The Role of MET and c-Met in Advanced NSCLC


cMET-US-00002-MC V2 6/2023

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As the understanding of the molecular mechanisms and underlying pathophysiology associated with NSCLC has advanced, the treatment armamentarium for non–small cell lung cancer (NSCLC) has changed immensely over the last several decades. Initially, chemotherapy was the standard of care for patients with NSCLC; however, the identification of clinically relevant subtypes with various oncogenic driver mutations has led to the discovery of novel therapeutic targets and, ultimately, target-specific agents for the management of NSCLC. Common driver mutations include epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements. Tyrosine kinase inhibitors (TKIs) that target these drivers have greatly extended the lives of many patients with NSCLC whose tumors harbor these gene alterations. Additional driver mutations include BRAF, MET exon 14 skipping, RET, NTRK1/2, ERBB2 (HER2), KRAS, and ROS1 for which targeted agents are available.

While dysregulation of the MET pathway can occur as a resistance mechanism to other treatments for NSCLC including EGFR inhibitors in patients whose tumors harbor EGFR mutations, MET amplification and c-Met (also known as MET protein) overexpression can occur de novo and therapies that target these alterations are under investigation. The de novo alterations of the MET signaling pathway and agents directed toward these alterations are the focus of this article.


MET is a proto-oncogene located on chromosome 7q31.2 that encodes c-Met, a transmembrane tyrosine kinase receptor.1,2 The c-Met receptor is normally expressed at low levels in healthy epithelial cells; however, overexpression of c-Met, typically ranging from 2 to 50 times that noted in normal cells, has been observed in certain tumor cell types, including renal cell carcinoma, NSCLC, colorectal cancer, and liver cancer.1,3-5

Hepatocyte growth factor (HGF), also known as scatter factor, is the natural ligand for c-Met; it is produced primarily by mesenchymal cells.6 HGF elicits action on epithelial cells in an endocrine or paracrine fashion, and it is involved in regulating several cellular functions, including those related to cell proliferation, survival, apoptosis, motility, invasion, angiogenesis, and branching morphogenesis.6 c-Met receptor activation occurs upon binding with HGF, which leads to the phosphorylation of multiple serine and tyrosine residues involved in the initiation of signal transduction.7 Initiation of c-Met-mediated signaling can lead to the activation of a number of different downstream pathways, including MAPK, PI3K/AKT, JAK/STAT, and NF-кB.


Dysregulation of c-Met signaling can occur through various mechanisms, including MET amplification, MET activating mutations, MET exon 14 skipping mutations, gene fusions, transcriptional upregulation, c-Met receptor overexpression, or ligand-dependent mechanisms, such as HGF overexpression.8,9 Aberrant c-Met signaling contributes to tumor progression, angiogenesis, tumor invasiveness, and metastatic tumor activity, and it is associated with therapeutic resistance and poor prognosis.8-10

MET Mutations, Rearrangements, and Amplifications in NSCLC

MET mutations have been identified in several functional gene domains, including the sema, kinase, and juxamembrane domains.11,12 Exon 14 of the MET gene encodes the juxtamembrane domain, which includes Y1003, the direct binding site for CBL E3-ligase tyrosine kinase protein.13 The CBL protein plays an important role in regulating the signaling of c-Met. Ubiquitin ligase activity exhibited by the CBL protein allows targeting of c-Met for degradation and subsequent termination of signaling.14 MET exon 14 mutations resulting in Y1003 deletion lead to decreased CBL binding, prolonged c-Met-mediated cell signaling (including downstream signaling effects), and increased proliferation and tumorgenesis.13

MET Exon 14 Skipping Mutations

MET exon 14 mutations can result from deletions or point mutations. They are more frequently associated with adenocarcinoma subtypes and older patients (median age, ≈ 72.5 years); in 1 study, 64% of patients had a history of tobacco use.15 Specific alterations in MET exon 14, known as skipping mutations, were first identified in 1994.16 MET exon 14 mutations are the most frequently reported type of MET alteration, occurring in approximately 2% to 3% of patients with NSCLC.17 These mutations are characterized by an absence of 47 amino acids in the juxtamembrane domain, which causes a loss of c-Met receptor degradationand leads to an upregulation of c-Met-mediated signaling and tumorigenesis. 1,13,15,18

MET Rearrangements

MET kinase domain rearrangements (KDREs) have been identified in several cancer types, including gliomas, lung adenocarcinomas, and liver and thyroid carcinomas.19,20 In contrast with MET mutations and amplifications, MET KDREs are relatively rare, occurring in approximately 0.2% of patients with NSCLC.21 MET KDREs may be drivers of and potential mechanisms of resistance to EGFR and ALK inhibitors in NSCLC.20,22

MET Amplification

MET amplification is a common mechanism known to drive c-Met overexpression that can occur de novo in treatment-naïve patients and can emerge after treatment with TKIs, especially EGFR TKIs.23-25 De novo MET amplifications occur in approximately 1% to 5% of patients with NSCLC, mostly in cases of adenocarcinoma.26,27 Among those receiving EGFR TKI treatment, MET amplification occurs in approximately 5% to 21% of cases.25,28 MET amplifications are not mutually exclusive with other driver mutations.A retrospective analysis of oncogene overlap of 855 tumor samples from patients with confirmed lung adenocarcinoma found that MET amplification (defined by the mean number of MET genes per cell [MET/cell ratio]) were associated with other oncogenic drivers mutations in 61% of all samples.27 Among patients in the high MET/cell group (defined as mean MET/cell ≥7) concomitant oncogenic drivers included ALK (9%), EGFR (22%), KRAS ERBB2 (6%), BRAF (1%), and NRAS (1%). When MET to centromere of chromosome 7 (MET/CEP7) ratios were used to determine MET amplification, additional oncogenic drivers were also noted in 47% of samples; however, no addition driver mutations were identified in samples with high MET amplification (defined as MET/CEP7 ≥5). Importantly, there were only 4 patients out of a total of 270 patients that had MET/CEP7 ≥5.27

c-Met Overexpression in NSCLC

Overexpression of c-Met mRNA is present in up to 50% of patients with NSCLC, with overexpression more frequently observed among patients with adenocarcinoma (35%) and large cell undifferentiated NSCLC (23%) than those with squamous cell NSCLC (11%).29,30 Corresponding c-Met protein expression in squamous cell NSCLC can be 2- to 5-fold greater than noted in healthy lung tissues and 10-fold or greater than seen in adenocarcinomas and large cell undifferentiated carcinomas. A meta-analysis of 22 studies involving 4454 patients estimated the c-Met immunohistochemistry (IHC) positivity rate to be 44% among patients with NSCLC, with higher rates observed in nonsquamous NSCLC and stage III or IV tumors.31 c-Met IHC positivity correlates with poor overall survival (OS), which may suggest c-Met’s potential utility as a prognostic biomarker.31,32


In oncogene addiction, tumor cells become physiologically dependent on continued activity of specific oncogenes to maintain their malignant phenotype.33 Evidence for oncogene addiction in patients with NSCLC has emerged, showing that patients with mutationally activated or amplified EGFR exhibit more favorable responses to such TKIs as gefitinib and erlotinib.34-38

Because driver mutations confer certain survival advantages to tumor cells, they can be major contributing factors to oncogene addiction.39 In NSCLC tumors, driver mutations have been identified in more than 15 different genes, including less common mutations in MET, ARAF, CRAF, RIT1, HRAS, and NRAS.40 MET-associated oncogene addiction can be caused by MET mutations (eg, exon 14 skipping mutations), HGF-mediated MET activation, MET amplification leading to c-Met overexpression and ligand-independent MET activation, and MET gene fusions.41 Patients with NSCLC and confirmed presence of these anomalies tend to experience favorable responses to MET TKIs, such as crizotinib.22,42,43

Although overexpression of c-Met is present in approximately 50% of patients with NSCLC, it does not lead to oncogenic addiction in the majority of cases.29,41,44-50 Thus, while c-Met overexpression can overlap with other MET driver and codriver states such as MET exon 14 mutations, it may exist independently, for example through overexpression of HGF and cell-matrix adhesion.51-54 Consequently, c-Met overexpression may pose a potential therapeutic target regardless of the MET-signaling addiction status of the tumor.30,55

c-Met Testing for Treatment Decision-Making in NSCLC

MET exon 14 skipping mutations are recognized as a predictive biomarker for therapeutic efficacy of certain MET-targeted therapies, and testing is recommended for eligible patients with stage IV NSCLC.56 High-level MET amplification is another emerging biomarker; however, supporting data are limited for available agents, some of which have not yet received FDA approval. c-Met expression is quantitated through IHC staining and is graded according to intensity: IHC 0, less than 50% of cells (low intensity); IHC 1+, greater than 50% or cells (low intensity) or less than 50% of cells (median intensity); IHC 2+, greater than 50% median intensity or less than 50% high intensity; IHC 3+, greater than 50% high intensity.57 Expression of c-Met strongly has correlated with tumor histology, with highest c-Met expression found among adenocarcinomas (56%). Therefore, determining c-Met expression status may be helpful in guiding therapeutic decision-making.


Treatment guidelines for NSCLC recommend specific biomarker testing to guide treatment decisions and determine eligibility for targeted therapy approaches.56 Treatment approaches targeting c-Met include direct receptor inhibition using MET-directed monoclonal antibodies (mAbs), small-molecule TKIs, EGFR- and MET-directed bispecific antibodies, and c-Met-directed antibody-drug conjugates (ADCs). An example of a MET-directed mAb is emibetuzumab, which is under clinical development, and an example of an EGFR- and a MET-directed bispecific antibody is amivantamab.58,59 Crizotinib, capmatinib, and tepotinib are TKIs that target MET and are recommended for patients with metastatic NSCLC that harbor MET exon 14 skipping mutations or high-level MET amplification.56 Savolitinib is a MET-targeted TKI that blocks c-Met signaling and received conditional approval in China in patients with MET exon 14-skipping alterations who have progressed after or who are unable to tolerate platinum-based chemotherapy.60 Importantly, tumors treated with these agents eventually acquire resistance resulting in poor long-term outcomes.61

The c-Met-directed ADC, telisotuzumab vedotin (Teliso-V), is an investigational drug under development. It is being studied for the treatment of patients with advanced/metastatic EGFR wild-type, nonsquamous NSCLC with high levels of c-Met overexpression whose disease has progressed on or after platinum-based therapy.62

It is important to note that all of these drug classes, except ADCs, function to inhibit the addiction of the tumor to the MET pathway by several mechanisms including preventing binding of c-Met to HGF, c-Met internalization and degradation, or preventing c-Met phosphorylation and subsequent activation of c-Met-dependent downstream signaling pathways.54,57-62 Previous investigational drugs (eg, onartuzumab and tivantinib) blocked c-Met signaling but used overexpression, which was not specific enough, and those drugs failed to meet clinical end points.63,64 Conversely, telisotuzumab vedotin uses the over-expression of c-Met as a target for identifying tumor cells for delivering the payload. Once telisotuzumab vedotin interacts with c-Met, it is internalized and the conjugated cytotoxic payload (the microtubule inhibitor monomethyl auristatin E) is released resulting in death of tumor cells as well as surrounding cells.65

MET-Directed Antibodies

Emibetuzumab and ABT-700 (telisotuzumab), which are under clinical development, are bivalent, c-Met-directed mAbs that inhibit both ligand-dependent and -independent signaling.58,66,67 Emibetuzumab inhibits ligand-dependent c-Met activation by directly blocking HGF from binding to c-Met, whereas ligand-independent inhibitory activity results from the downregulation of c-Met expression by emibetuzumab-induced internalization of the c-Met receptor. Emibetuzumab has been evaluated when used alone or with erlotinib in the first-line therapy setting for EGFR-mutant NSCLC and in patients with NSCLC and acquired resistance to erlotinib.67 In a phase 2 trial (NCT01897480), patients with EGFR-mutant NSCLC received erlotinib alone or in combination with emibetuzumab.58 No significant difference in median PFS (mPFS) was observed in the combination group vs the erlotinib monotherapy group (9.3 months vs 9.5 months, respectively). However, an exploratory post-hoc analysis found an improvement in mPFS among patients with the highest MET expression (3+ in 90% of tumor cells) who received combination treatment compared with erlotinib monotherapy (20.7 months vs 5.4 months, respectively). A second phase 2 trial (NCT01900652) included patients with advanced NSCLC who had acquired resistance to erlotinib and had at least 10% of cells expressing c-Met at 2+ or greater IHC staining intensity at any time.67 Patients were randomized 3:1 to emibetuzumab with or without erlotinib. The objective response rate (ORR) were similar among the treatment groups regardless of c-Met expression; however, the disease control rate and PFS were higher in the combination treatment group (50% and 3.3 months, respectively) compared with the emibetuzumab monotherapy group (26% and 1.6 months, respectively).

ABT-700 (telisotuzumab) is a humanized recombinant bivalent antibody under clinical development that targets cellular c-Met and prevents dimerization induced by HGF binding.68 It was evaluated in a phase 1 study in patients with advanced solid tumors which demonstrated that 40% of patients with MET-amplified tumors experienced a partial response to treatment and the median PFS was 17.9 weeks.68,69

c-Met TKIs

Small-molecule TKIs can impede c-Met activity resulting from HGF-dependent or -independent mechanisms, a property that can provide advantages over anti-c-Met antibodies that specifically inhibit ligand-dependent receptor activity and that are unable elicit disruptive activity with c-Met-active dimers and intracellular fusion proteins.70

Capmatinib is a TKI that targets c-Met, including the variant produced by exon 14 skipping mutations.71 Capmatinib was granted accelerated approval for the treatment of metastatic NSCLC with MET exon 14 skipping mutations based on initial results from the phase 2 GEOMETRY mono-1 trial (NCT02414139) (Table 1).72 Regular approval for the same indication was granted on August 10, 2022, based on the release of long-term study data, including information on an additional 63 patients and an additional 22 months of follow-up.72

Table 1. Clinical Trials of c-Met TKIs in PatientsWith NSCLC and MET Alterations71,73-75

DCR, disease control rate; DOR, duration of response; IRC, institutional review committee; mDOR, median duration of response; mo, month(s); mOS, median overall survival; mPFS, median progression-free survival; ND, not defined; NSCLC, non–small cell lung cancer; ORR, objective response rate; OS, overall survival; TKIs, tyrosine kinase inhibitors.

Tepotinib is a competitive TKI with high selectivity for c-Met.73,76 Competitive inhibition by tepotinib prevents c-Met phosphorylation, activation, and downstream signaling. Based on results from the phase 2 VISION trial (NCT02864992), the FDA granted accelerated approval to tepotinib for the treatment of metastatic NSCLC with MET exon 14 skipping alterations.77 The results from the study are shown in Table 1.73

Savolitinib is a potent, highly selective c-Met TKI under development for the treatment of metastatic NSCLC, clear cell renal cell carcinoma, gastric cancer, and colorectal cancer.74,78 Based on results from a phase 2 study (NCT02897479), savolitinib received conditional approval in China for the treatment of NSCLC with MET exon 14 skipping alterations in patients who are intolerant to or have progressed following use of a platinum-based chemotherapy regimen (Table 1).74 SAFFRON (NCT05261399), a phase 3 trial investigating savolitinib in combination with osimertinib, is currently recruiting participants with NSCLC who have progressed on osimertinib treatment.79

Crizotinib is currently approved for patients with metastatic NSCLC identified as ALK- or ROS1-positive.80 In the PROFILE 1001 study (NCT00585195), crizotinib was associated with an ORR of 32% in patients with MET exon 14 alterations (Table 1).75 In a subgroupanalysis of patients with MET amplification, the ORR was similar at 28.9%.81

Cabozantinib acts by inhibiting a number of tyrosine kinase receptors, including c-Met, and has FDA-approved indications for the treatment of renal cell carcinoma, hepatocellular carcinoma, and metastatic differentiated thyroid cancer.82 CABinMET (NCT03911193) is an ongoing phase 2, single arm study assessing cabozantinib in patients with MET amplifications or MET exon 14 skipping mutations.83 Patients were included regardless of previous treatment with MET inhibitors. The primary end point of the trial is ORR; secondary efficacy end points are PFS, OS, and disease control rate.

Bispecific Antibodies

Amivantamab is a bispecific antibody directed towards EGFR and c-Met receptors with FDA-approved indications for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.84 Amivantamab acts by disrupting EGFR and c-Met signaling by blocking ligand binding, inducing EGFR and c-Met receptor degradation, and triggering tumor cell destruction via antibody-dependent cellular cytotoxicity (ADCC). The phase 1 CHRYSALIS trial (NCT0209776) analyzed amivantamab use in patients (N = 81) with NSCLC with EGFR mutations or MET mutations or amplifications.85 The ORR by blinded independent central review was 40%, the mPFS was 8.3 months, and the median OS was 22.8 months. Based on the results of this trial, amivantamab was granted accelerated approval for treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. 86

REGN5093 is a novel, bispecific antibody that prevents c-Met-mediated signaling by blocking HGF binding and inducing internalization and degradation of c-Met.87 REGN5093 is currently under investigation in patients with MET exon 14 mutations, MET gene amplification, and elevated c-Met expression.

MCLA-129 is an ADCC-enhanced bispecific antibody that inhibits EGFR and c-Met activation and downstream signaling and promotes tumor cell destruction via ADCC and antibody-dependent cell-mediated phagocytosis.88 MCLA-129 was developed to overcome c-Met signaling–dependent EGFR TKI–resistance mechanisms; it is currently under investigation in patients with EGFR- or MET-mutant NSCLC.88,89

c-Met-targeting ADCs

Several c-Met ADCs are currently in clinical trials including SHR-A1403, TR1801-ADC, hucMet27, and Teliso-V. SHR-A1403 consists of an anti-MET mAb HTI-1066 combined with auristatin analog SHR152852 using a non-cleavable linker.90-92 It has shown cytotoxic properties in in vitro studies and xenograft models and recently completed a phase I trial (NCT03856541) in patients with solid tumors.90-93

TR1801-ADC is a third-generation ADC consisting of the humanized anti-MET mAb hD12 conjugated to the pyrrolobenzodiazepine toxin-linker tesirine which has also shown activity in in vitro­ and xenograft models of cancer and isin a phase I clinical trial(NCT03859752) in patients with solid tumors.94,95

The humanized anti-MET mAb hucMet27 has been conjugated to both a highly potent indolinobenzodiazepine DNA-alkylating payload (hucMet27-DGN549) as well as maytansine derivative DM4 (hucMet27-DM4).96 In vivo studies have demonstrated that hucMet27-DGN549 is cytotoxic to a vast number of MET-expressing cancer cell lines; however, hucMet27-DM4 mainly shows activity in MET amplified cell lines. Both versions showed antitumor activity in MET-amplified xenograft mouse models.

Teliso-V is an ADC comprised of a c-Met-directed mAb conjugated to the potent microtubule inhibitor monomethyl auristatin E via a cleavable linker.30 The phase 2 LUMINOSITY study (NCT03539536), which included several patient cohorts with locally advanced or metastatic NSCLC and was designed to determine which patient populations would derive the most benefit from Teliso-V. 97,98 The cohorts included patients with nonsquamous NSCLC who had EGFR that was either wild-type or mutant and patients with squamous NSCLC. The nonsquamous group was further divided based on c-Met overexpression. c-Met intermediate overexpression was defined as 25% to 49% IHC 3+ staining and high overexpression was defined as at least 50% IHC 3+ staining. For the squamous cohort, overexpression was considered to be at least 75% IHC 1+ staining. The interim response rates in the nonsquamous EGFR wild-type and squamous subgroups with overexpression of c-Met are shown in Table 3.98 Additional studies of Teliso-V in NSCLC are ongoing.

Table 3. Interim Analysis of theLUMINOSITY Study of Teliso-V in Patients With Nonsquamous NSCLC and c-Met Overexpression98

NSCLC, non–small cell lung cancer; NSQ, nonsquamous; OE, overexpression;ORR, overall response rate; SQ, squamous.


Antitumor activity associated with c-Met inhibitors is often limited to oncogene addicted tumors driven by c-Met signaling resulting from MET-activated mechanisms; however, c-Met overexpression frequently occurs independent of MET mutations or gene amplification.99,100 Expression of c-Met has been shown to be correlated with tumor histology, with highest c-Met expression found among adenocarcinomas (56%). Thus, therapies designed to target c-Met overexpression have the potential to impact a broader group of patients. Aberrant c-Met signaling contributes to tumor progression, angiogenesis, tumor invasiveness, and metastatic tumor activity. As this article has discussed, c-Met overexpression can occur de novo in treatment-naïve patients as well as emerge as a secondary vulnerability after treatment with TKIs, especially EGFR TKIs;23-25 thus, therapies designed to target c-Met overexpression have the potential to impact a broad group of patients. Additionally, the correlation of c-Met overexpression, with EGFR-mutant NSCLC, poor prognosis, and with resistance to EGFR-TKI therapy highlights a potential role for c-Met biomarker testing to help guide future treatment decision-making.32,57 Further research focused on c-Met-directed therapies is needed to shed light on the future roles of these agents in the treatment landscape and of c-Met biomarker testing which may help guide treatment decision-making.


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