https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-telisotuzumab-vedotin-tllv-nsclc-high-c-met-protein-overexpression
[3] https://www.drugs.com/history/rybrevant.html  
[4] https://www.drugs.com/history/Xalkori.html
[5] https://www.drugs.com/history/Cometriq.html
[6] https://www.drugs.com/history/Tabrecta.html 
[7] https://www.drugs.com/history/Tepmetko.html