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Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

Journal of Thoracic Oncology, Volume 12, Issue 1, January 2017, Pages 15 - 26

Commentary by Tom Stinchcombe

Alteration in the MET tyrosine kinase (MET) is recognized as an important molecular alteration in non-small cell lung cancer (NSCLC). However, successfully targeting the MET pathway has been difficult with debate about the optimal biomarker (IHC testing, MET amplification, MET mutation), and whether the MET alteration is the primary oncogenic driver or secondary event. A number phase 3 trials of MET targeting agents (e.g. monoclonal antibodies, tyrosine kinase inhibitor) did not reveal a survival benefit.

Recently, there has been interest MET exon 14 alterations as therapeutic target. These mutations disrupt the splice sites flanking MET exon 14, and result in MET exon 14 skipping. This produces a truncated MET receptor, which lacks the binding site for degradation of the MET protein resulting in increased MET protein activity and pathway activation. Multiple molecular events can result in MET exon 14 alterations, and the primary test for detection is next-generation sequencing. MET exon 14 alterations are detected in 3-4% of lung adenocarcinoma samples, and in approximately 20-30% of pulmonary sarcomatoid carcinomas. Treatment with agents that target the MET pathway (e.g. crizotinib, capmatinib, and cabozantinib) result in durable responses. 

MET amplification is a separate category and is an oncogenic driver through increased protein expression and kinase activation. MET copy number gain can occur through polysomy (i.e. high copy number due multiple copies of chromosome 7) and amplification (focal or regional gene duplication), and amplification is the more biologically relevant event. With the use fluorescence in situ hybridization (FISH) and the ratio of MET to the centromeric portion of chromosome 7 (CEP7) can be used to distinguish polysomy from amplification (i.e. the higher ratio favors amplification). The prevalence of MET amplification is estimated to be 1-5% in NSCLC. MET amplification is detected in 20% of case with MET exon 14 alterations. Patients with intermediate and high MET/CEP7 ratio have responded to crizotinib. MET copy number gain includes the number of copies of MET per cell (which includes cases of polysomy) or the MET/CEP7 ratio. The optimal cut-points for the ratio have not been determined, but the MET/CEP7 ratio is thought to be the best method of identifying cases where MET activation is the primary oncogenic driver.

MET amplification is a mechanism of acquired resistance to EGFR TKI’s, including third-generation EGFR TKI’s, and should be considered in this clinical setting. The reported prevalence is 5-20%. Clinical trials of EGFR and MET targeting agents are ongoing for this patient population.


The hepatocyte growth factor receptor (MET) is a potential therapeutic target in a number of cancers, including NSCLC. In NSCLC, MET pathway activation is thought to occur through a diverse set of mechanisms that influence properties affecting cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggests a role for MET activation as both a primary oncogenic driver in subsets of lung cancer and as a secondary driver of acquired resistance to targeted therapy in other genomic subsets. In this review, we explore the biology and clinical significance behind MET proto-oncogene receptor tyrosine kinase (MET) exon 14 alterations and MET amplification in NSCLC, the role of MET amplification in the setting of acquired resistance to EGFR tyrosine kinase inhibitor therapy in EGFR-mutant NSCLC, and the history of MET pathway inhibitor drug development in NSCLC, highlighting current strategies that enrich for biomarkers likely to be predictive of response. Whereas previous trials that focused on MET pathway–directed targeted therapy in unselected or MET-overexpressing NSCLC yielded largely negative results, more recent investigations focusing on MET exon 14 alterations and MET amplification have been notable for meaningful clinical responses to MET inhibitor therapy in a substantial proportion of patients.

Keywords: MET exon 14 skipping alterations, MET amplification, non-small cell lung cancer, crizotinib, MET inhibitor, MET overexpression.


Phase III randomized trials of tyrosine kinase inhibitor (TKI) therapy for EGFR-mutant and anaplastic lymphoma receptor tyrosine kinase (ALK)-rearranged lung cancers have documented improvements in response and progression-free survival (PFS),1 and 2 and seven TKIs have gained regulatory approval for the treatment of patients with these tumors. The treatment landscape continues to evolve as durable responses to targeted therapy have been reported in a growing number of other genomic subsets.3 and 4

The path to approval of targeted therapy for lung cancers with alterations of the MET proto-oncogene receptor tyrosine kinase (MET), however, has not been straightforward. First discovered in the mid-1980s, the hepatocyte growth factor receptor (MET) pathway was found in the 1990s to be dysregulated in lung cancer (Fig. 1A).5 and 6 More than 20 agents targeting MET or its ligand, hepatocyte growth factor (HGF), have undergone preclinical and clinical study, but findings have ranged from relatively high response rates in molecularly preselected subtypes of NSCLC in single-arm trials to the prominent failure of large phase III studies in different trial populations.


Figure 1

(A) Time line of discovery in lung cancers harboring alterations of the hepatocyte growth factor receptor (MET) pathway. (B) The MET receptor and selected MET pathway–directed targeted therapies. MET, MET proto-oncogene receptor tyrosine kinase; HGF, hepatocyte growth factor; mAb, monoclonal antibody; PSI, plexin-semaphorin-integrin; IPT, immunoglobulin-plexin transcription; TKI, tyrosine kinase inhibitor.


This review summarizes MET pathway dysregulation in lung cancers and critiques different scientific methods and clinical trial approaches taken for translating these into predictive biomarkers of benefit from MET inhibition.

The MET Pathway and Targeted Therapy

The MET gene, located on chromosome 7q21–q31, is approximately 125 kilobases long, with 21 exons.7 and 8 The 150-kDa MET polypeptide undergoes glycosylation to a 190-kDa glycoprotein that functions as a transmembrane receptor tyrosine kinase.8 The extracellular region of MET contains semaphorin, cysteine-rich, and immunoglobulin domains; the intracellular region consists of a juxtamembrane domain, a tyrosine kinase catalytic domain, and a carboxy terminal docking site (Fig. 1B).9 and 10

MET is activated when the HGF ligand binds to the MET receptor, inducing homodimerization and phosphorylation of intracellular tyrosine residues.8 This activates the downstream RAS/ERK/MAPK, PI3K/AKT, Wnt/β-catenin, and STAT signaling pathways. Depending on the cellular context, these pathways can drive cell proliferation, survival, migration, motility, invasion, angiogenesis, and the epithelial-to-mesenchymal transition.9 and 11 In embryonic development, MET and HGF are important in placental trophoblast and hepatocyte formation.12 In adults, both are broadly expressed in a variety of tissues and can be up-regulated in response to tissue injury.8

Dysregulation of the MET pathway in lung cancer occurs through a variety of mechanisms, including gene mutation, amplification, rearrangement, and protein overexpression. MET was first discovered as an oncogene with the identification of a translocated promoter region, nuclear basket protein gene (TPR)-MET fusion in a mutagenized osteosarcoma cell line. The fusion oncoprotein lacked the juxtamembrane Y1003 and was unaffected by c-Cbl recruitment and ubiquitination.13 A kinesin family member 5B gene (KIF5B)-MET fusion has since been detected by The Cancer Genome Atlas by RNA sequencing in a sample from a patient with lung adenocarcinoma14; however, MET rearrangements are likely rare events in lung cancers.

Several agents have been developed to target MET or HGF (see Fig. 1B). These are divided into small molecule inhibitors and monoclonal antibodies. The small molecule TKIs are further subdivided into multikinase and selective MET inhibitors. Examples of multikinase MET inhibitors include crizotinib, cabozantinib, MGCD265, AMG208, altiratinib, and golvatinib. Selective MET inhibitors include the adenosine triphosphate–competitive agents capmatinib and tepotinib (MSC2156119J)15 and 16 and the adenosine triphosphate–noncompetitive agent tivantinib.17 Monoclonal antibody therapy is divided into anti-MET antibodies (e.g., onartuzumab and emibetuzumab [LY2875358])18, 19, and 20 and anti-HGF antibodies (e.g., ficlatuzumab [AV-299] and rilotumumab [AMG 102]).10 and 21

In recognition of the diversity of putative alterations resulting in MET pathway activation in NSCLC, the challenge has been to determine the best way to distinguish a true sensitizing MET signature, either as a primary driver state or as a codriver state in the setting of acquired resistance to EGFR-directed therapy. For diagnostic purposes, this would involve selection from a combination of continuous and potentially overlapping MET-related biomarkers.

MET as a Primary Driver in NSCLC

By analogy with ALK rearrangements and EGFR mutations, it is conceivable that some NSCLCs may be primarily driven by, and therefore addicted to, the MET pathway alone. In the presence of an active MET inhibitor, precedent from other driver states suggests that monotherapy against MET should display clear evidence of anticancer activity. To date, two partially overlapping MET-related states in NSCLC have shown promise: MET exon 14 (METex14) alterations and MET gene amplification.

METex14-Altered Lung Cancers

Whereas tumors such as sporadic and hereditary renal cell carcinomas harbor activating mutations of the MET kinase domain,22 lung cancers frequently harbor mutations in the extracellular/juxtamembrane domains.23 The extracellular semaphorin domain is thought to be required for receptor activation and dimerization24; however, the relevance of mutations in this domain remains unclear. In contrast, juxtamembrane domain mutations often result in METex14 alterations.

Cancers with METex14 alterations, a prime example of the association between aberrant splicing and oncogenesis, were initially reported in SCLC and NSCLC in 2003 and 2005, respectively.25 and 26 Normally, introns flanking METex14 in pre-mRNA are spliced out, resulting in mRNA containing METex14 that is translated into a functional MET receptor (Fig. 2A). METex14 encodes part of the juxtamembrane domain containing Y1003, the c-Cbl E3 ubiquitin ligase binding site.27 Ubiquitination tags the MET receptor for degradation. Juxtamembrane domain mutations that disrupt splice sites flanking METex14 result in aberrant splicing (Fig. 2B). These mutations result in METex14 skipping, producing a truncated MET receptor lacking the Y1003 c-Cbl binding site. Losing this binding site results in decreased ubiquitination and degradation of the MET protein, sustained MET activation, and oncogenesis.28 Decreased degradation of the MET receptor is thought to potentially cause MET overexpression on some tumors that is detectable by methods such as immunohistochemistry (IHC).


Figure 2

The pathobiology of MET proto-oncogene receptor tyrosine kinase (MET) exon 14 alterations and MET amplification. MET, hepatocyte growth factor receptor; CEP7, centromeric portion of chromosome 7.


METex14 alterations are extremely diverse. Base substitutions or indels disrupt several gene positions important for splicing out introns flanking METex14,29 including the branch point, the polypyrimidine tract, the 3′ splice site of intron 13, and the 5′ splice site of intron 14.27, 28, and 30 The Cancer Genome Atlas project identified METex14 alterations resulting in incomplete splicing from the mature mRNA, leaving low-level expression of untruncated MET.31 Notably, point mutations or deletions within METex14 can affect the Y1003 residue, resulting in c-Cbl binding site loss of function without necessarily causing METex14 skipping.29, 30, and 31

The diversity of METex14 alterations presents challenges for diagnostic testing.12 and 29 Algorithms for molecular profiling will need to rapidly move toward comprehensive clinical sequencing platforms permitting routine detection of these mutations.32 Currently, DNA-based broad, hybrid capture next-generation sequencing (NGS) represents the most frequently used tool. RNA-based sequencing using anchored multiplex polymerase chain reaction33 or NanoString technology (NanoString Technologies, Inc., Seattle, WA) provide complementary tools.32 It should be noted that NGS is a platform, not a standardized test, and detection of specific genomic alterations crucially depends on the primers within the NGS panel. It cannot be assumed that the wide array of METex14 variants will be equally detected (or detected at all) by every NGS panel used in clinical practice. Similarly, RNA-based testing, although a means of getting around the underlying variety of DNA-based changes by focusing on the more uniform resultant RNA-related splice-altered message, is not routinely performed in the clinic. Furthermore, the amount of tissue available after DNA-based NGS can be scant and inadequate for further RNA-based testing. Future diagnostic investigation must explore tests that will detect these changes in a manner suitable for widespread clinical use.

Lung cancers harboring METex14 alterations have been found to overexpress MET by means of IHC (3+ in 100% of cells in select cases).32 MET overexpression is not found in all cases documented in the literature. In one series, stage IV METex14-altered lung cancers were more likely to display strong MET IHC expression compared with stage IA–IIIB METex14-altered lung cancers.30 Rapid initial IHC screening has been proposed to narrow the population to undergo more comprehensive molecular profiling. To estimate the validity of this approach, better data on the prevalence of MET IHC 3+ cases that contain METex14 variants are required.34

METex14 alterations are detected in 3% to 4% of lung adenocarcinoma samples (Table 1),27, 29, 31, 34, 35, and 36 a prevalence comparable to that in ALK-rearranged lung cancers.37 These mutations occur in tumors from older patients, with a lower percentage of never-smokers than in the case of patients with tumors harboring other oncogenes.30 In a series of 687 Asian patients with resected NSCLC, METex14 alterations were poor prognostic factors for overall survival (OS).34

Table 1

Prevalence of MET Exon 14 Alterations and MET Amplification in NSCLC Using Different Testing Methods


Study Genomic Alteration Diagnostic Method Prevalence
METex14 alterations
 The Cancer Genome Atlas. 201431 Exon 14 alterations WES 4.3% (10 of 230)
 Frampton et al. 201529 Exon 14 alterations Parallel DNA sequencing 3% (131 of 4402)
 Okuda et al. 200835 Exon 14 alterations Direct sequencing 1.7% (3 of 178)
 Onozato et al. 200927 Exon 14 alterations Direct sequencing 3.3% (7 of 211)
 Tong et al. 201634 Exon 14 alterations Direct sequencing 2.6% (10 of 392)
MET amplification
 Cancer Genome Atlas. 201431 Somatic copy number WES 5.2% (12 of 230)
 Capuzzo et al. 200936 MET copy number ≥5 (polysomy + gene amplification) FISH 11.1% (48 of 435)
MET copy number ≥5 (gene amplification only) 4.1% (18 of 435)
 Okuda et al. 200835 MET copy-number >3 qRT-PCR 5.6% (12 of 213)
 Tong et al. 201634 MET/CEP7 ratio ≥5 FISH 1.0% (4 of 392)
 Onozato et al. 200927 MET amplification
MET splice mutations
Direct sequencing
1.4% (2 of 148)
3.3% (7 of 211)

MET, MET proto-oncogene receptor tyrosine kinase; METex14, MET exon 14; WES, whole-exome sequencing; FISH, fluorescence in situ hybridization; qRT-PCR, quantitative real-time polymerase chain reaction.

METex14 alterations are mutually exclusive with other lung cancer drivers, suggesting they represent a true oncogenic driver state.29 In a study of 933 patients with nonsquamous NSCLC,30 no patients with METex14 alterations had activating mutations in KRAS, EGFR, or erb-b2 receptor tyrosine kinase 2 gene (ERBB2), or rearrangements involving ALK, ROS1, or ret proto-oncogene (RET).30 In contrast, METex14 alterations can overlap with other alterations such as MET and MDM2 proto-oncogene (MDM2) amplification. METex14 alterations can co-occur with MET copy number gain/amplification, with the frequency of overlap being heavily influenced by the definition of amplification used.34

Although many cases of METex14 alterations are found in lung adenocarcinomas, these events have a much higher incidence in pulmonary sarcomatoid carcinomas. Approximately 20% to 30% of sarcomatoid carcinomas harbor METex14 alterations.34 and 38 In one series, these were more likely to be associated with sarcomatoid carcinomas with an adenocarcinoma component,38 suggesting the possibility of a shared tumor origin. The therapeutic implications of METex14 alterations in sarcomatoid carcinomas are discussed later.

METex14 alterations are likely to be highly predictive of response to MET inhibition (Table 2).29, 30, 32, 38, 39, 40, 41, 42, 43, and 44 Dramatic and durable partial responses (PRs) to crizotinib were first reported in mid-2015 in patients with advanced lung cancers with METex14 alterations.32 The same authors reported a complete metabolic response (according to the Positron Emission Tomography Response Criteria in Solid Tumors) to cabozantinib therapy (stable disease by the Response Evaluation Criteria in Solid Tumors). Durable PRs to capmatinib or crizotinib have been reported in patients with advanced METex14-altered lung cancers.29 Subsequent case reports have confirmed these observations with use of different MET TKIs and in all NSCLC histologic types.30, 39, 40, 41, and 42

Table 2

Case Reports of NSCLCs with MET Exon 14 Alterations Responding to MET Inhibitors


Reference Age/Sex Smoking History METex14 Alteration MET IHC MET Amplification Agent Best Response
Awad et al. 201630 64 F Never Splice donor mutation NA Yes Crizotinib PR
Frampton et al. 201529 82 F Former Splice donor mutation 3+ Yes Capmatinib PR
Frampton et al. 201529 66 F Former Splice donor mutation 3+ Not tested Capmatinib PR
Jenkins et al. 201539 86 M Never Splice acceptor deletion 2+ NA Crizotinib PR
Jorge et al. 201540 68 F Former Splice donor mutation NA NA Crizotinib PR
Lee et al. 201541 61 M Never Splice donor deletion NA NA Crizotinib PR
Liu et al. 201538 74 F Former Splice site mutation NA NA Crizotinib PR
Mahjoubi et al. 201642 67 F Never Splice donor mutation NA NA Crizotinib PR
Mendenhall et al. 201543 76 F Former Splice donor mutation NA NA Crizotinib PR
Paik et al. 201532 65 M Former Splice donor mutation NA NA Crizotinib PR
Paik et al. 201532 78 M Former Splice donor deletion 3+ NA Crizotinib PR (lung)
PD (liver)
Paik et al. 201532 80 F Never Splice donor mutation 3+ Yes Cabozantinib CR (PERCIST)
Paik et al. 201532 90 F Never Splice donor mutation NA NA Crizotinib PR
Waqar et al. 201544 71 M Former Splice donor mutation NA No Crizotinib PR

MET, MET proto-oncogene receptor tyrosine kinase; METex14, MET exon 14; MET, mesenchymal epithelial transition receptor; IHC, immunohistochemistry; F, female; NA, not applicable/available; PR, partial response; M, male; PD, progressive disease; CR, complete response; PERCIST, Positron Emission Tomography Response Criteria in Solid Tumors.

Pulmonary sarcomatoid carcinomas were thought to be relatively refractory to cytotoxic chemotherapies; however, a dramatic PR was reported in a patient with advanced pulmonary sarcomatoid carcinoma harboring both a METex14 alteration and MET amplification. No responses to an anti-MET or anti-HGF monoclonal antibody in a patient with lung cancer with a METex14 alteration have been reported, although such a response is not unlikely given our knowledge of these tumors’ biology, coupled with preclinical data supporting the use of these agents.28

Reports of response to MET inhibitors have prompted drug development plans focused on molecular enrichment for METex14 alterations. The phase I trial that resulted in approval of crizotinib for ALK- and ROS1-rearranged lung cancers (NCT00585195) is currently treating patients with advanced lung cancer with METex14 alterations in an enriched cohort.41 Of the 18 response-evaluable patients at the latest available data cutoff, eight experienced a confirmed PR (overall response rate 44% [95% confidence interval: 22–69]) with tumor shrinkage in 14 of 18 patients.45 We look forward to studies of potential mechanisms of acquired resistance to MET TKIs, but already MET D1228N has been reported as a putative mechanism.46

MET-Amplified Lung Cancers

MET amplification is thought to dysregulate MET pathway signaling through protein overexpression and constitutive kinase activation. Identification of MET copy number gains in the setting of acquired resistance to EGFR TKI therapy in lung cancer stimulated interest in these alterations.

MET copy number gains arise from two distinct processes: polysomy and amplification.47 High polysomy occurs when there are multiple copies of chromosome 7 in tumor cells secondary to factors such as chromosomal duplication.48 True amplification occurs in the setting of focal or regional gene duplication through processes such as breakage-fusion-bridge mechanisms.49 As opposed to polysomy, amplification is thought to represent a state of true biologic selection for MET activation as an oncogenic driver. Additionally, each type of MET gene copy number change represents a continuous variable. Placing a cutpoint to define positivity may dramatically alter the reported frequency, overlap with other NSCLC subtypes, and ultimately affect its potential to act as a predictive biomarker for benefit from MET inhibition.

With the use of fluorescence in situ hybridization (FISH), the ratio of MET to the centromeric portion of chromosome 7 (CEP7) can be used to distinguish between polysomy and true amplification. In polysomy, each copy of MET is associated with a corresponding centromere, preserving the MET/CEP7 ratio as copy number increases.47 In true MET amplification, copy number increases without an increase in CEP7 and the MET/CEP7 ratio increases.47 Broad, hybrid capture NGS assays are able to detect amplification events. Copy number changes can be identified by comparing sequence coverage of targeted regions in tumors relative to a diploid normal sample, and select platforms have been validated against tumor samples that previously tested positive for amplification of other genes such as ERBB2 by FISH.50 and 51 As with FISH, copy number gains detected by NGS are reported as continuous variables, and cutoffs can vary significantly between assays. In contrast to FISH, NGS and anchored multiplex polymerase chain reaction may provide additional information on other potentially clinically relevant, concurrent genomic alterations.33

No consensus on the definition of MET positivity based on gene copy number has yet been reached. Examples of a positive MET FISH result include five or more MET signals per cell (Cappuzzo scoring system),36 and a MET/CEP7 ratio of 2 or higher (PathVysion kit [Abbott Molecular, Des Plaines, IL]).34 and 52MET amplification has also been classified by using the MET/CEP7 ratio as low (≥1.8 to ≤2.2), intermediate (>2.2 to <5), and high (≥5), as summarized in Table 3. Variation of classification thresholds between studies complicates comparisons of reported MET amplification/copy number gain relative to the underlying frequency, associated factors, and outcomes from therapy, although more rigorous data are now emerging.11

Table 3

MET/CEP7 Ratio and Classification of MET Amplification


MET/CEP7 Ratio MET Amplification Classification Percentage of Total
<1.8 Negative 92.6
≥1.8 to ≤2.2 Low 3.6
>2.2 to <5.0 Intermediate 3.0
≥5.0 High 0.8
Total 100.0

Note: Data from a personal communication from L. Garcia (University of Colorado).

MET, MET proto-oncogene receptor tyrosine kinase; CEP7, centromeric portion of chromosome 7.

The reported prevalence of de novo MET amplification in NSCLC ranges from 1% to 5%, depending on the level of preselection, the assay, and the positivity cutpoint used (see Table 1).27, 29, 35, 36, and 53 In adenocarcinoma, because most true oncogenic drivers are mutually exclusive, so-called oncogene overlap analysis was used in 1164 cases to see whether there was a level of MET copy number gain by using either the mean number of copies of MET per cell (which would include high-polysomy cases) or the MET/CEP7 ratio, which could define a group in which the degree of overlap with other known oncogenic drivers (EGFR, KRAS, ALK, ERBB2, BRAF, NRAS, ROS1, or RET) disappeared.54 Across all levels of mean increase in MET per cell (low, ≥5 to <6; intermediate, ≥6 to <7; and high, ≥7) oncogene overlap occurred in 41% to 63% of cases. Similarly, when the MET/CEP7 ratio was used, at low (≥1.8 to ≤2.2) and intermediate (>2.2 to <5) levels of MET amplification, oncogene overlap occurred in 52% and 50% of cases, respectively. However, zero oncogene overlap was seen in the high-MET amplification category (MET/CEP7 ratio ≥5). Only this high-level amplification category was associated with a dramatic rate of response to crizotinib. These data suggest that high MET copy number (MET/CEP7 ratio ≥5) represents the best case for a true MET copy number gain–dependent MET-driven state, whereas lower or different MET copy number definitions of positivity may more likely represent MET as a coincident event.54

There are two important issues related to exploring MET amplification as a predictive biomarker for benefit from MET inhibition. The first is that a MET/CEP7 ratio of 5 or higher represented only 0.34% of adenocarcinomas in a large series,54 which is approximately 10% of the frequency of METex14 variants in the same population. The second is that the degree of benefit in this population independent of METex14 mutations remains under investigation. METex14 alterations harbor concurrent high-level MET copy number gain in approximately 20% of cases, with the degree of overlap increasing (just as with other known oncogenes) as less stringent definitions of MET amplification are used.30, 32, and 34 The case for METex14 variants to act as predictive biomarkers in the absence of MET amplification seems to have been made, as responses in this setting have been documented. Whether MET amplification is only a surrogate for some cases of METex14 (in which case testing should focus exclusively on the METex14 approach) or can truly function as an independent MET-addicted state capable of driving clinical responses without METex14 changes (requiring an all-inclusive testing approach for actionable abnormalities in lung cancer in addition to METex14 testing) is undetermined. Therefore, testing for both MET amplification and METex14 changes should be conducted in all MET TKI trials and then used to retrospectively investigate differential responses based on MET amplification status. As both MDM2 and cyclin-dependent kinase 4 gene (CDK4) amplification are strongly coincident with METex14 alterations,29 a similar approach could be taken to investigate MET TKI response with concurrent MDM2 and CDK4 amplification.

The first report of a response to MET inhibition in a patient with a de novo MET-amplified lung cancer was published in 2011. The patient was a 77-year-old woman with a 45 pack-year history of smoking and advanced lung adenocarcinoma. Her cancer had high-level MET amplification according to FISH (MET/CEP7 ratio >5). She was treated on the phase I trial of crizotinib (NCT00585195) and achieved a dramatic and durable PR.55 Preliminary results were presented in 2014 and showed PRs in one of six patients (16.7%) with intermediate-level MET amplification (MET/CEP7 ratio >2.2 to <5) and in three of six patients (50%) with high-level MET amplification (MET/CEP7 ratio ≥5).56 Responses were not seen in patients with low-level MET amplification (MET/CEP7 ratio ≥1.8 to ≤2.2).

MET as a Codriver in NSCLC

There is significant cross-talk between the MET pathway and other signaling pathways. Historically, many investigators have chosen to explore combination MET inhibitor and EGFR inhibitor therapy in clinical trials on patients with NSCLCs (Table 4). This strategy was partially based on the synergy of MET and EGFR in driving oncogenesis in both EGFR wild-type lung and mutant lung cancer models in the setting of acquired resistance to EGFR TKIs.59 and 60 In 2007, MET amplification was found to be associated with acquired resistance to first-generation EGFR TKIs.61 Although most EGFR-mutant lung cancers develop resistance to EGFR TKI therapy through acquired T790M mutation, activation of the MET pathway as a bypass tract represents a distinct acquired resistance mechanism driven by ERBB3-dependent phosphoinositide-3 kinase pathway activation. MET exon 14 alterations are generally thought to be mutually exclusive with other major lung cancer drivers and have not been associated with acquired resistance to EGFR TKI therapy in EGFR-mutant lung cancers.27

Table 4

Clinical Experience with Select MET- and HGF-Directed Targeted Therapies


Agent Target(s) Patients Phase Results
Multikinase MET TKIs
Crizotinib MET, ALK, ROS1 Crizotinib monotherapy
Patients with MET exon 14-altered and MET-amplified NSCLC
I/II MET exon 14–altered NSCLC: responses observed in 8 of 18 patients (44%); MET-amplified NSCLC: at data cutoff, partial responses were observed in 1 of 6 patients (16.7%) with a MET/CEP7 ratio of >2.2 to <5 and in 3 of 6 patients (50%) with a MET/CEP7 ratio of ≥556
Cabozantinib MET, RET, ROS1, VEGFR2 Erlotinib ± cabozantinib
Patients with nonsquamous NSCLC and no EGFR mutation. MET expression assessed by IHC
II Overall improvement in PFS with cabozantinib but MET IHC score was not predictive57
MET-selective TKIs
Tivantinib MET Erlotinib ± tivantinib
MARQUEE: Western cohort of patients with nonsquamous NSCLC. Not selected on the basis of MET analysis
III Tivantinib was not associated with any improvement in OS, although PFS was increased in the tivantinib group compared with the group receiving erlotinib alone58
Erlotinib ± tivantinib
ATTENTION: East Asian cohort of patients with nonsquamous NSCLC. Not selected on the basis of MET analysis
III Tivantinib was not associated with any improvement in OS, although PFS was increased in the tivantinib group compared with in the group receiving erlotinib alone. Trial terminated early because of an increase of interstitial lung disease in the tivantinib group17
Capmatinib MET Gefitinib + capmatinib
Patients with EGFR-mutated NSCLC, refractory to EGFR TKIs, and MET amplification or MET overexpression
Ib/II Partial responses in 6 of 41 patients (15%), all with either high MET amplification or MET overexpression15
Anti-MET monoclonal antibody
Onartuzumab MET Erlotinib ± onartuzumab
Patients with stage IIIB or IV NSCLC. MET expression evaluated at baseline
II Onartuzumab plus erlotinib did not show an OS advantage, although an OS advantage was evident in the MET-positive subgroup20
Erlotinib ± onartuzumab
Patients with previously treated MET-positive stage IIIB or IV NSCLC
III Stopped for futility as there was no improvement in OS, PFS, or ORR19
Emibetuzumab (LY2875358) MET Emibetuzumab monotherapy
Patients with locally advanced or metastatic CRPC with bone metastasis, RCC, NSCLC, and HCC. Patients with RCC, NSCLC, and HCC were required to have ≥50% of tumor cells to be ≥2+ for MET expression by IHC
I In patients with NSCLC, the disease control rate (PR + stable disease) was 26% (5 of 19), and the median duration of disease stabilization was 3.9 months (range 2.5–6.4) in NSCLC18
Anti-HGF monoclonal antibody
Ficlatuzumab HGF Gefitinib ± ficlatuzumab
Asian patients with stage IIIB or IV pulmonary adenocarcinoma. Patients were not selected on the basis of MET analysis
II Failed to demonstrate significant improvement in PFS and overall response21
Rilotumumab HGF Erlotinib + rilotumumab
Patients with recurrent or progressive NSCLC. Not selected on the basis of MET analysis
II Ongoing (NCT01233687)

MET, hepatocyte growth factor receptor; HGF, hepatocyte growth factor; TKI, tyrosine kinase inhibitor; ALK, anaplastic lymphoma kinase; MET, MET proto-oncogene receptor tyrosine kinase; CEP7, centromeric portion of chromosome 7; RET, ret proto-oncogene; VEGFR, vascular endothelial growth factor receptor; PFS, progression-free survival; IHC, immunohistochemistry; OS, overall survival; ORR, overall response rate; CRPC, castration-resistant prostate cancer; RCC, renal cell carcinoma; HCC, hepatocellular carcinoma; PR, partial response.

Unfortunately, significant variation in preselection criteria for identifying those patients who are potentially sensitive to EGFR and MET inhibition has contributed to some confusion over the results of trials combining EGFR and MET inhibition in NSCLC.

Combination Trials Not Focused on EGFR-Mutant Lung Cancers

Increased expression of MET alone is sufficient to induce oncogenic transformation in vitro and in vivo.62 and 63 Although overexpression of both MET and HGF have been identified in unselected NSCLC specimens, the role of increased expression alone as a clinically relevant oncogenic driver has come into question.5 and 6 The prevalence of MET overexpression in unselected NSCLCs ranges from 15% to 70%.64, 65, 66, and 67 This frequency depends on the antibody, the assay, and the positivity cutpoint. Although MET protein expression has been associated with poor prognostic outcomes in lung cancer,64 and 68 it has thus far served as a poor predictive biomarker of response to targeted therapy.

Interest in the treatment of patients with MET-overexpressing lung cancers was initially piqued by a subset analysis of a phase II combination trial of erlotinib and onartuzumab.20 In this study, unselected second-line patients with advanced NSCLC were randomized to receive erlotinib with or without onartuzumab. Although the coprimary end points of OS (hazard ratio [HR] = 0.80, p = 0.34) and PFS (HR = 1.09, p = 0.69) were not met in the overall population, patients whose tumors expressed higher levels of MET (IHC result 2 to 3+) showed an improvement in both PFS (HR = 0.53, p = 0.04) and OS (HR = 0.37, p < 0.05).20

Disappointingly, a subsequent phase III trial randomizing 499 patients with advanced NSCLC with MET-overexpressing tumors (IHC result 2 to 3+) to erlotinib with or without onartuzumab was terminated early owing to futility.19 The primary end point of OS was not different between groups (HR = 1.27, p = 0.07).19 Median OS was numerically decreased in patients who received combination therapy, suggesting the possibility of harm.19

Two phase III combination studies of tivantinib that had reported anti-MET activity and treated largely unselected patients with NSCLC did not meet their primary end point. The ATTENTION trial randomized 307 patients with advanced, EGFR wild-type, nonsquamous NSCLC to receive erlotinib with or without tivantinib. Although the study was terminated early secondary to an increased incidence of interstitial lung disease in the tivantinib arm, the primary end point of OS was not significantly different between groups (HR = 0.89, p = 0.43).17 The MARQUEE trial randomized 1048 patients with advanced, nonsquamous NSCLC to receive erlotinib with or without tivantinib. This trial was terminated early owing to an interim analysis revealing futility, and the primary end point of OS did not differ between groups (HR = 0.98, p = 0.81).58 Although the secondary end point of PFS was improved by the combination in both trials, the absolute difference compared with single-agent erlotinib was small.58 Of note, tivantinib is thought to potentially function as a mitotic spindle poison.69

Recently, a phase II study randomizing 118 patients with advanced, EGFR wild-type NSCLC to receive erlotinib, cabozantinib, or both in combination reached its primary end point of PFS (HR = 0.38, p < 0.05 for cabozantinib versus erlotinib; HR = 0.35, p < 0.05 for combination versus erlotinib). Unlike the MET-selective inhibitor tivantinib that was tested in the ATTENTION and MARQUEE studies, cabozantinib is a multikinase inhibitor with activity against several other potentially sensitive subgroups that may have been contained within this trial population, including both ROS1-rearranged and RET-rearranged lung cancers. This cohort of patients did not undergo comprehensive molecular profiling to rule out the presence of these alterations or other events, such as METex14 alterations. The contribution of these potentially undetected cases to these results remains unclear.

MET Inhibition in EGFR-Mutant Lung Cancers

The prevalence of MET amplification in EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy was initially reported at 15% to 20%.61 and 70 A subsequent series noted a lower prevalence at 5% and found that MET amplification overlapped with other resistance mechanisms such as EGFR T790M acquisition or small cell transformation.71 Unsurprisingly, the acquisition of MET amplification has also been reported as a mechanism of resistance to third-generation EGFR TKI therapy in patients with EGFR T790M–positive lung cancer.72

Clinical trials preselected or enriched for EGFR-mutant NSCLC exploring combined MET and EGFR inhibition have focused on either the EGFR TKI–naive setting as a means of preventing MET-driven resistance or the acquired resistance setting, with varying degrees of preselection to identify a MET-codriven state at the time of its emergence. The former approach does not depend on having specific biomarkers of MET activation. As an EGFR TKI is associated with significant benefit in an EGFR-mutant TKI-naive population, clinical investigations must rely on randomized data to make the case for combination therapy being superior to monotherapy with an EGFR TKI. In addition, this approach, with PFS as the primary end point, is inherently dependent on the expected underlying frequency of MET activation that would otherwise emerge to size the study to detect a change compared with the benefit from an EGFR TKI alone. The lower the frequency of MET as a predicted mechanism of acquired resistance, the larger the study must be to prove the combination adds unequivocal benefit. In a phase II trial comparing emibetuzumab with or without erlotinib, in patients whose tumors developed acquired resistance to erlotinib and harbored MET overexpression, the overall response rate (ORR) was higher in both the combination and monotherapy arms (3.8% and 4.8%, respectively) for patients with at least 60% of cells determined to be MET positive by IHC (n = 74) than for patients with at least 10% of cells determined to be positive (n = 89), in which case the ORR was 3.0% in the combination arm and 4.3% in the monotherapy arm.73 In the acquired resistance setting, the same challenges associated with defining the appropriate method and positivity cutpoint for identifying MET gene copy number gain as a primary driver apply to defining MET positivity as a codriver state. Data converging with the literature on primary drivers recently emerged from a small phase II study in EGFR-mutant patients with acquired resistance to an EGFR TKI who were then treated with the combination of gefitinib and capmatinib. When new biopsy specimens obtained at the time of acquired resistance were analyzed, the rate of response to the combination was 40% among those with a MET copy number of 5 or higher (the ratio was not reported), but zero among those with a copy number less than 5.15 Clinical trials focusing on combination MET and EGFR inhibitor therapy for patients with acquired resistance to EGFR TKIs and using differing degrees of MET preselection are ongoing.74


Although research into the MET pathway as a driver of oncogenesis has stretched well over three decades, advances in technology and appropriate patient selection have reinvigorated the search for an effective targeted therapeutic for lung cancers harboring METex14 alterations and/or MET amplification as their primary oncogenic driver. Attempts to define the criteria for optimal use of a combination of MET and EGFR inhibitors in which MET acts as a targetable codriver, particularly in EGFR-mutant patients, continue. Ongoing and future drug development plans with a strong focus on molecular enrichment are likely to succeed in this arena. Both patients and providers look forward to eventual regulatory approval.


Medical writing support was provided by Ash Dunne at inScience Communications (Chester, United Kingdom) and Wendy Sacks and Thierry Deltheil at ACUMED (New York, NY, and Tytherington, United Kingdom) and funded by Pfizer Inc.


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a Memorial Sloan Kettering Cancer Center, New York, New York

b Azienda Unità Sanitaria Locale della Romagna, Ravenna, Italy

c Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California

d University of Colorado Cancer Center, Aurora, Colorado

Corresponding author. Address for correspondence: Alexander Drilon, MD, Thoracic Oncology Service and Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., New York, NY, 10065.

Disclosure: Dr. Ou is a consultant for Pfizer, Roche/Genentech/Chugai, AstraZeneca, and Boehringer Ingelheim and has received speaker honoraria from Roche/Genentech, AstraZeneca, and Boehringer Ingelheim. Dr. Camidge has received honoraria from Pfizer and Eli Lilly. The remaining authors declare no conflict of interest.