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The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping

Open AccessPublished:April 09, 2020DOI:https://doi.org/10.1016/j.ctrv.2020.102022

      Highlights

      • MET exon 14 skipping is a primary oncogenic driver sensitive to MET inhibition.
      • Selective MET inhibitors have potential for improved efficacy in selected patients.
      • Selective agents may have favorable tolerability compared with non-selective agents.
      • The sensitivity of MET exon 14 skipping tumors to these drugs is being established.

      Abstract

      Dysregulated activation of the MET tyrosine kinase receptor is implicated in the development of solid tumors and can arise through several mechanisms, including gene amplification, overexpression of the receptor and/or its ligand hepatocyte growth factor (HGF), and the acquisition of activating mutations. The most common activating mutations cause exon 14 to be skipped during MET mRNA splicing. This in-frame deletion, known as MET exon 14, results in production of a shortened receptor that lacks a juxtamembrane domain but retains affinity for HGF. However, the negative regulatory function located within this protein sequence is lost, leading to receptor accumulation on the cell surface and prolonged activation by HGF. MET mutations causing exon 14 skipping appear to be true oncogenic drivers and occur in patients and tumors with distinct characteristics.
      Increasing evidence suggests that tumors carrying such mutations are sensitive to MET inhibition, raising the hope that selective MET inhibitors will provide patients with optimal anticancer activity with minimal toxicity.
      We discuss the prospects for selective MET inhibitors in the treatment of non-small cell lung cancer harboring MET exon 14 skipping.

      Keywords

      Introduction

      Molecules that inhibit receptor tyrosine kinases (RTKs) have shown promise as therapies in a range of tumor types. This is because activated RTKs are able to act as primary driver oncogenes: through acquired mutations, they can initiate carcinogenesis and play a key role in tumor development. For example, oncogenic activation of the epidermal growth factor receptor (EGFR) through EGFR mutation is observed in non-small cell lung cancer (NSCLC), and such tumors are sensitive to EGFR-targeted tyrosine kinase inhibitors (TKIs). Although the MET RTK is also often aberrantly active in NSCLC, its clinical significance in NSCLC was primarily thought to be in conferring resistance to certain therapies, including EGFR TKIs. However, interest in MET as a therapeutic target, particularly in NSCLC, has increased with the realization that it may act as a bona fide primary oncogenic driver when activated by mutations causing skipping of exon 14 in the MET gene (MET exon 14).
      To date, there have been three therapeutic approaches to targeting MET: MET TKIs, anti-MET or anti-hepatocyte growth factor (HGF; natural ligand of MET) antibodies, and anti-MET antibody–drug conjugates [
      • Kim K.H.
      • Kim H.
      Progress of antibody-based inhibitors of the HGF-cMET axis in cancer therapy.
      ,
      • Ma Y.
      • Zhang M.
      • Wang J.
      • Huang X.
      • Kuai X.
      • Zhu X.
      • et al.
      High-affinity human anti-c-met IgG conjugated to oxaliplatin as targeted chemotherapy for hepatocellular carcinoma.
      ]. Anti-MET antibodies have failed to show efficacy better than placebo in patients selected for MET overexpression; two phase III trials were halted due to poorer survival with anti-MET antibodies than with placebo [
      • Catenacci D.V.T.
      • Tebbutt N.C.
      • Davidenko I.
      • Murad A.M.
      • Al-Batran S.E.
      • Ilson D.H.
      • et al.
      Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Spigel D.R.
      • Edelman M.J.
      • O'Byrne K.
      • Paz-Ares L.
      • Mocci S.
      • Phan S.
      • et al.
      Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung.
      ]. Anti-MET antibody–drug conjugates are a more recent approach; telisotuzumab vedotin, an anti-MET antibody conjugated with monomethyl auristatin E (a tubulin polymerization inhibitor), has shown favorable antitumor activity in patients with NSCLC and MET overexpression in a phase I study and is being investigated in a phase II trial (NCT03539536) [
      • Strickler J.H.
      • Weekes C.D.
      • Nemunaitis J.
      • Ramanathan R.K.
      • Heist R.S.
      • Morgensztern D.
      • et al.
      First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody-drug conjugate targeting c-met, in patients with advanced solid tumors.
      ,
      • Heist R.S.
      • Motwani M.
      • Barlesi F.
      • Goldman J.W.
      • Kelly K.
      • Sun Y.
      • et al.
      c-Met expression and response to telisotuzumab vedotin (teliso-v) in patients with non-small cell lung cancer.
      ,
      • Ocampo C.
      • Wu J.
      • Dey J.
      • Sun Z.
      • Motwani M.
      • Reddy A.
      • et al.
      Phase 2 study of telisotuzumab vedotin (Teliso-V) in previously treated c-MET+ non-small cell lung cancer: trial in progress.
      ]. MET TKIs have been investigated in patients with NSCLC harboring MET overexpression, MET amplification, or MET exon 14 skipping; case reports have reported activity in NSCLC with MET fusions [
      • Wang W.X.
      • Xu C.
      • Chen Y.
      • Zhu Y.-C.
      • Liu Y.
      • Wang H.
      • et al.
      MET gene fusions in non-small cell lung cancer (NSCLC) in the Chinese population: A multicenter study.
      ,
      • Yu L.
      • Wu Y.
      • Zhang B.
      • Ma R.
      • Yan N.
      • Mou H.
      Tumor heterogeneity with novel MET fusion showed different response to cabozantinib in non-small cell lung cancer.
      ,
      • Gow C.-H.
      • Liu Y.-N.
      • Li H.-Y.
      • Hsieh M.-S.
      • Chang S.-H.
      • Luo S.-C.
      • et al.
      Oncogenic function of a KIF5B-MET fusion variant in non-small cell lung cancer.
      ].
      In this review, we discuss the prospects for selective MET TKIs in the treatment of NSCLC harboring MET exon 14 skipping.

      The MET receptor tyrosine kinase

      The MET gene is located on human chromosome 7 (7q31), includes 21 exons and 20 introns, and encodes a protein with an apparent molecular weight of 190 kDa [
      • Zhang J.
      • Babic A.
      Regulation of the MET oncogene: molecular mechanisms.
      ] (Fig. 1). MET is a RTK normally expressed by epithelial cells, and is also found on endothelial cells, neurons, hepatocytes, and hematopoietic cells [
      • Gentile A.
      • Trusolino L.
      • Comoglio P.M.
      The Met tyrosine kinase receptor in development and cancer.
      ]. MET has one known natural ligand: HGF. HGF binding to MET induces receptor dimerization and autophosphorylation of tyrosine residues located in the intracellular portion of the receptor [
      • Garajova I.
      • Giovannetti E.
      • Biasco G.
      • Peters G.J.
      c-Met as a target for personalized therapy.
      ] (Fig. 2). These residues can also be transphosphorylated by other RTKs, such as the EGFR and, in particular, receptor originated from Nantes (RON), a receptor with structural homology to MET that appears to be required for oncogenic addiction to MET in some circumstances [
      • Huang L.
      • Fu L.
      Mechanisms of resistance to EGFR tyrosine kinase inhibitors.
      ,
      • Chang K.
      • Karnad A.
      • Zhao S.
      • Freeman J.W.
      Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets.
      ]. Phosphorylation of tyrosine residues in the MET cytoplasmic tail creates docking sites that engage molecules involved in intracellular signaling pathways, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), signal transducers and activators of transcription (STAT), and nuclear factor kappa B (NFκ-B) [
      • Garajova I.
      • Giovannetti E.
      • Biasco G.
      • Peters G.J.
      c-Met as a target for personalized therapy.
      ]. These pathways regulate the transcriptional activity of genes that mediate the cellular effects of MET activation.
      Figure thumbnail gr1
      Fig. 1MET gene and the encoded MET receptor. IPT: found in Immunoglobulins, Plexins, Transcription factors; PSI: found in Plexins, Semaphorins, Integrins; Sema: semaphorin domain.
      Figure thumbnail gr2
      Fig. 2Wild-type MET signaling. HGF: hepatocyte growth factor.
      Phosphorylation of tyrosine residue Y1003 in the cytoplasmic juxtamembrane domain, encoded by exon 14 of MET, creates a docking site for the E3 ubiquitin ligase Casitas B-lineage lymphoma (CBL), initiating the ubiquitination of MET and removal of HGF-bound MET from the cell surface [
      • Paik P.K.
      • Drilon A.
      • Fan P.D.
      • Yu H.
      • Rekhtman N.
      • Ginsberg M.S.
      • et al.
      Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.
      ]. MET activity depends upon a dynamic balance between MET activation and its removal from the cell surface, with both processes driven by binding of HGF [
      • Cecchi F.
      • Rabe D.C.
      • Bottaro D.P.
      Targeting the HGF/Met signaling pathway in cancer therapy.
      ]. CBL can also be deleted or mutated in NSCLC, which can lead to activation of MET [
      • Paik P.K.
      • Drilon A.
      • Fan P.D.
      • Yu H.
      • Rekhtman N.
      • Ginsberg M.S.
      • et al.
      Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.
      ,
      • Tan Y.C.
      • Mirzapoiazova T.
      • Won B.M.
      • Zhu L.
      • Srivastava M.K.
      • Vokes E.E.
      • et al.
      Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL.
      ].
      MET activation induces cellular proliferation, survival, mobilization, and invasion, while altered cell morphology and remodeling of cell–cell and cell–matrix adhesions initiate epithelial–mesenchymal transition [
      • Gentile A.
      • Trusolino L.
      • Comoglio P.M.
      The Met tyrosine kinase receptor in development and cancer.
      ]. MET has a critical role in embryogenesis, enabling tissue remodeling, and in adults plays a more subtle role in tissue repair [
      • Trusolino L.
      • Bertotti A.
      • Comoglio P.M.
      MET signalling: principles and functions in development, organ regeneration and cancer.
      ].
      Abnormal MET activity is observed in a wide range of solid tumors [
      • Ma P.C.
      • Tretiakova M.S.
      • MacKinnon A.C.
      • Ramnath N.
      • Johnson C.
      • Dietrich S.
      • et al.
      Expression and mutational analysis of MET in human solid cancers.
      ], and can be caused by activating MET mutations, MET amplification, overexpression of MET or HGF, or transactivation by other RTKs such as RON [
      • Cecchi F.
      • Rabe D.C.
      • Bottaro D.P.
      Targeting the HGF/Met signaling pathway in cancer therapy.
      ,
      • Tan Y.C.
      • Mirzapoiazova T.
      • Won B.M.
      • Zhu L.
      • Srivastava M.K.
      • Vokes E.E.
      • et al.
      Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL.
      ]. MET aberrations are associated with rapid tumor growth, aggressively invasive disease, and poor prognosis [
      • Boccaccio C.
      • Comoglio P.M.
      Invasive growth: a MET-driven genetic programme for cancer and stem cells.
      ], as well as resistance to anticancer therapy. Different MET aberrations may, however, vary in their oncogenic potential; for example, poor prognosis in NSCLC appears to be more clearly associated with MET amplification than with MET overexpression.

      MET exon 14 skipping

      Following transcription of the MET gene, the 21-exon precursor messenger ribonucleic acid (RNA) is spliced, guided by specific sequences in the 5′ and 3′ introns [

      Atlas of Genetics and Cytogenetics in Oncology and Haematology. MET met proto-oncogene (hepatocyte growth factor receptor), http://atlasgeneticsoncology.org//Genes/METID131.html; 2001 [accessed 15 January 2020].

      ]. Skipping of exon 14 during splicing is associated with a mutation in one of the exon 14 splice regions located within the exon–intron boundaries (MET exon 14 mutation hotspots; Fig. 3), although additional genomic alterations within exon 14 have also been noted [
      • Ma P.C.
      • Jagadeeswaran R.
      • Jagadeesh S.
      • Tretiakova M.S.
      • Nallasura V.
      • Fox E.A.
      • et al.
      Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer.
      ,
      • Ma P.C.
      • Kijima T.
      • Maulik G.
      • Fox E.A.
      • Sattler M.
      • Griffin J.D.
      • et al.
      c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions.
      ]. The resulting in-frame deletion of 141 base pairs leads to translation of a shortened MET receptor lacking the juxtamembrane domain on the cytoplasmic side of the plasma membrane. Because the deletion is in frame and exon 14 encodes a discrete domain, the resulting shortened MET receptor retains affinity for HGF and a transmembrane location with catalytic activity.
      Figure thumbnail gr3
      Fig. 3MET exon 14 skipping and loss of the juxtamembrane domain. IPT: found in Immunoglobulins, Plexins, Transcription factors; PSI: found in Plexins, Semaphorins, Integrins; Sema: semaphorin domain.
      The first somatic mutation causing MET exon 14 skipping was found in the 5′ splice site junction of MET exon 14. This mutation was reported in deoxyribonucleic acid (DNA) isolated from small cell lung cancer (SCLC) in 2003, with the occurrence of mutations in NSCLC being reported in 2005 [
      • Ma P.C.
      • Jagadeeswaran R.
      • Jagadeesh S.
      • Tretiakova M.S.
      • Nallasura V.
      • Fox E.A.
      • et al.
      Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer.
      ,
      • Ma P.C.
      • Kijima T.
      • Maulik G.
      • Fox E.A.
      • Sattler M.
      • Griffin J.D.
      • et al.
      c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions.
      ]. A mutational analysis of a series of NSCLC samples in 2006 subsequently identified a 22-base-pair deletion in the 5′ splice site junction of exon 14, a 28-base-pair deletion in the 3′ splice site, and a point mutation in the 3′ splice site, all of which generated MET exon 14 transcripts [
      • Kong-Beltran M.
      • Seshagiri S.
      • Zha J.
      • Zhu W.
      • Bhawe K.
      • Mendoza N.
      • et al.
      Somatic mutations lead to an oncogenic deletion of met in lung cancer.
      ]. Moreover, in 2015, Frampton et al. conducted comprehensive genome profiling of 38,028 tumor specimens from unique patients, and identified 224 mutations responsible for MET exon 14 transcripts, including 126 distinct sequence variants in 221 specimens [
      • Frampton G.M.
      • Ali S.M.
      • Rosenzweig M.
      • Chmielecki J.
      • Lu X.
      • Bauer T.M.
      • et al.
      Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
      ].

      MET exon 14 skipping alterations are distinct from other MET aberrations and are strong oncogenic drivers

      As a result of MET exon 14 skipping, MET lacks the juxtamembrane domain, which contains multiple sites involved in the regulation of MET signaling and cell survival, including the CBL binding site (Y1003) and associated ubiquitination sites [
      • Cortot A.B.
      • Kherrouche Z.
      • Descarpentries C.
      • Wislez M.
      • Baldacci S.
      • Furlan A.
      • et al.
      Exon 14 deleted MET receptor as a new biomarker and target in cancers.
      ] (Fig. 4). Consequently, endocytosis of HGF-activated MET exon 14 is compromised, leading to its accumulation as an active ligand/receptor complex on the cell surface [
      • Lee J.
      • Ou S.H.
      • Lee J.M.
      • Kim H.C.
      • Hong M.
      • Kim S.Y.
      • et al.
      Gastrointestinal malignancies harbor actionable MET exon 14 deletions.
      ] and sustained dysregulated activation of downstream signaling pathways [
      • Gherardi E.
      • Birchmeier W.
      • Birchmeier C.
      • Vande Woude G.
      Targeting MET in cancer: rationale and progress.
      ]. In addition, the juxtamembrane domain is key to negative regulation of the intracellular kinase domain via protein kinase C phosphorylation of S985 [
      • Cortot A.B.
      • Kherrouche Z.
      • Descarpentries C.
      • Wislez M.
      • Baldacci S.
      • Furlan A.
      • et al.
      Exon 14 deleted MET receptor as a new biomarker and target in cancers.
      ]. Therefore, its disruption through MET exon 14 skipping can likely transition the closed kinase conformation to a more active conformation [
      • Ma P.C.
      MET receptor juxtamembrane exon 14 alternative spliced variant: novel cancer genomic predictive biomarker.
      ].
      Figure thumbnail gr4
      Fig. 4Impact of MET exon 14 skipping on receptor ubiquitination and downstream effects. CBL: Casitas B-lineage lymphoma; HGF: hepatocyte growth factor; Ub: ubiquitination.
      MET exon 14 skipping has been shown to drive the growth of tumor cells in preclinical models through high and persistent MET signaling [
      • Kong-Beltran M.
      • Seshagiri S.
      • Zha J.
      • Zhu W.
      • Bhawe K.
      • Mendoza N.
      • et al.
      Somatic mutations lead to an oncogenic deletion of met in lung cancer.
      ,
      • Togashi Y.
      • Mizuuchi H.
      • Tomida S.
      • Terashima M.
      • Hayashi H.
      • Nishio K.
      • et al.
      MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor.
      ]. MET exon 14 skipping is often found to be mutually exclusive with other known oncogenic drivers such as Kirsten rat sarcoma (KRAS), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER2), indicating that MET exon 14 can promote oncogenesis in the absence of other oncogenic drivers [
      • Frampton G.M.
      • Ali S.M.
      • Rosenzweig M.
      • Chmielecki J.
      • Lu X.
      • Bauer T.M.
      • et al.
      Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
      ,
      • Pilotto S.
      • Gkountakos A.
      • Carbognin L.
      • Scarpa A.
      • Tortora G.
      • Bria E.
      MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy.
      ].
      The prevalence of MET exon 14 skipping across different cancer types differs from those of other MET aberrations. MET amplifications and MET protein overexpression are common in many solid tumors, particularly hepatocellular carcinoma [
      • Hu C.T.
      Screening of c-Met-positive hepatocellular carcinoma for c-Met-based target therapy.
      ]. In contrast, an extensive study by Frampton et al. detected MET exon 14 skipping most frequently in lung adenocarcinoma (3%), other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown origin (0.4%) [
      • Frampton G.M.
      • Ali S.M.
      • Rosenzweig M.
      • Chmielecki J.
      • Lu X.
      • Bauer T.M.
      • et al.
      Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
      ]. Similarly, analysis of 4422 samples from 12 different malignancies showed that MET exon 14 skipping was most common in lung adenocarcinoma (~3%), with lower prevalence in bladder urothelial carcinoma, head and neck squamous cell carcinoma, kidney renal clear cell carcinoma, lung squamous cell carcinoma, and colon adenocarcinoma, and none in other tumor types [
      • Lu X.
      • Peled N.
      • Greer J.
      • Wu W.
      • Choi P.
      • Berger A.H.
      • et al.
      MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma.
      ]. Comprehensive genomic profiling of 11,205 lung cancers identified 298 MET exon 14 NSCLC samples (2.7%) [
      • Schrock A.B.
      • Frampton G.M.
      • Suh J.
      • Chalmers Z.R.
      • Rosenzweig M.
      • Erlich R.L.
      • et al.
      Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations.
      ]. MET exon 14 skipping was most frequently detected in patients with adenosquamous (8.2% of 98 samples) or sarcomatoid (7.7% of 104 samples) histologies. In patients with adenocarcinoma (n = 7149), squamous cell carcinoma (n = 1206), or NSCLC histologic subtype not otherwise specified (n = 1659), MET exon 14 skipping was detected in 205 (2.8%), 25 (2.1%), and 49 (3.0%), respectively. At a lower frequency, MET exon 14 skipping was also reported in patients with large cell NSCLC (0.8%) or SCLC (0.2%). In a large cohort of Chinese patients with NSCLC, MET exon 14 skipping rates were 2.6% in adenocarcinoma, 4.8% in adenosquamous carcinoma, and 31.8% in sarcomatoid carcinoma [
      • Tong J.H.
      • Yeung S.F.
      • Chan A.W.
      • Chung L.Y.
      • Chau S.L.
      • Lung R.W.
      • et al.
      MET amplification and exon 14 splice site mutation define unique molecular subgroups of Non-small Cell Lung Carcinoma with poor prognosis.
      ].
      The prognostic impact of MET exon 14 skipping has not been studied extensively, although both MET exon 14 skipping and high-level MET amplification have been found to be independent prognostic factors of poor survival in a multivariable analysis [
      • Tong J.H.
      • Yeung S.F.
      • Chan A.W.
      • Chung L.Y.
      • Chau S.L.
      • Lung R.W.
      • et al.
      MET amplification and exon 14 splice site mutation define unique molecular subgroups of Non-small Cell Lung Carcinoma with poor prognosis.
      ]. The prognosis of patients with MET dysregulation who do not receive treatment with a MET inhibitor appears to be inferior, for both NSCLC harboring MET exon 14 skipping or MET amplification, or both alterations concurrently [
      • Awad M.M.
      • Leonardi G.C.
      • Kravets S.
      • Dahlberg S.E.
      • Drilon A.
      • Noonan S.A.
      • et al.
      Impact of MET inhibitors on survival among patients with non-small cell lung cancer harboring MET exon 14 mutations: a retrospective analysis.
      ,

      Wolf W, Baik C, Heist RS, Neal JW, Mansfield AS, Buettner R, et al. Natural history, treatment (Tx) patterns, and outcomes in MET dysregulated non-small cell lung cancer (NSCLC) patients (Pts). Presented at the EORTC/AACR/NCI symposium (ENA), Dublin, Ireland; 13–16 November 2018.

      ].
      In another study of East Asian patients with stage I to stage IIIA NSCLC, multivariate analysis showed that patients with tumors harboring MET exon 14 skipping had a higher recurrence rate post-resection than patients with ALK (ALK fusion versus MET exon 14 skipping, hazard ratio [HR] 0.283; 95% confidence interval [CI], 0.119–0.670; P = 0.004), although overall survival was similar to that in patients with other mutations (EGFR mutation, ROS1 fusion, ALK fusion, RET fusion) or none of these mutations, after adjusting for pathologic stage and other factors [
      • Lee G.D.
      • Lee S.E.
      • Oh D.Y.
      • Yu D.B.
      • Jeong H.M.
      • Kim J.
      • et al.
      MET Exon 14 skipping mutations in lung adenocarcinoma: clinicopathologic implications and prognostic values.
      ]. Overall, there is evidence that MET exon 14 skipping alterations are associated with poorer outcomes in patients with NSCLC, which, together with its oncogenic driver potential and prevalence in NSCLC, makes MET exon 14 an attractive therapeutic target.

      Tumors with MET exon 14 skipping are sensitive to MET TKIs

      Preclinical and clinical evidence suggest that tumors with MET exon 14 skipping alterations are sensitive to MET TKIs (see Table 1 for an overview of MET TKIs that have shown activity and/or are in ongoing clinical development). In particular, MET exon 14 skipping tumor models have been shown to respond to MET TKIs [
      • Togashi Y.
      • Mizuuchi H.
      • Tomida S.
      • Terashima M.
      • Hayashi H.
      • Nishio K.
      • et al.
      MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor.
      ], including capmatinib [
      • Frampton G.M.
      • Ali S.M.
      • Rosenzweig M.
      • Chmielecki J.
      • Lu X.
      • Bauer T.M.
      • et al.
      Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
      ,
      • Liu S.Y.
      • Gou L.Y.
      • Li A.N.
      • Lou N.N.
      • Gao H.F.
      • Su J.
      • et al.
      The unique characteristics of MET Exon 14 mutation in Chinese patients with NSCLC.
      ], glesatinib [
      • Engstrom L.D.
      • Aranda R.
      • Lee M.
      • Tovar E.A.
      • Essenburg C.J.
      • Madaj Z.
      • et al.
      Glesatinib exhibits antitumor activity in lung cancer models and patients harboring MET Exon 14 mutations and overcomes mutation-mediated resistance to type I MET inhibitors in nonclinical models.
      ], AMG337 [

      Cecchi F, Rabizadeh S, Weingarten P, Tsai C, Zhou L, Hembrough T. MET activation via exon 14 skipping mutations (METex14del): gastrointestinal prevalence and sensitivity to MET inhibitor AMG337. Ann Oncol 2016;27(suppl_2):ii11. Abstract P-038. https://doi.org/10.1093/annonc/mdw199.36.

      ], and tepotinib [
      • Bladt F.
      • Faden B.
      • Friese-Hamim M.
      • Knuehl C.
      • Wilm C.
      • Fittschen C.
      • et al.
      EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors.
      ].
      Table 1Agents with evidence of activity against tumors harboring MET exon 14 skipping and/or that are in ongoing clinical development.
      AgentAgent type, target, and selectivityKnown target(s)Stage of developmentEvidence of activity against MET exon 14 skipping
      Bozitinb (APL-101/PLB-1001; formerly CBT-101)

      (Apollomics/Beijing Pearl Biotechnology Co. Ltd.)
      ATP-competitive TKIMETPhase IPhase I dose-escalation trial reported signs of preliminary efficacy in two patients with MET-altered gliomas resistant to chemotherapy, including one with MET exon 14
      • Hu H.
      • Mu Q.
      • Bao Z.
      • Chen Y.
      • Liu Y.
      • Chen J.
      • et al.
      Mutational landscape of secondary glioblastoma guides MET-targeted trial in brain tumor.
      Cabozantinib (XL184)

      (Exelixis)
      ATP-competitive TKIMET, VEGFR-1, VEGFR-2, VEGFR-3, RET, Kit, Tie-2, Flt-3Phase IIICase report on activity in intracranial metastasis of MET exon 14 mutation-positive NSCLC
      • Klempner S.J.
      • Borghei A.
      • Hakimian B.
      • Ali S.M.
      • Ou S.I.
      Intracranial activity of cabozantinib in MET exon 14-positive NSCLC with brain metastases.
      Crizotinib

      (PF-02341066)

      (Pfizer)
      ATP-competitive TKIALK, MET, RON, ROS1Phase IIPhase I (PROFILE 1001) dose-expansion cohort data reported encouraging outcomes among patients with MET exon 14 skipping
      • Drilon A.
      • Clark J.W.
      • Weiss J.
      • Ou S.I.
      • Camidge D.R.
      • Solomon B.J.
      • et al.
      Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration.


      Phase II AcSé
      • Moro-Sibilot D.
      • Cozic N.
      • Perol M.
      • Mazieres J.
      • Otto J.
      • Souquet P.J.
      • et al.
      Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSe phase II trial.
      and National Lung Matrix Trial

      Middleton GW, Popat S, Fletcher P, Summers YJ, Greystoke A, Gilligan D, et al. Abstract PL02.09: National Lung Matrix Trial (NLMT): First Results from an Umbrella Phase II Trial in Advanced Non-Small Cell Lung Cancer (NSCLC). Presented at the World Conference on Lung Cancer, Barcelona, Spain, 7–10 September 2019.

      studies reported encouraging responses in patients with MET exon 14 skipping NSCLC

      Phase II trial data showed limited activity in patients with MET exon 14 mutation-positive NSCLC

      Landi L, Chiari R, Tiseo M, D'Incà F, Dazzi C, Chella A, et al. Crizotinib in MET deregulated or ROS1 rearranged pretreated non-small-cell lung cancer (METROS): a phase II, prospective, multicentre, two-arms trial. Clin Cancer Res 2019:clincanres.0994.2019. https://doi.org/10.1158/1078-0432.Ccr-19-0994.

      Merestinib (LY2801653)

      (Eli Lilly and Company)

      ATP-competitive TKIRON, MET, Flt-3, AXL, MERTK, TEK, ROS1, NTRK1/2/3, DDR1/2Phase IIActivity as a single agent and when combined with emibetuzumab in a mouse model of MET exon 14 skipping gastric cancer
      • Yan S.B.
      • Um S.L.
      • Peek V.L.
      • Stephens J.R.
      • Zeng W.
      • Konicek B.W.
      • et al.
      MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping.
      Glesatinib (MGCD265)

      (Mirati Therapeutics)

      ATP-competitive TKIAXL, METPhase IIPreclinical and clinical activity in NSCLC harboring MET exon 14 skipping
      • Engstrom L.D.
      • Aranda R.
      • Lee M.
      • Tovar E.A.
      • Essenburg C.J.
      • Madaj Z.
      • et al.
      Glesatinib exhibits antitumor activity in lung cancer models and patients harboring MET Exon 14 mutations and overcomes mutation-mediated resistance to type I MET inhibitors in nonclinical models.
      ,

      Der-Torossian H, Shapiro G, Janne PA, Awad MM, Reckamp K, Miller W, et al. MET mutant allele frequency (MAF) is correlated with glesatinib anti-tumor activity in patients with advanced non-small cell lung cancer (NSCLC) harboring MET alterations. Eur J Cancer 2018;103(suppl_1):e133. Abstract 410 (PB-073). https://doi.org/10.1016/S0959-8049(18)31491-6.

      AMG337

      (Amgen)
      ATP-competitive TKIMETPhase IIPreclinical data indicating activity in MET exon 14 skipping gastric cancer cell lines

      Cecchi F, Rabizadeh S, Weingarten P, Tsai C, Zhou L, Hembrough T. MET activation via exon 14 skipping mutations (METex14del): gastrointestinal prevalence and sensitivity to MET inhibitor AMG337. Ann Oncol 2016;27(suppl_2):ii11. Abstract P-038. https://doi.org/10.1093/annonc/mdw199.36.

      Capmatinib (INC280)

      (Novartis)
      ATP-competitive TKIMETPhase IIData from phase II GEOMETRY mono-1 trial demonstrating activity in patients with NSCLC harboring MET exon 14 skipping (across treatment lines)

      Wolf J, Seto T, Han J-Y, Reguart N, Garon EB, Groen HJM, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      Emibetuzumab (LY2875358)

      (Eli Lilly & Company)
      Antagonist MAbMETPhase IIINo activity as a single agent in a mouse model of MET exon 14 mutation-positive gastric cancer, but combination with merestinib may be active
      • Yan S.B.
      • Um S.L.
      • Peek V.L.
      • Stephens J.R.
      • Zeng W.
      • Konicek B.W.
      • et al.
      MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping.
      Savolitinib (AZD6094)

      (AstraZeneca)
      ATP-competitive TKIMETPhase IIInterim data from phase II study in patients with MET exon 14 skipping NSCLC showed encouraging ORR

      Lu S, Fang J, Cao L, Li X, Guo Q, Zhou J, et al. Preliminary efficacy and safety results of savolitinib treating patients with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations. Cancer Res 2019;79:Abstract CT031. https://doi.org/10.1158/1538-7445.Am2019-ct031.

      Tepotinib

      (MSC2156119J)

      (Merck KGaA, Darmstadt, Germany)
      ATP-competitive TKIMETPhase IIInterim data from phase II VISION trial demonstrating activity in patients with NSCLC harboring MET exon 14 skipping (across treatment lines)

      Paik P, Veillon R, Cortot AB, Felip E, Sakai H, Mazieres J, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      ALK: anaplastic lymphoma kinase; ATP: adenosine triphosphate; DDR1/2: discoidin domain receptor tyrosine kinase 1/2; FLT3: fms-like tyrosine kinase 3; MAb: monoclonal antibody; MERTK: MER receptor tyrosine kinase; NSCLC: non-small cell lung cancer; NTRK: neurotrophic-tropomyosin receptor kinase; ORR: objective response rate; RON: receptor originated from Nantes; ROS1: c-ros oncogene 1; Tie-2: tyrosine-protein kinase receptor; TKI: tyrosine kinase inhibitor; VEGFR: vascular endothelial growth factor receptor.
      The first clinical evidence of MET exon 14 skipping tumors responding to MET TKIs came from studies using crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), and RON, as well as MET [
      • Paik P.K.
      • Drilon A.
      • Fan P.D.
      • Yu H.
      • Rekhtman N.
      • Ginsberg M.S.
      • et al.
      Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.
      ,
      • Leprieur E.G.
      • Fallet V.
      • Cadranel J.
      • Wislez M.
      Spotlight on crizotinib in the first-line treatment of ALK-positive advanced non-small-cell lung cancer: patients selection and perspectives.
      ]. Crizotinib showed efficacy in patients with MET exon 14 skipping tumors, possibly due to its MET-inhibitory activity [
      • Paik P.K.
      • Drilon A.
      • Fan P.D.
      • Yu H.
      • Rekhtman N.
      • Ginsberg M.S.
      • et al.
      Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.
      ,
      • Waqar S.N.
      • Morgensztern D.
      • Sehn J.
      MET mutation associated with responsiveness to crizotinib.
      ,
      • Mendenhall M.A.
      • Goldman J.W.
      MET-mutated NSCLC with major response to crizotinib.
      ,
      • Jorge S.E.
      • Schulman S.
      • Freed J.A.
      • VanderLaan P.A.
      • Rangachari D.
      • Kobayashi S.S.
      • et al.
      Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation.
      ,
      • Drilon A.E.
      • Camidge D.R.
      • Ou S.H.I.
      • Clark J.W.
      • Socinski M.A.
      • Weiss J.
      • et al.
      Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC).
      ]. Data from a large dose-expansion cohort (N = 69) of a phase I trial with crizotinib (PROFILE 1001; NCT00585195) reported encouraging outcomes in patients with advanced NSCLC and MET exon 14 skipping [
      • Drilon A.
      • Clark J.W.
      • Weiss J.
      • Ou S.I.
      • Camidge D.R.
      • Solomon B.J.
      • et al.
      Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration.
      ]. Based on this, crizotinib received breakthrough therapy designation from the United States Food and Drug Administration (US FDA) in May 2018 for the treatment of metastatic NSCLC in patients with MET exon 14 skipping alterations and progression on or after platinum-based chemotherapy [
      • Drilon A.E.
      • Camidge D.R.
      • Ou S.H.I.
      • Clark J.W.
      • Socinski M.A.
      • Weiss J.
      • et al.
      Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC).
      ,

      Pfizer. Pfizer’s XALKORI® (crizotinib) Receives FDA Breakthrough Therapy Designation in Two New Indications, https://www.pfizer.com/news/press-release/press-release-detail/pfizer_s_xalkori_crizotinib_receives_fda_breakthrough_therapy_designation_in_two_new_indications-0; 2018 [accessed 15 January 2020].

      ]. The AcSé crizotinib program developed by the French National Cancer Institute performed biomarker testing to identify patients with molecular alterations targeted by crizotinib and enrolled them into a phase II study of crizotinib [
      • Moro-Sibilot D.
      • Cozic N.
      • Perol M.
      • Mazieres J.
      • Otto J.
      • Souquet P.J.
      • et al.
      Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSe phase II trial.
      ]. Tumor samples of 1192 NSCLC patients were tested for MET mutations (exons 14 and 16–19) using next-generation sequencing: 74 (6.2%) were positive and 28 enrolled in the study (25 patients had MET exon 14 skipping). In these 25 pretreated patients, an encouraging overall response rate of 40% was reported. However, a phase II trial of crizotinib in 26 patients with pretreated NSCLC with MET amplification (n = 16) or MET exon 14 mutation (n = 10 [one patient had both MET amplification and MET exon 14 mutation]) (METROS study, NCT02499614) recently reported limited benefit in terms of objective response rate (ORR), progression-free survival, or overall survival among patients with MET exon 14 skipping [

      Landi L, Chiari R, Tiseo M, D'Incà F, Dazzi C, Chella A, et al. Crizotinib in MET deregulated or ROS1 rearranged pretreated non-small-cell lung cancer (METROS): a phase II, prospective, multicentre, two-arms trial. Clin Cancer Res 2019:clincanres.0994.2019. https://doi.org/10.1158/1078-0432.Ccr-19-0994.

      ]. A phase II study of crizotinib in Japanese patients with NSCLC harboring MET alterations is ongoing (Co-MET; UMIN000031623). Nineteen patients with MET exon 14 skipping will be recruited in Cohort A; Cohort B will recruit ten patients with tumors harboring MET amplification. The primary endpoint is ORR [

      Shimokawa M, Nosaki K, Seto T, Ohashi K, Morise M, Fujiwara Y, et al. Phase II study of crizotinib in Japanese patients with advanced non-small cell lung cancer harboring a MET gene alteration: Co-MET study. Ann Oncol 2019;30(suppl_2):mdz063.79. Abstract 181TiP. https://doi.org/10.1093/annonc/mdz063.079.

      ].
      The TKI cabozantinib, which inhibits multiple RTKs in addition to MET, has also been reported to have efficacy in MET exon 14 skipping tumors [
      • Klempner S.J.
      • Borghei A.
      • Hakimian B.
      • Ali S.M.
      • Ou S.I.
      Intracranial activity of cabozantinib in MET exon 14-positive NSCLC with brain metastases.
      ,
      • Wang S.X.Y.
      • Zhang B.M.
      • Wakelee H.A.
      • Koontz M.Z.
      • Pan M.
      • Diehn M.
      • et al.
      Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib.
      ]. An Italian phase II trial is currently evaluating cabozantinib in patients with MET-amplified NSCLC or MET exon 14 skipping NSCLC (CABinMET study, NCT03911193). A phase II trial of the multitargeted TKI merestinib (LY2801653) [
      • He A.R.
      • Cohen R.B.
      • Denlinger C.S.
      • Sama A.
      • Birnbaum A.
      • Hwang J.
      • et al.
      First-in-human phase I study of merestinib, an oral multikinase inhibitor, in patients with advanced cancer.
      ] in patients with advanced NSCLC with MET exon 14 skipping is ongoing (NCT02920996). An overview of pivotal clinical trials of MET inhibitors in patients with NSCLC harboring MET exon 14 skipping is presented in Table 2.
      Table 2Pivotal clinical trials of MET inhibitors in patients with NSCLC harboring MET exon 14 skipping and baseline characteristics of patients enrolled.
      Crizotinib
      • Drilon A.E.
      • Camidge D.R.
      • Ou S.H.I.
      • Clark J.W.
      • Socinski M.A.
      • Weiss J.
      • et al.
      Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC).
      ,
      • Drilon A.
      • Clark J.W.
      • Weiss J.
      • Ou S.I.
      • Camidge D.R.
      • Solomon B.J.
      • et al.
      Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration.
      Capmatinib

      Wolf W, Baik C, Heist RS, Neal JW, Mansfield AS, Buettner R, et al. Natural history, treatment (Tx) patterns, and outcomes in MET dysregulated non-small cell lung cancer (NSCLC) patients (Pts). Presented at the EORTC/AACR/NCI symposium (ENA), Dublin, Ireland; 13–16 November 2018.

      ,

      Wolf J, Seto T, Han J-Y, Reguart N, Garon EB, Groen HJM, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      ,

      Heist RS, Garon EB, Tan DSW, Groen HJM, Seto T, Smit EF, et al. Biomarker analysis of patients with METΔex14 mutated non-small-cell lung cancer (NSCLC) treated with capmatinib in the GEOMETRY mono-1 study. Mol Cancer Ther 2019;18(12 Suppl):Abstract A029. https://doi.org/10.1158/1535-7163.TARG-19-A029.

      Savolitinib

      Lu S, Fang J, Li X, Zhou J, Cao L, Cheng Y, et al. Abstract 5707: Phase II Study of Savolitinib in Patients with NSCLC Harboring MET Exon 14 Skipping Mutations: Preliminary Efficacy and Safety Results. Presented at the 22nd Annual Meeting of the Chinese Society of Clinical Oncology (CSCO), Xiamen, China, 18–22 September 2019.

      ,

      Lu S, Fang J, Cao L, Li X, Guo Q, Zhou J, et al. Preliminary efficacy and safety results of savolitinib treating patients with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations. Cancer Res 2019;79:Abstract CT031. https://doi.org/10.1158/1538-7445.Am2019-ct031.

      Tepotinib

      Paik P, Veillon R, Cortot AB, Felip E, Sakai H, Mazieres J, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      StudyPROFILE 1001GEOMETRY mono-1VISION
      ClinicalTrials.gov identifierNCT00585195NCT02414139NCT02897479NCT02864992
      Study designPhase I, open label, multicenterPhase II, open label, multicenterPhase II, open label, multicenterPhase II, open label, multicenter
      Overall patients600 (actual)364 (estimated)50 (estimated)280 (estimated)
      Patients with MET exon 14 skippingN = 69N = 97 enrolled at Feb 26, 2019 cut-off

      Cohort 4: pretreated patients with MET exon 14, regardless of MET GCN (N = 69)

      Cohort 5b: treatment-naïve MET exon 14 regardless of GCN (N = 28)

      Expansion: pretreated MET exon 14 regardless of GCN (N = 30)

      Expansion: treatment-naïve MET exon 14 regardless of GCN (N = 27)
      N = 50 enrolled at Apr 10, 2019 cut-off

      Additional cohort of patients pre-treated with MET inhibitor
      N = 87 enrolled at Feb 18, 2019 cut-off
      Recruitment as of April 2020CompleteComplete: Cohorts 4 and 5b

      Ongoing: 6 and 7
      OngoingOngoing
      Treatment250 mg orally twice daily until disease progression, death, or unacceptable toxicity400 mg orally twice daily until disease progression, death, or unacceptable toxicity600 mg (BW ≥ 50 kg) or 400 mg (BW < 50 kg) orally once daily until disease progression, death, or unacceptable toxicity500 mg (500 mg tepotinib hydrochloride hydrate, which contains 450 mg tepotinib free base) orally once daily until disease progression, death, or unacceptable toxicity
      Inclusion criteriaAdvanced NSCLC

      ECOG PS of 0 or 1
      Advanced NSCLC (any histology). Stage IIIB/IV NSCLC

      ECOG PS 0–1

      EGFR wt, ALK-negative
      Histologically or cytologically documented locally advanced or metastatic PSC or other NSCLC

      ECOG PS 0–1 (2 may be allowed)

      EGFR/ALK/ROS1 wt
      Histologically confirmed advanced NSCLC (all histologies)

      ECOG PS 0–1

      EGFR wt, ALK wt
      Prior treatmentNo prior MET-directed targeted therapy

      For pretreated patients, no major surgery, radiation therapy, or anticancer therapy within 2–4 weeks of starting study treatment
      No prior MET inhibitor

      For pretreated patients, no previous anticancer agents within 4 weeks or ≤ 5 × half-life of the agent before first dose
      No prior MET inhibitor (Cohort 1)

      Palliative radiotherapy allowed

      For pretreated patients, no radiotherapy or any anticancer therapy within 3 weeks prior to initiation of study treatment, or received TKI treatment within 2 weeks prior to initiation of study treatment
      No prior MET inhibitor

      Palliative radiotherapy allowed

      For pretreated patients, no radiotherapy or anticancer therapy within 21 days prior to the first dose of trial treatment
      MET exon 14 detectedMET exon 14 status identified by local molecular profiling

      Retrospective analysis for MET exon 14 status was performed by:

      Central testing of available tumor tissue (FoundationOne companion diagnostic, Foundation Medicine, Inc.)

      Circulating cell-free DNA analysis (PlasmaSELECT 64, PGDx)
      MET exon 14 status determined centrally by RT-PCR

      Patients with MET exon 14 skipping had tissue biopsy samples retrospectively tested using the FoundationOne hybrid capture assay (next-generation sequencing)
      MET exon 14 skipping identified in tumor, plasma, and/or pleural effusion. Mutations identified by local lab required to be confirmed by central lab testNext-generation sequencing panels Guardant360® (73-gene) and Oncomine™ Focus Assay (OFA; 52-gene) were used to identify MET exon 14 skipping in circulating tumor DNA and tumor tissue respectively. Archer® Lung FUSIONPlex® was also used. Analyses performed by a central laboratory DNA
      Brain metastasesTreated brain metastases allowed if stable for ≥ 2 weeksNeurologically stable or asymptomatic brain metastases allowed

      Exclusion: symptomatic CNS metastases that are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms
      Patients who are neurologically stable on symptomatic therapy allowed. Asymptomatic untreated brain metastases ≤ 1 cm longest diameter allowed

      Exclusion: patients with active brain metastases or who have brain metastases as the only measurable lesion
      Primary endpoint for METex14ORR per investigator assessment (RECIST v1.0)ORR per IRC (RECIST v1.1)ORR per investigator assessment (RECIST v1.1)ORR per IRC (RECIST v1.1)
      Secondary endpoint for METex14DoR, TTR, PFS, OS

      Safety
      ORR per investigator assessment, DoR, TTR, DCR, PFS, OS

      Safety, PK, biomarkers, and patient-reported outcomes
      DCR, DoR, TTR, PFS, 6-month PFS rate, OS

      Safety
      ORR per investigator assessment, DoR, objective disease control, PFS, OS

      Safety, PK, and patient-reported outcomes
      Baseline characteristics
      n (%)Overall

      (N = 69)
      1st line Cohort

      (N = 28)
      2nd/3rd line Cohort

      (N = 69)
      Overall

      (N = 50)
      Overall

      (N = 87)
      AgeMedian (range)72 (34–91)71 (57–86)71 (49–90)68.8 (52.6–85.0)74 (39–89)
      SexMale29 (42)29 (42)10 (36)29 (58)47 (54)
      RaceCaucasian

      Asian

      Other
      50 (73)

      11 (16)

      8 (12)
      24 (86)

      4 (14)

      0
      49 (71)

      19 (28)

      1 (1)
      NR (likely all Asian)66 (76)

      17 (20)

      4 (5)
      Smoking historyNo

      Yes
      26 (38)

      43 (62)
      18 (64)

      10 (36)
      40 (58)

      29 (42)
      28 (56)

      22 (44)
      38 (44)

      40 (46)
      ECOG PS0

      1

      ≥ 2
      19 (28)

      49 (71)

      1 (1)
      7 (25)

      21 (75)

      0
      16 (23)

      52 (75)

      1 (1)
      8 (16)

      41 (82)

      1 (2)
      22 (25)

      65 (75)

      0
      HistologyAdenocarcinoma

      Squamous

      Sarcomatoid

      Others
      58 (84)

      3 (4)

      6 (9)

      2 (3)
      25 (89)

      2 (7)

      NR

      1 (46)
      53 (77)

      6 (9)

      NR

      10 (5)
      26 (52)

      NR

      20 (40)

      4 (8)
      75 (86)

      7 (8)

      1 (1)

      4 (5)
      Brain metastasesNR3 (11)11 (16)11 (22)8 (9)
      No. of prior regimens for advanced diseases0

      1

      ≥ 2
      26 (38)

      29 (42)

      14 (20)
      28 (100)

      0

      0
      0

      51 (74)

      18 (26)
      18 (36)

      ≥ 1: 32 (64)

      NR
      33 (38)

      31 (36)

      23 (26)
      BW: bodyweight; CNS: central nervous system; DCR: disease control rate; DNA: deoxyribonucleic acid; DoR: duration of response; ECOG PS: Eastern Cooperative Oncology Group performance status; GCN: gene copy number; IRC: independent review committee; NR: not reported; NSCLC: non-small cell lung cancer; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; PK: pharmacokinetics; PSC: pulmonary sarcomatoid carcinoma; RNA: ribonucleic acid; RT-PCR: reverse transcription polymerase chain reaction; TKI: tyrosine kinase inhibitor; TTR: time to therapeutic response; wt: wild-type.
      A multicenter retrospective analysis conducted to determine whether treatment with MET TKIs impacts survival in patients with NSCLC harboring MET exon 14 skipping found that, of 27 patients with metastatic disease who received at least one MET TKI (including crizotinib, glesatinib, and capmatinib), median overall survival was 24.6 months. A model adjusting for first- or second-line MET TKI therapy as a time-dependent covariate showed that MET TKI treatment significantly prolonged survival versus no MET TKI treatment (HR 0.11; 95% CI, 0.01–0.92; P = 0.04) [
      • Awad M.M.
      • Leonardi G.C.
      • Kravets S.
      • Dahlberg S.E.
      • Drilon A.E.
      • Noonan S.
      • et al.
      Impact of MET inhibitors on survival among patients (pts) with MET exon 14 mutant (METdel14) non-small cell lung cancer (NSCLC).
      ]. Further data from 87 patients with MET exon 14 skipping NSCLC reported a median overall survival of 25.3 months for those who had received a MET inhibitor (n = 36) versus 10.9 months for those who had not (n = 51) [

      Wolf W, Baik C, Heist RS, Neal JW, Mansfield AS, Buettner R, et al. Natural history, treatment (Tx) patterns, and outcomes in MET dysregulated non-small cell lung cancer (NSCLC) patients (Pts). Presented at the EORTC/AACR/NCI symposium (ENA), Dublin, Ireland; 13–16 November 2018.

      ]. MET exon 14 skipping NSCLC tumors can also express high levels of programmed cell death-ligand 1 (PD-L1) [

      Wolf W, Baik C, Heist RS, Neal JW, Mansfield AS, Buettner R, et al. Natural history, treatment (Tx) patterns, and outcomes in MET dysregulated non-small cell lung cancer (NSCLC) patients (Pts). Presented at the EORTC/AACR/NCI symposium (ENA), Dublin, Ireland; 13–16 November 2018.

      ,
      • Mazieres J.
      • Drilon A.
      • Lusque A.
      • Mhanna L.
      • Cortot A.B.
      • Mezquita L.
      • et al.
      Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.
      ,
      • Sabari J.K.
      • Leonardi G.C.
      • Shu C.A.
      • Umeton R.
      • Montecalvo J.
      • Ni A.
      • et al.
      PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers.
      ]; however, notably, this does not appear to translate into clinical benefit with PD-L1-targeted immunotherapies [
      • Mazieres J.
      • Drilon A.
      • Lusque A.
      • Mhanna L.
      • Cortot A.B.
      • Mezquita L.
      • et al.
      Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.
      ,
      • Sabari J.K.
      • Leonardi G.C.
      • Shu C.A.
      • Umeton R.
      • Montecalvo J.
      • Ni A.
      • et al.
      PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers.
      ]. This finding, together with the evidence of clinical activity of MET inhibitors, suggests that targeted therapy with selective MET inhibitors is a more appropriate treatment choice than immunotherapy in patients with NSCLC harboring MET exon 14 skipping.
      Given that MET exon 14 skipping alterations drive carcinogenesis through MET activity in the absence of other oncogenic drivers, it is likely that despite the lack of selectivity of the aforementioned TKIs, MET inhibition is central to their activity in tumors harboring MET exon 14 skipping. However, appropriate trials of agents that are potent and selective inhibitors of MET will confirm this.

      Selective MET inhibitors are promising therapies for patients with MET exon 14 skipping-positive tumors

      MET-selective TKIs are attractive potential treatments for MET exon 14 skipping tumors because they target only the activity associated with this primary driver. Thus, unlike non-selective MET inhibitors, they cause little off-target toxicity. Reduced toxicity improves tolerability and enables dosing at levels that cause profound inhibition of MET kinase activity, thus maximizing efficacy. Based on this rationale, several selective MET inhibitors are being investigated in patients with MET exon 14 skipping lung tumors, including capmatinib, savolitinib, and tepotinib (Table 1, Table 2).
      Capmatinib (INC280) is an oral, adenosine triphosphate (ATP)-competitive MET inhibitor that has shown potent and selective inhibitory activity against MET in vitro, as well as antitumor activity in MET-dependent cell lines and in a MET-driven mouse xenograft model [
      • Liu X.
      • Wang Q.
      • Yang G.
      • Marando C.
      • Koblish H.K.
      • Hall L.M.
      • et al.
      A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3.
      ,
      • Baltschukat S.
      • Engstler B.S.
      • Huang A.
      • Hao H.-X.
      • Tam A.
      • Wang H.Q.
      • et al.
      Capmatinib (INC280) Is Active Against Models of Non-Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation.
      ]. A phase I study (NCT01324479) recruiting patients with advanced NSCLC and aberrant MET expression identified four patients harboring MET exon 14 skipping. Of these, two patients had a confirmed partial response and one a complete response [

      Schuler M, Berardi R, Lim W-T, de Jonge M, Bauer TM, Azaro A, et al. Phase I dose expansion results from a multicenter, open-label study of the MET inhibitor capmatinib (INC280) in adult patients with MET-dysregulated advanced NSCLC. Presented at the EORTC/AACR/NCI symposium (ENA), Dublin, Ireland, 13–16 November 2018.

      ]. A current phase II trial of capmatinib (GEOMETRY mono-1; NCT02414139) includes cohorts of patients with advanced EGFR wild-type, ALK rearrangement-negative NSCLC with MET alterations, including MET exon 14 skipping, who are either treatment naïve or have received 1–2 prior lines of therapy, but not with a MET inhibitor. Data from 97 capmatinib-treated patients with MET exon 14 skipping advanced NSCLC, reported a higher ORR in treatment-naïve patients (which included patients with MET gene amplifications) than in the subgroup who had received 1–2 previous lines of therapy. Additionally, progression-free survival was also higher in treatment-naïve patients, while duration of response was similar between groups [

      Wolf J, Seto T, Han J-Y, Reguart N, Garon EB, Groen HJM, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      ]. Notwithstanding these promising response results, longer-term data will be required to inform the ideal treatment sequence. Capmatinib was recently granted breakthrough therapy and orphan drug designation for patients with NSCLC harboring MET exon 14 skipping by the US FDA [

      Novartis. Novartis Shows Growing Strength in Lung Cancer Innovation with New Capmatinib Investigational Data and Novel Canakinumab Clinical Trials, https://www.novartis.com/news/media-releases/novartis-shows-growing-strength-lung-cancer-innovation-new-capmatinib-investigational-data-and-novel-canakinumab-clinical-trials; 2019 [accessed 15 January 2020].

      ]. A phase II study under an umbrella trial for NSCLC is ongoing in Korea in pretreated patients with NSCLC carrying MET exon 14 skipping alterations who have not received more than two lines of prior systemic therapy (STARTER_cMET study, NCT03693339). An additional phase II trial is ongoing in patients with MET exon 14 mutation-positive NSCLC who have received or refused prior platinum-containing chemotherapy and received MET inhibitor therapy immediately prior to trial therapy (NCT02750215). In patients with treatment-naïve NSCLC harboring MET exon 14 skipping, a randomized phase II trial is evaluating the combination of capmatinib with immunotherapy (spartalizumab, an anti-PD-1 antibody) compared with capmatinib alone (NCT04323436).
      Savolitinib is an orally available, selective MET inhibitor that has demonstrated inhibitory activity against cell lines with exon 14 skipping mutations [

      Barry E, Henry R, Borodovsky A, Maloney E, Ladd B, Frigault M, et al. Activity of Savolitinib against MET Ex14 mutations and resistance to METi through decoupling from MYC expression. Presented at the American Association of Cancer Research (AACR) Annual Meeting, New Orleans, Louisiana, USA, 16–20 April 2016.

      ], and is being assessed in a phase II trial of patients with locally advanced/metastatic MET exon 14 mutation-positive NSCLC of sarcomatoid and other histologies (NCT02897479). Preliminary data from 50 patients with MET exon 14 skipping mutation-positive NSCLC showed an encouraging ORR [

      Lu S, Fang J, Li X, Zhou J, Cao L, Cheng Y, et al. Abstract 5707: Phase II Study of Savolitinib in Patients with NSCLC Harboring MET Exon 14 Skipping Mutations: Preliminary Efficacy and Safety Results. Presented at the 22nd Annual Meeting of the Chinese Society of Clinical Oncology (CSCO), Xiamen, China, 18–22 September 2019.

      ].
      Bozitinib (APL-101/PLB-1001, formerly CBT-101) is an ATP-competitive, small-molecule oral MET inhibitor currently under investigation in phase I/II trials as a single agent in patients with solid tumors, NSCLC, and glioblastomas, and in combination with PD-L1 inhibitors in patients with hepatocellular carcinoma and renal cell carcinoma. The drug has demonstrated anticancer effects in a variety of human xenograft tumor models with MET dysregulation and has shown promise in glioblastoma owing to its ability to cross the blood–brain barrier. The safety and preliminary efficacy of the drug have been demonstrated in a limited number of patients with chemotherapy-resistant, MET-altered gliomas [
      • Shih J.
      • Zhong B.
      • Shi H.
      • Xue D.
      • Choy G.S.
      • Redkar S.
      Bozitinib, a highly selective inhibitor of cMet, demonstrates robust activity in gastric, lung, hepatic and pancreatic in vivo models.
      ,
      • Hu H.
      • Mu Q.
      • Bao Z.
      • Chen Y.
      • Liu Y.
      • Chen J.
      • et al.
      Mutational landscape of secondary glioblastoma guides MET-targeted trial in brain tumor.
      ]. A phase II trial is evaluating bozitinib in patients with NSCLC harboring MET exon 14 skipping in China (NCT04258033).
      Tepotinib, an oral, ATP-competitive, and highly selective MET inhibitor, showed potent inhibitory activity against MET in cancer cell lines, and antitumor activity in mouse xenograft models of human tumors, regardless of whether MET activation was HGF dependent or independent [
      • Bladt F.
      • Faden B.
      • Friese-Hamim M.
      • Knuehl C.
      • Wilm C.
      • Fittschen C.
      • et al.
      EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors.
      ]. A phase II study is ongoing, assessing tepotinib in treatment-naïve or previously treated patients with advanced NSCLC harboring MET exon 14 skipping as detected by tissue or liquid biopsy (VISION study, NCT02864992). The primary endpoint is ORR and preliminary data has shown encouraging signs of activity [

      Paik P, Veillon R, Cortot AB, Felip E, Sakai H, Mazieres J, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      ]. The Japanese Ministry of Health, Labour and Welfare approved tepotinib for use in patients with advanced NSCLC harboring MET exon 14 skipping in March 2020 [

      Merck KGaA. TEPMETKO (Tepotinib) Approved in Japan for Advanced NSCLC with METex14 Skipping Alterations, https://www.merckgroup.com/en/news/tepotinib-25-03-2020.html; 2020 [accessed 25 March 2020].

      ], alongside Archer®MET companion diagnostic for detection of MET exon 14 skipping [

      ArcherDX. ArcherDX Receives Approval for Archer®MET Companion Diagnostic for TEPMETKO® (Tepotinib) in Advanced Non-Small Cell Lung Cancer in Japan, https://archerdx.com/archerdx-receives-approval-for-archermet-companion-diagnostic-for-tepmetko-tepotinib-in-advanced-non-small-cell-lung-cancer-in-japan; 2020 [accessed 25 March 2020].

      ]. In September 2019, tepotinib received US FDA breakthrough therapy designation in patients with metastatic NSCLC harboring MET exon 14 skipping alterations who progressed following platinum-based cancer therapy [

      Merck KGaA. Merck Announces FDA Breakthrough Therapy Designation for Investigational Therapy Tepotinib in Patients with Metastatic NSCLC with METex14 Skipping Alterations, https://www.merckgroup.com/en/news/tepotinib-breakthrough-therapy-designation-11-09-2019.html; 2019 [accessed 15 January 2020].

      ].

      Outstanding questions regarding MET inhibition in MET exon 14 skipping tumors

      How do MET exon 14 mutations interact with other tumor aberrations? MET exon 14 mutations are notable in that they appear to drive tumors in the absence of other driver oncogenes but do co-exist with mutations in KRAS, ROS1, and EGFR, likely as a result of low MET exon 14 mutant allele frequency in these tumors [
      • Frampton G.M.
      • Ali S.M.
      • Rosenzweig M.
      • Chmielecki J.
      • Lu X.
      • Bauer T.M.
      • et al.
      Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
      ,
      • Pilotto S.
      • Gkountakos A.
      • Carbognin L.
      • Scarpa A.
      • Tortora G.
      • Bria E.
      MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy.
      ,

      Wolf W, Baik C, Heist RS, Neal JW, Mansfield AS, Buettner R, et al. Natural history, treatment (Tx) patterns, and outcomes in MET dysregulated non-small cell lung cancer (NSCLC) patients (Pts). Presented at the EORTC/AACR/NCI symposium (ENA), Dublin, Ireland; 13–16 November 2018.

      ,
      • Bruno R.
      • Lupi C.
      • Landi L.
      • All G.
      • Sensi E.
      • Proietti A.
      • et al.
      MET exon 14 mutations in advanced lung adenocarcinoma: Frequency and coexisting alterations.
      ,
      • Clavé S.
      • Dalmases A.
      • Longarón R.
      • Pijuan L.
      • Casadevall D.
      • Taus Á.
      • et al.
      MET Exon 14 skipping mutations and gene amplifications are not simultaneous events in NSCLC.
      ]. Genomic profiling of 298 MET exon 14 NSCLC samples found concurrent MDM2 amplification in 35% of tumors [
      • Schrock A.B.
      • Frampton G.M.
      • Suh J.
      • Chalmers Z.R.
      • Rosenzweig M.
      • Erlich R.L.
      • et al.
      Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations.
      ]. In another study, overexpression of mouse double minute 2 (MDM2) or p53 protein was found in nine (60.0%) and two (13%) tumors, respectively [
      • Lee G.D.
      • Lee S.E.
      • Oh D.Y.
      • Yu D.B.
      • Jeong H.M.
      • Kim J.
      • et al.
      MET Exon 14 skipping mutations in lung adenocarcinoma: clinicopathologic implications and prognostic values.
      ]. Resistance to crizotinib has also been shown to occur due to wild-type KRAS amplification [
      • Bahcall M.
      • Awad M.M.
      • Sholl L.M.
      • Wilson F.H.
      • Xu M.
      • Wang S.
      • et al.
      Amplification of wild-type KRAS imparts resistance to crizotinib in MET exon 14 mutant non-small cell lung cancer.
      ] and KRAS G12 mutations have been found in 4% of patients with MET exon 14 mutations [
      • Suzawa K.
      • Offin M.
      • Lu D.
      • Kurzatkowski C.
      • Vojnic M.
      • Smith R.S.
      • et al.
      Activation of KRAS mediates resistance to targeted therapy in MET Exon 14-mutant non-small cell lung cancer.
      ], suggesting this pathway could be a resistance mechanism to MET TKI inhibitors [
      • Rotow J.K.
      • Gui P.
      • Wu W.
      • Raymond V.M.
      • Lanman R.B.
      • Kaye F.J.
      • et al.
      Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment in MET exon 14 skipping mutation-positive lung cancer.
      ]. Therefore, it may be necessary to combine selective MET inhibitors with other targeted therapies where co-mutations have the potential to confer resistance to MET inhibitor monotherapy [
      • Clavé S.
      • Dalmases A.
      • Longarón R.
      • Pijuan L.
      • Casadevall D.
      • Taus Á.
      • et al.
      MET Exon 14 skipping mutations and gene amplifications are not simultaneous events in NSCLC.
      ].
      Has resistance to MET inhibitors been described in patients with MET exon 14 mutation skipping? Impressive tumor responses to MET inhibitors such as crizotinib, cabozantinib, tepotinib, and capmatinib have been reported in NSCLC harboring MET exon 14 skipping [
      • Paik P.K.
      • Drilon A.
      • Fan P.D.
      • Yu H.
      • Rekhtman N.
      • Ginsberg M.S.
      • et al.
      Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.
      ,
      • Frampton G.M.
      • Ali S.M.
      • Rosenzweig M.
      • Chmielecki J.
      • Lu X.
      • Bauer T.M.
      • et al.
      Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
      ,
      • Waqar S.N.
      • Morgensztern D.
      • Sehn J.
      MET mutation associated with responsiveness to crizotinib.
      ,
      • Mendenhall M.A.
      • Goldman J.W.
      MET-mutated NSCLC with major response to crizotinib.
      ,
      • Jorge S.E.
      • Schulman S.
      • Freed J.A.
      • VanderLaan P.A.
      • Rangachari D.
      • Kobayashi S.S.
      • et al.
      Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation.
      ,
      • Drilon A.E.
      • Camidge D.R.
      • Ou S.H.I.
      • Clark J.W.
      • Socinski M.A.
      • Weiss J.
      • et al.
      Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC).
      ,
      • Klempner S.J.
      • Borghei A.
      • Hakimian B.
      • Ali S.M.
      • Ou S.I.
      Intracranial activity of cabozantinib in MET exon 14-positive NSCLC with brain metastases.
      ,

      Paik P, Veillon R, Cortot AB, Felip E, Sakai H, Mazieres J, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      ,
      • Bauer T.M.
      • Schuler M.
      • Berardi R.
      • Lim W.T.
      • Van Geel R.
      • De Jonge M.
      • et al.
      MINI01.03: Phase (Ph) I study of the safety and efficacy of the cMET inhibitor capmatinib (INC280) in patients with advanced cMET+ NSCLC: topic: medical oncology.
      ]. However, several resistance mechanisms have been reported, including additional mutations in MET exon 14 [
      • Heist R.S.
      • Sequist L.V.
      • Borger D.
      • Gainor J.F.
      • Arellano R.S.
      • Le L.P.
      • et al.
      Acquired resistance to crizotinib in NSCLC with MET Exon 14 skipping.
      ,
      • Ou S.I.
      • Young L.
      • Schrock A.B.
      • Johnson A.
      • Klempner S.J.
      • Zhu V.W.
      • et al.
      Emergence of preexisting MET Y1230C mutation as a resistance mechanism to crizotinib in NSCLC with MET Exon 14 skipping.
      ], upregulation of bypass signaling pathways, and/or the acquisition of additional oncogenic mutations. A study of mechanisms of resistance to the MET TKIs crizotinib and glesatinib reported acquired mutated MET exon 14 allele amplification or MET tyrosine kinase domain secondary site mutations and bypass track activation, including amplification of wild-type KRAS, BRAF, and/or EGFR [
      • Awad M.M.
      • Bahcall M.
      • Sholl L.M.
      • Wilson F.H.
      • Paweletz C.
      • Capelletti M.
      Mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKIs) in MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC).
      ]. Interestingly, the same study showed that one patient who acquired resistance to glesatinib through mutated MET exon 14 allele amplification reported a confirmed partial response after switching to crizotinib [
      • Awad M.M.
      • Bahcall M.
      • Sholl L.M.
      • Wilson F.H.
      • Paweletz C.
      • Capelletti M.
      Mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKIs) in MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC).
      ]. Another study of paired tumor biopsies reported resistance acquired via additional MET pathway alterations or via activation of other pathways, including EGFR and RAS [

      Guo R, Offin M, Brannon AR, Chow A, Delasos L, Somwar R, et al. Primary and acquired resistance to MET inhibiton in patients with MET exon 14-altered lung cancers. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      ]. Assessment of cell-free circulating tumor DNA from 289 patients with NSCLC harboring MET exon 14 skipping found frequent RAS-MAPK pathway alterations were associated with a lower response to MET TKIs [
      • Rotow J.K.
      • Gui P.
      • Wu W.
      • Raymond V.M.
      • Lanman R.B.
      • Kaye F.J.
      • et al.
      Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment in MET exon 14 skipping mutation-positive lung cancer.
      ]. This resistance to MET TKIs was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib. Another preclinical study, in which resistance was induced in a cell line harboring MET exon 14 skipping by exposure to high levels of MET TKIs, provided evidence that resistance to type I and II MET TKIs may often be through different pathways [
      • Fujino T.
      • Kobayashi Y.
      • Suda K.
      • Koga T.
      • Nishino M.
      • Ohara S.
      • et al.
      Sensitivity and resistance of MET Exon 14 mutations in lung cancer to eight MET tyrosine kinase inhibitors in vitro.
      ].
      Taken together, these findings suggest that mechanisms of resistance to different MET inhibitors are complex and diverse, and may vary due to differing mechanisms of action of MET inhibitors [
      • Engstrom L.D.
      • Aranda R.
      • Lee M.
      • Tovar E.A.
      • Essenburg C.J.
      • Madaj Z.
      • et al.
      Glesatinib exhibits antitumor activity in lung cancer models and patients harboring MET Exon 14 mutations and overcomes mutation-mediated resistance to type I MET inhibitors in nonclinical models.
      ]. Clearly, novel therapeutic strategies will be needed to combat multiple complex resistance mechanisms [
      • Awad M.M.
      • Bahcall M.
      • Sholl L.M.
      • Wilson F.H.
      • Paweletz C.
      • Capelletti M.
      Mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKIs) in MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC).
      ], possibly in the form of sequencing or combination approaches [
      • Rotow J.K.
      • Gui P.
      • Wu W.
      • Raymond V.M.
      • Lanman R.B.
      • Kaye F.J.
      • et al.
      Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment in MET exon 14 skipping mutation-positive lung cancer.
      ,
      • Fujino T.
      • Kobayashi Y.
      • Suda K.
      • Koga T.
      • Nishino M.
      • Ohara S.
      • et al.
      Sensitivity and resistance of MET Exon 14 mutations in lung cancer to eight MET tyrosine kinase inhibitors in vitro.
      ].
      What is the optimal position in the treatment sequence for selective MET inhibitors for patients with NSCLC harboring MET exon 14 skipping? Most patients treated with MET inhibitors in clinical studies will have received prior therapy, although ongoing studies with capmatinib, savolitinib, and tepotinib are also enrolling previously untreated patients. Data from capmatinib suggest the objective response could be higher if MET inhibitors are used for first-line treatment [

      Wolf J, Seto T, Han J-Y, Reguart N, Garon EB, Groen HJM, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      ]; however, this was not observed in the studies with tepotinib [

      Paik P, Veillon R, Cortot AB, Felip E, Sakai H, Mazieres J, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      ] or savolitinib [

      Lu S, Fang J, Li X, Zhou J, Cao L, Cheng Y, et al. Abstract 5707: Phase II Study of Savolitinib in Patients with NSCLC Harboring MET Exon 14 Skipping Mutations: Preliminary Efficacy and Safety Results. Presented at the 22nd Annual Meeting of the Chinese Society of Clinical Oncology (CSCO), Xiamen, China, 18–22 September 2019.

      ]. Confirmation of whether selective MET inhibitors are most effective in first or later lines, and as monotherapy or in combination with other therapies – including chemotherapy or immunotherapies (e.g. programmed cell death-1/PD-L1 inhibitors) – will require dedicated studies.

      Challenges ahead for trials of MET inhibitors in patients with MET exon 14 skipping tumors

      A major challenge is to identify enough patients with MET exon 14 skipping for ongoing and planned trials. The relatively low incidence of MET exon 14 mutations, estimated to be approximately 3% in NSCLC, as well as additional criteria such as poor patient health and inappropriate clinical histories, limit the number of eligible patients. Until recently, screening for MET exon 14 skipping was technically challenging. Despite being appropriate for analyzing MET overexpression [
      • Pyo J.S.
      • Kang G.
      • Cho H.
      Clinicopathological significance and diagnostic accuracy of c-MET expression by immunohistochemistry in gastric cancer: a meta-analysis.
      ], immunohistochemistry has proved unsuitable for detecting MET exon 14 skipping, as, so far, anti-MET antibodies are not able to distinguish the exon 14-skipped splice variant from wild-type MET [
      • O'Brien O.
      • Wright M.C.
      • O'Brien C.
      • Geoghegan O.
      • Leonard N.
      • Nicholson S.
      • et al.
      Cost-efficient and easy to perform PCR-based assay to identify met exon 14 skipping in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) samples.
      ]. DNA- or RNA-based approaches are more appropriate. DNA-based sequencing approaches are able to detect a range of genomic changes in the MET gene (point mutations, insertions, or deletions), any of which can interfere with the exon 14 splice sites [
      • Davies K.D.
      • Lomboy A.
      • Lawrence C.A.
      • Yourshaw M.
      • Bocsi G.T.
      • Camidge D.R.
      • et al.
      DNA-based versus RNA-based detection of MET exon 14 skipping events in lung cancer.
      ] and lead to exon 14 skipping. RNA-based approaches need only to detect the fusion of exons 13 and 15 in the transcribed product [
      • Davies K.D.
      • Lomboy A.
      • Lawrence C.A.
      • Yourshaw M.
      • Bocsi G.T.
      • Camidge D.R.
      • et al.
      DNA-based versus RNA-based detection of MET exon 14 skipping events in lung cancer.
      ]. As such, RNA in situ hybridization is possible [
      • O'Brien O.
      • Wright M.C.
      • O'Brien C.
      • Geoghegan O.
      • Leonard N.
      • Nicholson S.
      • et al.
      Cost-efficient and easy to perform PCR-based assay to identify met exon 14 skipping in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) samples.
      ], although RT-PCR-based sequencing approaches are also commonly used [
      • Davies K.D.
      • Lomboy A.
      • Lawrence C.A.
      • Yourshaw M.
      • Bocsi G.T.
      • Camidge D.R.
      • et al.
      DNA-based versus RNA-based detection of MET exon 14 skipping events in lung cancer.
      ,
      • Kim E.K.
      • Kim K.A.
      • Lee C.Y.
      • Kim S.
      • Chang S.
      • Cho B.C.
      • et al.
      Molecular diagnostic assays and clinicopathologic implications of MET exon 14 skipping mutation in non-small-cell lung cancer.
      ]. However, high-quality RNA is harder to obtain than DNA, as RNA is more susceptible to degradation [
      • Davies K.D.
      • Lomboy A.
      • Lawrence C.A.
      • Yourshaw M.
      • Bocsi G.T.
      • Camidge D.R.
      • et al.
      DNA-based versus RNA-based detection of MET exon 14 skipping events in lung cancer.
      ,
      • Pruis M.A.
      • Geurts-Giele W.R.R.
      • von der T.J.H.
      • Meijssen I.C.
      • Dinjens W.N.M.
      • Aerts J.
      • et al.
      Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer.
      ].
      Genomic analysis of resected tumor tissue has historically been the standard of care for identifying guideline-recommended biomarkers in metastatic NSCLC [
      • Leighl N.B.
      • Page R.D.
      • Raymond V.M.
      • Daniel D.B.
      • Divers S.G.
      • Reckamp K.L.
      • et al.
      Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer.
      ]. The presence of MET exon 14 skipping can now be analyzed in circulating tumor DNA or RNA extracted from patient plasma (‘liquid biopsies’). Indeed, liquid biopsies can overcome limitations imposed by tumor inaccessibility and allow the impact of therapies to be tracked over time [
      • Wan J.C.
      • Massie C.
      • Garcia-Corbacho J.
      • Mouliere F.
      • Brenton J.D.
      • Caldas C.
      • et al.
      Liquid biopsies come of age: towards implementation of circulating tumour DNA.
      ,
      • Yi X.
      • Ma J.
      • Guan Y.
      • Chen R.
      • Yang L.
      • Xia X.
      The feasibility of using mutation detection in ctDNA to assess tumor dynamics.
      ,
      • Matikas A.
      • Syrigos K.N.
      • Agelaki S.
      Circulating biomarkers in non-small-cell lung cancer: current status and future challenges.
      ]. Commercial liquid and tissue assays are now readily available for detection of MET exon 14 skipping. Assays are available that use both DNA sequencing and detection of exon 13–15 fusion in mRNA; see Table 3 for an overview of assays used in pivotal MET inhibitor NSCLC clinical trials. Other multi-gene assays are also available, as well as single tests for MET exon 14 skipping (such as NeoGenomics MET Exon 14 Deletion Analysis) [

      NeoGenomics Laboratories. MET Exon 14 Deletion Analysis, https://neogenomics.com/test-menu/met-exon-14-deletion-analysis; 2016 [accessed 12 February 2020].

      ].
      Table 3Comparison of assays for detecting MET exon 14 skipping used in pivotal trials in patients with NSCLC.
      CategoryFoundationOne® Liquid

      Foundation Medicine. Genomic Testing – FOUNDATIONONE®LIQUID, https://www.foundationmedicine.com/genomic-testing/foundation-one-liquid; 2018 [accessed 12 February 2020].

      FoundationOne® CDx

      Foundation Medicine. Genomic Testing – FOUNDATIONONE®CDx, https://www.foundationmedicine.com/genomic-testing/foundation-one-cdx; 2017 [accessed 18 March 2020].

      Archer® LiquidPlex™

      ArcherDX. Products – Liquid Biopsy Tests – LIQUIDPlex™, https://archerdx.com/liquidplex/; 2019 [accessed 4 March 2020].

      Archer® FusionPlex™ Lung

      ArcherDX. Products – Lung, https://archerdx.com/lung/; 2018 [accessed 12 February 2020].

      Guardant360®
      • Kim S.T.
      • Banks K.C.
      • Lee S.-H.
      • Kim K.
      • Park J.O.
      • Park S.H.
      • et al.
      Prospective feasibility study for using cell-free circulating tumor DNA–guided therapy in refractory metastatic solid cancers: an interim analysis.
      Oncomine Focus Assay

      Thermo Fisher Scientific Inc. An approach for establishing Oncomine Focus Assay performance, https://tools.thermofisher.com/content/sfs/brochures/oncomine-focus-assay-performance-white-paper.pdf; 2016 [accessed 4 March 2020].

      PlasmaSELECT™ 64

      Personal Genome Diagnostics. CAP/CLIA Services, https://www.personalgenome.com/cap-clia; 2019 [accessed 18 March 2020].

      Biopsy typeLiquid biopsyTissue biopsyLiquid biopsyTumor biopsyLiquid biopsyTumor biopsyLiquid biopsy
      Material readCirculating tumor DNATumor DNACirculating free DNATumor mRNACirculating free DNATumor DNA or mRNACirculating tumor DNA
      Sample required2 × 8.5 mL blood samples50–1000 ng DNA5–10 ng DNAFFPE tissue;

      20–250 ng DNA
      10 mL blood sample for

      5–30 ng DNA
      FFPE tissue;

      7 um thick and > 5 mm2
      2 × 10 mL blood samples
      Number of genes interrogated70 genes324 genes28 genes14 genes73 genes52 genes64 genes
      SensitivityCan detect mutations if present in > 0.5% sampleCan detect mutation that represents 2–5% allele frequencyCan detect mutations if present in

      > 1% sample
      Not reportedCan detect mutations if present in > 0.1% sample100% detection if mutation is

      > 5% allele frequency
      Not reported
      Turnaround time< 2 weeks< 2 weeksNot reportedNot reported7 days3 daysNot reported
      DNA: deoxyribonucleic acid; FFPE: formalin-fixed paraffin-embedded; mRNA: messenger RNA.
      The ongoing VISION trial of tepotinib is prospectively recruiting patients with tumors that are positive for MET exon 14 as assessed by liquid biopsy testing or tissue biopsy testing (NCT02864992). In addition to the diagnostic techniques described above, it would be useful to identify clinicopathologic features that may help to characterize a patient population with MET exon 14 skipping, who would most likely be amenable to treatment with selective MET TKIs. Numerous studies suggest that patients with tumors harboring MET exon 14 mutations tend to be of older age (median age 72–73 years in most studies) [
      • Schrock A.B.
      • Frampton G.M.
      • Suh J.
      • Chalmers Z.R.
      • Rosenzweig M.
      • Erlich R.L.
      • et al.
      Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations.
      ,
      • Tong J.H.
      • Yeung S.F.
      • Chan A.W.
      • Chung L.Y.
      • Chau S.L.
      • Lung R.W.
      • et al.
      MET amplification and exon 14 splice site mutation define unique molecular subgroups of Non-small Cell Lung Carcinoma with poor prognosis.
      ,

      Wolf W, Baik C, Heist RS, Neal JW, Mansfield AS, Buettner R, et al. Natural history, treatment (Tx) patterns, and outcomes in MET dysregulated non-small cell lung cancer (NSCLC) patients (Pts). Presented at the EORTC/AACR/NCI symposium (ENA), Dublin, Ireland; 13–16 November 2018.

      ,
      • Lee G.D.
      • Lee S.E.
      • Oh D.Y.
      • Yu D.B.
      • Jeong H.M.
      • Kim J.
      • et al.
      MET Exon 14 skipping mutations in lung adenocarcinoma: clinicopathologic implications and prognostic values.
      ,
      • Awad M.M.
      • Leonardi G.C.
      • Kravets S.
      • Dahlberg S.E.
      • Drilon A.E.
      • Noonan S.
      • et al.
      Impact of MET inhibitors on survival among patients (pts) with MET exon 14 mutant (METdel14) non-small cell lung cancer (NSCLC).
      ,
      • Awad M.M.
      • Oxnard G.R.
      • Jackman D.M.
      • Savukoski D.O.
      • Hall D.
      • Shivdasani P.
      • et al.
      MET Exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-met overexpression.
      ,
      • Reungwetwattana T.
      • Liang Y.
      • Zhu V.
      • Ou S.I.
      The race to target MET exon 14 skipping alterations in non-small cell lung cancer: the why, the how, the who, the unknown, and the inevitable.
      ,
      • Zheng D.
      • Wang R.
      • Ye T.
      • Yu S.
      • Hu H.
      • Shen X.
      • et al.
      MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer.
      ]. Consequently, screening for MET exon 14 skipping in elderly patients may be particularly beneficial [

      Reckamp KL. New drugs and resistance: have we MET Expectations? Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      ]. Likewise, MET exon 14 mutations appear to be enriched in tumors with sarcomatoid carcinoma [
      • Schrock A.B.
      • Frampton G.M.
      • Suh J.
      • Chalmers Z.R.
      • Rosenzweig M.
      • Erlich R.L.
      • et al.
      Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations.
      ,
      • Tong J.H.
      • Yeung S.F.
      • Chan A.W.
      • Chung L.Y.
      • Chau S.L.
      • Lung R.W.
      • et al.
      MET amplification and exon 14 splice site mutation define unique molecular subgroups of Non-small Cell Lung Carcinoma with poor prognosis.
      ,
      • Awad M.M.
      • Leonardi G.C.
      • Kravets S.
      • Dahlberg S.E.
      • Drilon A.E.
      • Noonan S.
      • et al.
      Impact of MET inhibitors on survival among patients (pts) with MET exon 14 mutant (METdel14) non-small cell lung cancer (NSCLC).
      ], and some studies suggest that they are most commonly identified in females, non-smokers, and at an earlier pathology stage [
      • Awad M.M.
      • Leonardi G.C.
      • Kravets S.
      • Dahlberg S.E.
      • Drilon A.E.
      • Noonan S.
      • et al.
      Impact of MET inhibitors on survival among patients (pts) with MET exon 14 mutant (METdel14) non-small cell lung cancer (NSCLC).
      ,
      • Zheng D.
      • Wang R.
      • Ye T.
      • Yu S.
      • Hu H.
      • Shen X.
      • et al.
      MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer.
      ]. The baseline characteristics of patients with NSCLC harboring MET exon 14 skipping enrolled in pivotal clinical trials for MET TKIs broadly reflect the characteristics described above (Table 2). Patients in these trials were older in age (69–74 years) and approximately 50% had a smoking history (36–62%), although proportions of female:male patients were quite variable, with the crizotinib and capmatinib trials enrolling more female patients than the savolitinib and tepotinib trials.

      Conclusions

      MET has been pursued as a therapeutic cancer target for many years, but phase III trials of MET inhibitors in patients with solid tumors, including NSCLC, have been largely disappointing [
      • Wu Y.L.
      • Soo R.A.
      • 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?.
      ]. One possible reason for trials failing to meet their efficacy endpoints is the inclusion of patients with MET aberrations that are dispensable for tumor growth and thus insensitive to MET inhibition. MET exon 14 mutations have been identified as primary oncogenic drivers, raising the possibility that tumors with these specific mutations will be largely sensitive to MET inhibitors, as supported by clinical evidence with non-selective MET TKIs. If MET activity is a primary driver of MET exon 14 mutation-positive tumor growth, there is good reason to suppose that selective MET inhibitors have the potential to deliver better efficacy with a favorable safety profile.

      Acknowledgments

      The authors thank Bioscript, Macclesfield, UK for providing medical writing support, which was funded by Merck KGaA , Darmstadt, Germany, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

      Funding

      This work was supported by Merck KGaA, Darmstadt, Germany . No grant number is applicable.

      Declaration of Competing Interest

      JS and CS are employees of Merck KGaA, Darmstadt, Germany. EF reports consulting, advisory or speaker’s bureau roles with AbbVie, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, and Touchtime. RS and MS report no conflicts of interest.

      References

        • Kim K.H.
        • Kim H.
        Progress of antibody-based inhibitors of the HGF-cMET axis in cancer therapy.
        Exp Mol Med. 2017; 49e307https://doi.org/10.1038/emm.2017.17
        • Ma Y.
        • Zhang M.
        • Wang J.
        • Huang X.
        • Kuai X.
        • Zhu X.
        • et al.
        High-affinity human anti-c-met IgG conjugated to oxaliplatin as targeted chemotherapy for hepatocellular carcinoma.
        Front Oncol. 2019; 9: 717https://doi.org/10.3389/fonc.2019.00717
        • Catenacci D.V.T.
        • Tebbutt N.C.
        • Davidenko I.
        • Murad A.M.
        • Al-Batran S.E.
        • Ilson D.H.
        • et al.
        Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2017; 18: 1467-1482https://doi.org/10.1016/S1470-2045(17)30566-1
        • Spigel D.R.
        • Edelman M.J.
        • O'Byrne K.
        • Paz-Ares L.
        • Mocci S.
        • Phan S.
        • et al.
        Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung.
        J Clin Oncol. 2017; 35: 412-420https://doi.org/10.1200/JCO.2016.69.2160
        • Strickler J.H.
        • Weekes C.D.
        • Nemunaitis J.
        • Ramanathan R.K.
        • Heist R.S.
        • Morgensztern D.
        • et al.
        First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody-drug conjugate targeting c-met, in patients with advanced solid tumors.
        J Clin Oncol. 2018; 36: 3298-3306https://doi.org/10.1200/JCO.2018.78.7697
        • Heist R.S.
        • Motwani M.
        • Barlesi F.
        • Goldman J.W.
        • Kelly K.
        • Sun Y.
        • et al.
        c-Met expression and response to telisotuzumab vedotin (teliso-v) in patients with non-small cell lung cancer.
        J Clin Oncol. 2019; 37: 9023https://doi.org/10.1200/JCO.2019.37.15_suppl.9023
        • Ocampo C.
        • Wu J.
        • Dey J.
        • Sun Z.
        • Motwani M.
        • Reddy A.
        • et al.
        Phase 2 study of telisotuzumab vedotin (Teliso-V) in previously treated c-MET+ non-small cell lung cancer: trial in progress.
        J Thorac Oncol. 2019; P2.01-19: S646https://doi.org/10.1016/j.jtho.2019.08.1363
        • Wang W.X.
        • Xu C.
        • Chen Y.
        • Zhu Y.-C.
        • Liu Y.
        • Wang H.
        • et al.
        MET gene fusions in non-small cell lung cancer (NSCLC) in the Chinese population: A multicenter study.
        J Clin Oncol. 2018; 36: e13539https://doi.org/10.1200/JCO.2018.36.15_suppl.e13539
        • Yu L.
        • Wu Y.
        • Zhang B.
        • Ma R.
        • Yan N.
        • Mou H.
        Tumor heterogeneity with novel MET fusion showed different response to cabozantinib in non-small cell lung cancer.
        Int J Clin Exp Med. 2019; 12: 10983-10986
        • Gow C.-H.
        • Liu Y.-N.
        • Li H.-Y.
        • Hsieh M.-S.
        • Chang S.-H.
        • Luo S.-C.
        • et al.
        Oncogenic function of a KIF5B-MET fusion variant in non-small cell lung cancer.
        Neoplasia. 2018; 20: 838-847https://doi.org/10.1016/j.neo.2018.06.007
        • Zhang J.
        • Babic A.
        Regulation of the MET oncogene: molecular mechanisms.
        Carcinogenesis. 2016; 37: 345-355https://doi.org/10.1093/carcin/bgw015
        • Gentile A.
        • Trusolino L.
        • Comoglio P.M.
        The Met tyrosine kinase receptor in development and cancer.
        Cancer Metastasis Rev. 2008; 27: 85-94https://doi.org/10.1007/s10555-007-9107-6
        • Garajova I.
        • Giovannetti E.
        • Biasco G.
        • Peters G.J.
        c-Met as a target for personalized therapy.
        Transl Oncogenom. 2015; 7: 13-31https://doi.org/10.4137/TOG.S30534
        • Huang L.
        • Fu L.
        Mechanisms of resistance to EGFR tyrosine kinase inhibitors.
        Acta Pharm Sin B. 2015; 5: 390-401https://doi.org/10.1016/j.apsb.2015.07.001
        • Chang K.
        • Karnad A.
        • Zhao S.
        • Freeman J.W.
        Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets.
        Oncotarget. 2015; 6: 3507-3518
        • Paik P.K.
        • Drilon A.
        • Fan P.D.
        • Yu H.
        • Rekhtman N.
        • Ginsberg M.S.
        • et al.
        Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.
        Cancer Discov. 2015; 5: 842-849https://doi.org/10.1158/2159-8290.CD-14-1467
        • Cecchi F.
        • Rabe D.C.
        • Bottaro D.P.
        Targeting the HGF/Met signaling pathway in cancer therapy.
        Expert Opin Ther Targets. 2012; 16: 553-572https://doi.org/10.1517/14728222.2012.680957
        • Tan Y.C.
        • Mirzapoiazova T.
        • Won B.M.
        • Zhu L.
        • Srivastava M.K.
        • Vokes E.E.
        • et al.
        Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL.
        Sci Rep. 2017; 7: 9192https://doi.org/10.1038/s41598-017-09078-4
        • Trusolino L.
        • Bertotti A.
        • Comoglio P.M.
        MET signalling: principles and functions in development, organ regeneration and cancer.
        Nat Rev Mol Cell Biol. 2010; 11: 834-848https://doi.org/10.1038/nrm3012
        • Ma P.C.
        • Tretiakova M.S.
        • MacKinnon A.C.
        • Ramnath N.
        • Johnson C.
        • Dietrich S.
        • et al.
        Expression and mutational analysis of MET in human solid cancers.
        Genes Chromosomes Cancer. 2008; 47: 1025-1037https://doi.org/10.1002/gcc.20604
        • Boccaccio C.
        • Comoglio P.M.
        Invasive growth: a MET-driven genetic programme for cancer and stem cells.
        Nat Rev Cancer. 2006; 6: 637-645https://doi.org/10.1038/nrc1912
      1. Atlas of Genetics and Cytogenetics in Oncology and Haematology. MET met proto-oncogene (hepatocyte growth factor receptor), http://atlasgeneticsoncology.org//Genes/METID131.html; 2001 [accessed 15 January 2020].

        • Ma P.C.
        • Jagadeeswaran R.
        • Jagadeesh S.
        • Tretiakova M.S.
        • Nallasura V.
        • Fox E.A.
        • et al.
        Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer.
        Cancer Res. 2005; 65: 1479-1488https://doi.org/10.1158/0008-5472.can-04-2650
        • Ma P.C.
        • Kijima T.
        • Maulik G.
        • Fox E.A.
        • Sattler M.
        • Griffin J.D.
        • et al.
        c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions.
        Cancer Res. 2003; 63: 6272-6281
        • Kong-Beltran M.
        • Seshagiri S.
        • Zha J.
        • Zhu W.
        • Bhawe K.
        • Mendoza N.
        • et al.
        Somatic mutations lead to an oncogenic deletion of met in lung cancer.
        Cancer Res. 2006; 66: 283-289https://doi.org/10.1158/0008-5472.can-05-2749
        • Frampton G.M.
        • Ali S.M.
        • Rosenzweig M.
        • Chmielecki J.
        • Lu X.
        • Bauer T.M.
        • et al.
        Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
        Cancer Discov. 2015; 5: 850-859https://doi.org/10.1158/2159-8290.cd-15-0285
        • Cortot A.B.
        • Kherrouche Z.
        • Descarpentries C.
        • Wislez M.
        • Baldacci S.
        • Furlan A.
        • et al.
        Exon 14 deleted MET receptor as a new biomarker and target in cancers.
        J Natl Cancer Inst. 2017; 109: djw262https://doi.org/10.1093/jnci/djw262
        • Lee J.
        • Ou S.H.
        • Lee J.M.
        • Kim H.C.
        • Hong M.
        • Kim S.Y.
        • et al.
        Gastrointestinal malignancies harbor actionable MET exon 14 deletions.
        Oncotarget. 2015; 6: 28211-28222
        • Gherardi E.
        • Birchmeier W.
        • Birchmeier C.
        • Vande Woude G.
        Targeting MET in cancer: rationale and progress.
        Nat Rev Cancer. 2012; 12: 89-103https://doi.org/10.1038/nrc3205
        • Ma P.C.
        MET receptor juxtamembrane exon 14 alternative spliced variant: novel cancer genomic predictive biomarker.
        Cancer Discov. 2015; 5: 802-805https://doi.org/10.1158/2159-8290.cd-15-0769
        • Togashi Y.
        • Mizuuchi H.
        • Tomida S.
        • Terashima M.
        • Hayashi H.
        • Nishio K.
        • et al.
        MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor.
        Lung Cancer. 2015; 90: 590-597https://doi.org/10.1016/j.lungcan.2015.10.020
        • Pilotto S.
        • Gkountakos A.
        • Carbognin L.
        • Scarpa A.
        • Tortora G.
        • Bria E.
        MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy.
        Ann Transl Med. 2017; 5: 2
        • Hu C.T.
        Screening of c-Met-positive hepatocellular carcinoma for c-Met-based target therapy.
        Hepatol Int. 2016; 10: S286https://doi.org/10.1007/s12072-016-9707-8
        • Lu X.
        • Peled N.
        • Greer J.
        • Wu W.
        • Choi P.
        • Berger A.H.
        • et al.
        MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma.
        Cancer Res. 2017; 77: 4498-4505https://doi.org/10.1158/0008-5472.CAN-16-1944
        • Schrock A.B.
        • Frampton G.M.
        • Suh J.
        • Chalmers Z.R.
        • Rosenzweig M.
        • Erlich R.L.
        • et al.
        Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations.
        J Thorac Oncol. 2016; 11: 1493-1502https://doi.org/10.1016/j.jtho.2016.06.004
        • Tong J.H.
        • Yeung S.F.
        • Chan A.W.
        • Chung L.Y.
        • Chau S.L.
        • Lung R.W.
        • et al.
        MET amplification and exon 14 splice site mutation define unique molecular subgroups of Non-small Cell Lung Carcinoma with poor prognosis.
        Clin Cancer Res. 2016; 22: 3048-3056https://doi.org/10.1158/1078-0432.ccr-15-2061
        • Awad M.M.
        • Leonardi G.C.
        • Kravets S.
        • Dahlberg S.E.
        • Drilon A.
        • Noonan S.A.
        • et al.
        Impact of MET inhibitors on survival among patients with non-small cell lung cancer harboring MET exon 14 mutations: a retrospective analysis.
        Lung Cancer. 2019; 133: 96-102https://doi.org/10.1016/j.lungcan.2019.05.011
      2. Wolf W, Baik C, Heist RS, Neal JW, Mansfield AS, Buettner R, et al. Natural history, treatment (Tx) patterns, and outcomes in MET dysregulated non-small cell lung cancer (NSCLC) patients (Pts). Presented at the EORTC/AACR/NCI symposium (ENA), Dublin, Ireland; 13–16 November 2018.

        • Lee G.D.
        • Lee S.E.
        • Oh D.Y.
        • Yu D.B.
        • Jeong H.M.
        • Kim J.
        • et al.
        MET Exon 14 skipping mutations in lung adenocarcinoma: clinicopathologic implications and prognostic values.
        J Thorac Oncol. 2017; 12: 1233-1246https://doi.org/10.1016/j.jtho.2017.04.031
        • Liu S.Y.
        • Gou L.Y.
        • Li A.N.
        • Lou N.N.
        • Gao H.F.
        • Su J.
        • et al.
        The unique characteristics of MET Exon 14 mutation in Chinese patients with NSCLC.
        J Thorac Oncol. 2016; 11: 1503-1510https://doi.org/10.1016/j.jtho.2016.05.016
        • Engstrom L.D.
        • Aranda R.
        • Lee M.
        • Tovar E.A.
        • Essenburg C.J.
        • Madaj Z.
        • et al.
        Glesatinib exhibits antitumor activity in lung cancer models and patients harboring MET Exon 14 mutations and overcomes mutation-mediated resistance to type I MET inhibitors in nonclinical models.
        Clin Cancer Res. 2017; 23: 6661-6672https://doi.org/10.1158/1078-0432.ccr-17-1192
      3. Cecchi F, Rabizadeh S, Weingarten P, Tsai C, Zhou L, Hembrough T. MET activation via exon 14 skipping mutations (METex14del): gastrointestinal prevalence and sensitivity to MET inhibitor AMG337. Ann Oncol 2016;27(suppl_2):ii11. Abstract P-038. https://doi.org/10.1093/annonc/mdw199.36.

        • Bladt F.
        • Faden B.
        • Friese-Hamim M.
        • Knuehl C.
        • Wilm C.
        • Fittschen C.
        • et al.
        EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors.
        Clin Cancer Res. 2013; 19: 2941-2951https://doi.org/10.1158/1078-0432.CCR-12-3247
        • Leprieur E.G.
        • Fallet V.
        • Cadranel J.
        • Wislez M.
        Spotlight on crizotinib in the first-line treatment of ALK-positive advanced non-small-cell lung cancer: patients selection and perspectives.
        Lung Cancer (Auckl). 2016; 7: 83-90https://doi.org/10.2147/lctt.s99303
        • Waqar S.N.
        • Morgensztern D.
        • Sehn J.
        MET mutation associated with responsiveness to crizotinib.
        J Thorac Oncol. 2015; 10: e29-e31https://doi.org/10.1097/jto.0000000000000478
        • Mendenhall M.A.
        • Goldman J.W.
        MET-mutated NSCLC with major response to crizotinib.
        J Thorac Oncol. 2015; 10: e33-e34https://doi.org/10.1097/jto.0000000000000491
        • Jorge S.E.
        • Schulman S.
        • Freed J.A.
        • VanderLaan P.A.
        • Rangachari D.
        • Kobayashi S.S.
        • et al.
        Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation.
        Lung Cancer. 2015; 90: 369-374https://doi.org/10.1016/j.lungcan.2015.10.028
        • Drilon A.E.
        • Camidge D.R.
        • Ou S.H.I.
        • Clark J.W.
        • Socinski M.A.
        • Weiss J.
        • et al.
        Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC).
        J Clin Oncol. 2016; 34: 108https://doi.org/10.1200/JCO.2016.34.15_suppl.108
        • Drilon A.
        • Clark J.W.
        • Weiss J.
        • Ou S.I.
        • Camidge D.R.
        • Solomon B.J.
        • et al.
        Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration.
        Nat Med. 2020; 26: 47-51https://doi.org/10.1038/s41591-019-0716-8
      4. Pfizer. Pfizer’s XALKORI® (crizotinib) Receives FDA Breakthrough Therapy Designation in Two New Indications, https://www.pfizer.com/news/press-release/press-release-detail/pfizer_s_xalkori_crizotinib_receives_fda_breakthrough_therapy_designation_in_two_new_indications-0; 2018 [accessed 15 January 2020].

        • Moro-Sibilot D.
        • Cozic N.
        • Perol M.
        • Mazieres J.
        • Otto J.
        • Souquet P.J.
        • et al.
        Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSe phase II trial.
        Ann Oncol. 2019; 30: 1985-1991https://doi.org/10.1093/annonc/mdz407
      5. Landi L, Chiari R, Tiseo M, D'Incà F, Dazzi C, Chella A, et al. Crizotinib in MET deregulated or ROS1 rearranged pretreated non-small-cell lung cancer (METROS): a phase II, prospective, multicentre, two-arms trial. Clin Cancer Res 2019:clincanres.0994.2019. https://doi.org/10.1158/1078-0432.Ccr-19-0994.

      6. Shimokawa M, Nosaki K, Seto T, Ohashi K, Morise M, Fujiwara Y, et al. Phase II study of crizotinib in Japanese patients with advanced non-small cell lung cancer harboring a MET gene alteration: Co-MET study. Ann Oncol 2019;30(suppl_2):mdz063.79. Abstract 181TiP. https://doi.org/10.1093/annonc/mdz063.079.

        • Klempner S.J.
        • Borghei A.
        • Hakimian B.
        • Ali S.M.
        • Ou S.I.
        Intracranial activity of cabozantinib in MET exon 14-positive NSCLC with brain metastases.
        J Thorac Oncol. 2017; 12: 152-156https://doi.org/10.1016/j.jtho.2016.09.127
        • Wang S.X.Y.
        • Zhang B.M.
        • Wakelee H.A.
        • Koontz M.Z.
        • Pan M.
        • Diehn M.
        • et al.
        Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib.
        Anticancer Drugs. 2019; 30: 537-541https://doi.org/10.1097/CAD.0000000000000765
        • He A.R.
        • Cohen R.B.
        • Denlinger C.S.
        • Sama A.
        • Birnbaum A.
        • Hwang J.
        • et al.
        First-in-human phase I study of merestinib, an oral multikinase inhibitor, in patients with advanced cancer.
        Oncologist. 2019; 24: e930-e942https://doi.org/10.1634/theoncologist.2018-0411
        • Awad M.M.
        • Leonardi G.C.
        • Kravets S.
        • Dahlberg S.E.
        • Drilon A.E.
        • Noonan S.
        • et al.
        Impact of MET inhibitors on survival among patients (pts) with MET exon 14 mutant (METdel14) non-small cell lung cancer (NSCLC).
        J Clin Oncol. 2017; 35: 8511https://doi.org/10.1200/JCO.2017.35.15_suppl.8511
        • Mazieres J.
        • Drilon A.
        • Lusque A.
        • Mhanna L.
        • Cortot A.B.
        • Mezquita L.
        • et al.
        Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.
        Ann Oncol. 2019; 30: 1321-1328https://doi.org/10.1093/annonc/mdz167
        • Sabari J.K.
        • Leonardi G.C.
        • Shu C.A.
        • Umeton R.
        • Montecalvo J.
        • Ni A.
        • et al.
        PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers.
        Ann Oncol. 2018; 29: 2085-2091https://doi.org/10.1093/annonc/mdy334
        • Liu X.
        • Wang Q.
        • Yang G.
        • Marando C.
        • Koblish H.K.
        • Hall L.M.
        • et al.
        A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3.
        Clin Cancer Res. 2011; 17: 7127-7138https://doi.org/10.1158/1078-0432.CCR-11-1157
        • Baltschukat S.
        • Engstler B.S.
        • Huang A.
        • Hao H.-X.
        • Tam A.
        • Wang H.Q.
        • et al.
        Capmatinib (INC280) Is Active Against Models of Non-Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation.
        Clin Cancer Res. 2019; 25: 3164-3175https://doi.org/10.1158/1078-0432.ccr-18-2814
      7. Schuler M, Berardi R, Lim W-T, de Jonge M, Bauer TM, Azaro A, et al. Phase I dose expansion results from a multicenter, open-label study of the MET inhibitor capmatinib (INC280) in adult patients with MET-dysregulated advanced NSCLC. Presented at the EORTC/AACR/NCI symposium (ENA), Dublin, Ireland, 13–16 November 2018.

      8. Wolf J, Seto T, Han J-Y, Reguart N, Garon EB, Groen HJM, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      9. Novartis. Novartis Shows Growing Strength in Lung Cancer Innovation with New Capmatinib Investigational Data and Novel Canakinumab Clinical Trials, https://www.novartis.com/news/media-releases/novartis-shows-growing-strength-lung-cancer-innovation-new-capmatinib-investigational-data-and-novel-canakinumab-clinical-trials; 2019 [accessed 15 January 2020].

      10. Barry E, Henry R, Borodovsky A, Maloney E, Ladd B, Frigault M, et al. Activity of Savolitinib against MET Ex14 mutations and resistance to METi through decoupling from MYC expression. Presented at the American Association of Cancer Research (AACR) Annual Meeting, New Orleans, Louisiana, USA, 16–20 April 2016.

      11. Lu S, Fang J, Li X, Zhou J, Cao L, Cheng Y, et al. Abstract 5707: Phase II Study of Savolitinib in Patients with NSCLC Harboring MET Exon 14 Skipping Mutations: Preliminary Efficacy and Safety Results. Presented at the 22nd Annual Meeting of the Chinese Society of Clinical Oncology (CSCO), Xiamen, China, 18–22 September 2019.

        • Shih J.
        • Zhong B.
        • Shi H.
        • Xue D.
        • Choy G.S.
        • Redkar S.
        Bozitinib, a highly selective inhibitor of cMet, demonstrates robust activity in gastric, lung, hepatic and pancreatic in vivo models.
        Cancer Res. 2017; 77 (Abstract 2096)https://doi.org/10.1158/1538-7445.AM2017-2096
        • Hu H.
        • Mu Q.
        • Bao Z.
        • Chen Y.
        • Liu Y.
        • Chen J.
        • et al.
        Mutational landscape of secondary glioblastoma guides MET-targeted trial in brain tumor.
        Cell. 2018; 175: 1665-1678https://doi.org/10.1016/j.cell.2018.09.038
      12. Paik P, Veillon R, Cortot AB, Felip E, Sakai H, Mazieres J, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

      13. Merck KGaA. TEPMETKO (Tepotinib) Approved in Japan for Advanced NSCLC with METex14 Skipping Alterations, https://www.merckgroup.com/en/news/tepotinib-25-03-2020.html; 2020 [accessed 25 March 2020].

      14. ArcherDX. ArcherDX Receives Approval for Archer®MET Companion Diagnostic for TEPMETKO® (Tepotinib) in Advanced Non-Small Cell Lung Cancer in Japan, https://archerdx.com/archerdx-receives-approval-for-archermet-companion-diagnostic-for-tepmetko-tepotinib-in-advanced-non-small-cell-lung-cancer-in-japan; 2020 [accessed 25 March 2020].

      15. Merck KGaA. Merck Announces FDA Breakthrough Therapy Designation for Investigational Therapy Tepotinib in Patients with Metastatic NSCLC with METex14 Skipping Alterations, https://www.merckgroup.com/en/news/tepotinib-breakthrough-therapy-designation-11-09-2019.html; 2019 [accessed 15 January 2020].

        • Bruno R.
        • Lupi C.
        • Landi L.
        • All G.
        • Sensi E.
        • Proietti A.
        • et al.
        MET exon 14 mutations in advanced lung adenocarcinoma: Frequency and coexisting alterations.
        J Clin Oncol. 2017; 35e20656https://doi.org/10.1200/JCO.2017.35.15_suppl.e20656
        • Clavé S.
        • Dalmases A.
        • Longarón R.
        • Pijuan L.
        • Casadevall D.
        • Taus Á.
        • et al.
        MET Exon 14 skipping mutations and gene amplifications are not simultaneous events in NSCLC.
        J Thorac Oncol. 2017; 12: S516-S517https://doi.org/10.1016/j.jtho.2016.11.632
        • Bahcall M.
        • Awad M.M.
        • Sholl L.M.
        • Wilson F.H.
        • Xu M.
        • Wang S.
        • et al.
        Amplification of wild-type KRAS imparts resistance to crizotinib in MET exon 14 mutant non-small cell lung cancer.
        Clin Cancer Res. 2018; 24: 5963-5976https://doi.org/10.1158/1078-0432.CCR-18-0876
        • Suzawa K.
        • Offin M.
        • Lu D.
        • Kurzatkowski C.
        • Vojnic M.
        • Smith R.S.
        • et al.
        Activation of KRAS mediates resistance to targeted therapy in MET Exon 14-mutant non-small cell lung cancer.
        Clin Cancer Res. 2019; 25: 1248-1260https://doi.org/10.1158/1078-0432.CCR-18-1640
        • Rotow J.K.
        • Gui P.
        • Wu W.
        • Raymond V.M.
        • Lanman R.B.
        • Kaye F.J.
        • et al.
        Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment in MET exon 14 skipping mutation-positive lung cancer.
        Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-1667
        • Bauer T.M.
        • Schuler M.
        • Berardi R.
        • Lim W.T.
        • Van Geel R.
        • De Jonge M.
        • et al.
        MINI01.03: Phase (Ph) I study of the safety and efficacy of the cMET inhibitor capmatinib (INC280) in patients with advanced cMET+ NSCLC: topic: medical oncology.
        J Thorac Oncol. 2016; 11: S257-S258https://doi.org/10.1016/j.jtho.2016.09.018
        • Heist R.S.
        • Sequist L.V.
        • Borger D.
        • Gainor J.F.
        • Arellano R.S.
        • Le L.P.
        • et al.
        Acquired resistance to crizotinib in NSCLC with MET Exon 14 skipping.
        J Thorac Oncol. 2016; 11: 1242-1245https://doi.org/10.1016/j.jtho.2016.06.013
        • Ou S.I.
        • Young L.
        • Schrock A.B.
        • Johnson A.
        • Klempner S.J.
        • Zhu V.W.
        • et al.
        Emergence of preexisting MET Y1230C mutation as a resistance mechanism to crizotinib in NSCLC with MET Exon 14 skipping.
        J Thorac Oncol. 2017; 12: 137-140https://doi.org/10.1016/j.jtho.2016.09.119
        • Awad M.M.
        • Bahcall M.
        • Sholl L.M.
        • Wilson F.H.
        • Paweletz C.
        • Capelletti M.
        Mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKIs) in MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC).
        J Clin Oncol. 2018; 36: 9069https://doi.org/10.1200/JCO.2018.36.15_suppl.9069
      16. Guo R, Offin M, Brannon AR, Chow A, Delasos L, Somwar R, et al. Primary and acquired resistance to MET inhibiton in patients with MET exon 14-altered lung cancers. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

        • Fujino T.
        • Kobayashi Y.
        • Suda K.
        • Koga T.
        • Nishino M.
        • Ohara S.
        • et al.
        Sensitivity and resistance of MET Exon 14 mutations in lung cancer to eight MET tyrosine kinase inhibitors in vitro.
        J Thorac Oncol. 2019; 14: 1753-1765https://doi.org/10.1016/j.jtho.2019.06.023
        • Pyo J.S.
        • Kang G.
        • Cho H.
        Clinicopathological significance and diagnostic accuracy of c-MET expression by immunohistochemistry in gastric cancer: a meta-analysis.
        J Gastric Cancer. 2016; 16: 141-151https://doi.org/10.5230/jgc.2016.16.3.141
        • O'Brien O.
        • Wright M.C.
        • O'Brien C.
        • Geoghegan O.
        • Leonard N.
        • Nicholson S.
        • et al.
        Cost-efficient and easy to perform PCR-based assay to identify met exon 14 skipping in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) samples.
        Diagnostics (Basel). 2019; 9https://doi.org/10.3390/diagnostics9010013
        • Davies K.D.
        • Lomboy A.
        • Lawrence C.A.
        • Yourshaw M.
        • Bocsi G.T.
        • Camidge D.R.
        • et al.
        DNA-based versus RNA-based detection of MET exon 14 skipping events in lung cancer.
        J Thorac Oncol. 2019; 14: 737-741https://doi.org/10.1016/j.jtho.2018.12.020
        • Kim E.K.
        • Kim K.A.
        • Lee C.Y.
        • Kim S.
        • Chang S.
        • Cho B.C.
        • et al.
        Molecular diagnostic assays and clinicopathologic implications of MET exon 14 skipping mutation in non-small-cell lung cancer.
        Clin Lung Cancer. 2019; 20: e123-e132https://doi.org/10.1016/j.cllc.2018.10.004
        • Pruis M.A.
        • Geurts-Giele W.R.R.
        • von der T.J.H.
        • Meijssen I.C.
        • Dinjens W.N.M.
        • Aerts J.
        • et al.
        Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer.
        Lung Cancer. 2020; 140: 46-54https://doi.org/10.1016/j.lungcan.2019.11.010
        • Leighl N.B.
        • Page R.D.
        • Raymond V.M.
        • Daniel D.B.
        • Divers S.G.
        • Reckamp K.L.
        • et al.
        Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer.
        Clin Cancer Res. 2019; 25: 4691-4700https://doi.org/10.1158/1078-0432.CCR-19-0624
        • Wan J.C.
        • Massie C.
        • Garcia-Corbacho J.
        • Mouliere F.
        • Brenton J.D.
        • Caldas C.
        • et al.
        Liquid biopsies come of age: towards implementation of circulating tumour DNA.
        Nat Rev Cancer. 2017; 17: 223-238https://doi.org/10.1038/nrc.2017.7
        • Yi X.
        • Ma J.
        • Guan Y.
        • Chen R.
        • Yang L.
        • Xia X.
        The feasibility of using mutation detection in ctDNA to assess tumor dynamics.
        Int J Cancer. 2017; 140: 2642-2647https://doi.org/10.1002/ijc.30620
        • Matikas A.
        • Syrigos K.N.
        • Agelaki S.
        Circulating biomarkers in non-small-cell lung cancer: current status and future challenges.
        Clin Lung Cancer. 2016; 17: 507-516https://doi.org/10.1016/j.cllc.2016.05.021
      17. NeoGenomics Laboratories. MET Exon 14 Deletion Analysis, https://neogenomics.com/test-menu/met-exon-14-deletion-analysis; 2016 [accessed 12 February 2020].

        • Awad M.M.
        • Oxnard G.R.
        • Jackman D.M.
        • Savukoski D.O.
        • Hall D.
        • Shivdasani P.
        • et al.
        MET Exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-met overexpression.
        J Clin Oncol. 2016; 34: 721-730https://doi.org/10.1200/JCO.2015.63.4600
        • Reungwetwattana T.
        • Liang Y.
        • Zhu V.
        • Ou S.I.
        The race to target MET exon 14 skipping alterations in non-small cell lung cancer: the why, the how, the who, the unknown, and the inevitable.
        Lung Cancer. 2017; 103: 27-37https://doi.org/10.1016/j.lungcan.2016.11.011
        • Zheng D.
        • Wang R.
        • Ye T.
        • Yu S.
        • Hu H.
        • Shen X.
        • et al.
        MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer.
        Oncotarget. 2016; 7: 41691-41702
      18. Reckamp KL. New drugs and resistance: have we MET Expectations? Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, Illinois, USA, 31 May – 4 June 2019.

        • Wu Y.L.
        • Soo R.A.
        • 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: 70-81https://doi.org/10.1016/j.ctrv.2017.10.003
      19. Middleton GW, Popat S, Fletcher P, Summers YJ, Greystoke A, Gilligan D, et al. Abstract PL02.09: National Lung Matrix Trial (NLMT): First Results from an Umbrella Phase II Trial in Advanced Non-Small Cell Lung Cancer (NSCLC). Presented at the World Conference on Lung Cancer, Barcelona, Spain, 7–10 September 2019.

        • Yan S.B.
        • Um S.L.
        • Peek V.L.
        • Stephens J.R.
        • Zeng W.
        • Konicek B.W.
        • et al.
        MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping.
        Invest New Drugs. 2018; 36: 536-544https://doi.org/10.1007/s10637-017-0545-x
      20. Der-Torossian H, Shapiro G, Janne PA, Awad MM, Reckamp K, Miller W, et al. MET mutant allele frequency (MAF) is correlated with glesatinib anti-tumor activity in patients with advanced non-small cell lung cancer (NSCLC) harboring MET alterations. Eur J Cancer 2018;103(suppl_1):e133. Abstract 410 (PB-073). https://doi.org/10.1016/S0959-8049(18)31491-6.

      21. Lu S, Fang J, Cao L, Li X, Guo Q, Zhou J, et al. Preliminary efficacy and safety results of savolitinib treating patients with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations. Cancer Res 2019;79:Abstract CT031. https://doi.org/10.1158/1538-7445.Am2019-ct031.

      22. Heist RS, Garon EB, Tan DSW, Groen HJM, Seto T, Smit EF, et al. Biomarker analysis of patients with METΔex14 mutated non-small-cell lung cancer (NSCLC) treated with capmatinib in the GEOMETRY mono-1 study. Mol Cancer Ther 2019;18(12 Suppl):Abstract A029. https://doi.org/10.1158/1535-7163.TARG-19-A029.

      23. Foundation Medicine. Genomic Testing – FOUNDATIONONE®LIQUID, https://www.foundationmedicine.com/genomic-testing/foundation-one-liquid; 2018 [accessed 12 February 2020].

      24. Foundation Medicine. Genomic Testing – FOUNDATIONONE®CDx, https://www.foundationmedicine.com/genomic-testing/foundation-one-cdx; 2017 [accessed 18 March 2020].

      25. ArcherDX. Products – Liquid Biopsy Tests – LIQUIDPlex™, https://archerdx.com/liquidplex/; 2019 [accessed 4 March 2020].

      26. ArcherDX. Products – Lung, https://archerdx.com/lung/; 2018 [accessed 12 February 2020].

        • Kim S.T.
        • Banks K.C.
        • Lee S.-H.
        • Kim K.
        • Park J.O.
        • Park S.H.
        • et al.
        Prospective feasibility study for using cell-free circulating tumor DNA–guided therapy in refractory metastatic solid cancers: an interim analysis.
        JCO Precis Oncol. 2017; : 1-15https://doi.org/10.1200/po.16.00059
      27. Thermo Fisher Scientific Inc. An approach for establishing Oncomine Focus Assay performance, https://tools.thermofisher.com/content/sfs/brochures/oncomine-focus-assay-performance-white-paper.pdf; 2016 [accessed 4 March 2020].

      28. Personal Genome Diagnostics. CAP/CLIA Services, https://www.personalgenome.com/cap-clia; 2019 [accessed 18 March 2020].