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Asian Thoracic Oncology Research Group (ATORG) Expert Consensus Statement on MET Alterations in NSCLC: Diagnostic and Therapeutic Considerations

Open AccessPublished:August 22, 2022DOI:https://doi.org/10.1016/j.cllc.2022.07.012

      Highlights

      • MET alterations are associated with tumorigenesis and TKI resistance in patients with non-small cell lung cancer (NSCLC)
      • ATORG provides recommendations for diagnosis of (Mesenchymal Epithelial Transition) MET alterations in NSCLC
      • ATORG recommends MET exon 14 testing within panels for driver mutations in NSCLC
      • MET inhibitors can be considered for first or subsequent lines of treatment
      • Enrolment of patients is encouraged in combination trials of tyrosine kinase inhibitors (TKIs) and MET inhibitors

      Abstract

      Non-small cell lung cancer (NSCLC) is a heterogeneous disease, with many oncogenic driver mutations, including de novo mutations in the Mesenchymal Epithelial Transition (MET) gene (specifically in Exon 14 [ex14]), that lead to tumourigenesis. Acquired alterations in the MET gene, specifically MET amplification is also associated with the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in patients with EGFR-mutant NSCLC. Although MET has become an actionable biomarker with the availability of MET-specific inhibitors in selected countries, there is differential accessibility to diagnostic platforms and targeted therapies across countries in Asia-Pacific (APAC).
      The Asian Thoracic Oncology Research Group (ATORG), an interdisciplinary group of experts from Australia, Hong Kong, Japan, Korea, Mainland China, Malaysia, the Philippines, Singapore, Taiwan, Thailand and Vietnam, discussed testing for MET alterations and considerations for using MET-specific inhibitors at a consensus meeting in January 2022, and in subsequent offline consultation.
      Consensus recommendations are provided by the ATORG group to address the unmet need for standardised approaches to diagnosing MET alterations in NSCLC and for using these therapies. MET inhibitors may be considered for first-line or second or subsequent lines of treatment for patients with advanced and metastatic NSCLC harbouring MET ex14 skipping mutations; MET ex14 testing is preferred within multi-gene panels for detecting targetable driver mutations in NSCLC. For patients with EGFR-mutant NSCLC and MET amplification leading to EGFR TKI resistance, enrolment in combination trials of EGFR TKIs and MET inhibitors is encouraged.

      Keywords

      Abbreviations:

      AE (Adverse event), ALK (Anaplastic lymphoma kinase gene), ALT (Alanine transaminase), APAC (Asia-Pacific), ASCO (American Society of Clinical Oncology), AST (Aspartate transaminase), ATORG (Asian Thoracic Oncology Research Group), BID (Twice daily), CDx (Companion diagnostics), CGP (Comprehensive genomic profiling), c-MET/MET (MET protein), CNS (Central nervous system), ctDNA (Circulating tumour DNA), ctRNA (Circulating tumour RNA), DoR (Duration of response), ECOG (Eastern Cooperative Oncology Group), EGFR (Epidermal growth factor receptor gene), ErbB3 (Human epidermal growth factor receptor 3), FISH (Fluorescence in-situ hybridisation), GCN (Gene copy number), IHC (Immunohistochemistry), KRAS (Kirsten rat sarcoma virus gene), mDoR (Median duration of response), MET (Mesenchymal Epithelial Transition gene), MET ex14 (MET exon 14), M (Mutation), mOS (Median overall survival), mPFS (Median progression-free survival), NGS (Next-generation sequencing), NSCLC (Non-small cell lung cancer), ORR (Overall response rate), OS (Overall survival), PCR (Polymerase chain reaction), PD-L1 (Programmed death-ligand 1), PFS (Progression-free survival), QD (Once daily), RT-PCR (Real-time polymerase chain reaction), SOC (Standard of care), TKI (Tyrosine kinase inhibitor), TMB (Tumour mutation burden), TRAE (Treatment-related adverse events)

      Introduction

      Background

      Non-small cell lung cancer (NSCLC), which comprises 85% of all lung cancer cases, represents a heterogeneous disease with many known driver mutations,
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      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
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      Novel therapies for metastatic non-small cell lung cancer with MET exon 14 alterations: A spotlight on capmatinib.
      Targeted therapies are now available for many oncogenic driver mutations in NSCLC, including for Mesenchymal Epithelial Transition (MET) exon 14 (MET ex14) skipping mutations
      • Socinski MA
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      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      ; patients who receive targeted therapies for NSCLC are known to have improved clinical outcomes.
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      The effect of advances in lung-cancer treatment on population mortality.
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      Clinical impact of hybrid capture–based next-generation sequencing on changes in treatment decisions in lung cancer.
      Moreover, acquired MET amplification leads to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance by activating EGFR-independent phosphorylation of human epidermal growth factor receptor 3 (ErbB3) and downstream activation of signalling pathways, providing a bypass pathway in the presence of an EGFR inhibitor.
      • Wang Q
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      MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer.
      Thus, concomitant inhibition of both EGFR and MET would be required to overcome resistance to EGFR TKIs, and new targeted MET inhibitors are being explored in combination with EGFR TKIs,
      • Wu Y-L
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      • et al.
      Tepotinib plus gefitinib in patients with EGFR mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial.
      • Wu Y-L
      • Zhang L
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      • et al.
      Phase Ib/II study of capmatinib (INC280) plus gefitinib after failure of epidermal growth factor receptor (EGFR) inhibitor therapy in patients with EGFR-mutated, MET factor–dysregulated non–small-cell lung cancer.
      • Yu H
      • Goldberg S
      • Le X
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      P2.01-22 ORCHARD: A phase II platform study in patients with advanced NSCLC who have progressed on first-line osimertinib therapy.
      • Bauml J
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      Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response.
      • Yang JCH
      • Ellers-Lenz B
      • Straub J
      • Johne A
      • Wu YL.
      INSIGHT 2: Tepotinib plus osimertinib in patients with EGFR-mutant NSCLC having acquired resistance to EGFR TKIs due to MET-amplification: A phase II trial in progress study.
      • Schmid S
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      • Leighl NB.
      Mechanisms of osimertinib resistance and emerging treatment options.
      with preliminary observations of clinical benefits in preselected populations.
      • Wu Y-L
      • Zhang L
      • Kim D-W
      • et al.
      Phase Ib/II study of capmatinib (INC280) plus gefitinib after failure of epidermal growth factor receptor (EGFR) inhibitor therapy in patients with EGFR-mutated, MET factor–dysregulated non–small-cell lung cancer.
      ,
      • Yu H
      • Goldberg S
      • Le X
      • et al.
      P2.01-22 ORCHARD: A phase II platform study in patients with advanced NSCLC who have progressed on first-line osimertinib therapy.
      ,
      • Yang JCH
      • Ellers-Lenz B
      • Straub J
      • Johne A
      • Wu YL.
      INSIGHT 2: Tepotinib plus osimertinib in patients with EGFR-mutant NSCLC having acquired resistance to EGFR TKIs due to MET-amplification: A phase II trial in progress study.
      However, diagnostic algorithms and the clinical protocols need to be adapted before MET testing or treatment can be integrated into clinical practice. This is especially the case where the prevalence of oncogenic driver mutations varies,
      • Vuong HG
      • Ho ATN
      • Altibi AMA
      • Nakazawa T
      • Katoh R
      • Kondo T.
      Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer - A systematic review and meta-analysis.
      and given that the availability of molecular testing and access to drugs are not the same in different countries across the world and within Asia. This necessitated a review of existing clinical data in Asia-Pacific (APAC) by the Asian Thoracic Oncology Research Group (ATORG), an interdisciplinary group of experts from Australia, Hong Kong, Japan, Korea, Mainland China, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. The expert panel discussed both diagnostic testing for MET alterations (MET ex14 and MET amplification) as well as the therapeutic considerations for using MET inhibitors, including for patients with mixed biomarker phenotypes and EGFR-mutant NSCLC. Consensus recommendations are provided by the ATORG group to address the unmet need for more regional perspectives and standardised approaches to using these new therapies, with the aim of raising scientific awareness and improving patient access to these targeted treatments.

      MET Biology: Introduction to MET Alterations in NSCLC

      MET is a tyrosine kinase receptor essential for cell proliferation and growth, including in tumour motility and invasion.
      • Tan AC
      • Loh TJ
      • Kwang XL
      • Tan GS
      • Lim KH
      • Tan DSW.
      Novel therapies for metastatic non-small cell lung cancer with MET exon 14 alterations: A spotlight on capmatinib.
      Exon 14 (ex14) of the MET gene plays a key regulatory function and controls cell signalling through this receptor. Disruption of ex14 function (either by alterations within ex14, in the surrounding intronic regions or complete genomic deletion of ex14) leads to constitutive MET signalling, resulting in cell proliferation and tumour growth.
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      Prevalence of MET ex14 mutations in Western patients (3%) is slightly higher than in Asian patients (2%)
      • Vuong HG
      • Ho ATN
      • Altibi AMA
      • Nakazawa T
      • Katoh R
      • Kondo T.
      Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer - A systematic review and meta-analysis.
      (Table 1). Patients with NSCLC and MET ex14 mutation are usually older (median age 65-76 years), more often female, less likely to have a history of smoking and often have concurrent MET protein (c-MET) overexpression, but no other oncogenic drivers.
      • Vuong HG
      • Ho ATN
      • Altibi AMA
      • Nakazawa T
      • Katoh R
      • Kondo T.
      Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer - A systematic review and meta-analysis.
      Prevalence of MET ex14 mutation is higher in sarcomatoid and adenosquamous carcinoma, in both ethnicities.
      • Vuong HG
      • Ho ATN
      • Altibi AMA
      • Nakazawa T
      • Katoh R
      • Kondo T.
      Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer - A systematic review and meta-analysis.
      Table 1Prevalence and Molecular Epidemiology of MET exon 14 Skipping Mutations in Asian Patients vs. Western Patients (partially adapted from
      • Vuong HG
      • Ho ATN
      • Altibi AMA
      • Nakazawa T
      • Katoh R
      • Kondo T.
      Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer - A systematic review and meta-analysis.
      )
      StudyCountryTotal NSCLCsType of assay usedPrevalence of MET exon 14 mutation, %Mutation typesMutation sites
      Deletion/ InsertionPoint MutationIntron 13 not disrupting SASAffecting Intron 13 SASEntirely in Exon 14Affecting Intron 14 SDS
      Western Patients
      Awad
      • Awad MM
      • Oxnard GR
      • Jackman DM
      • 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.
      US933Quantitative RT-PCR3.0171146612
      Shrock
      • Schrock AB
      • Frampton GM
      • Suh J
      • et al.
      Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations.
      US11205NGS2.714715771042191
      Ludovini
      • Ludovini V
      • Bianconi F
      • Pistola L
      • et al.
      Optimization of patient selection for EGFR-TKIs in advanced non-small cell lung cancer by combined analysis of KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations.
      Italy106Nested PCR3.8No information4No information
      Saffroy
      • Saffroy R
      • Fallet V
      • Girard N
      • et al.
      MET exon 14 mutations as targets in routine molecular analysis of primary sarcomatoid carcinoma of the lung.
      France231PCR (massARRAY iPLEX/high -resolution melting5.2665241
      Asian Patients
      Liu
      • Liu SY
      • Gou LY
      • Li AN
      • et al.
      The unique characteristics of MET exon 14 mutation in Chinese patients with NSCLC.
      China1296Sanger sequencing, IHC, FISH1.0750255
      Qiu
      • Qiu T
      • Li W
      • Zhang T
      • et al.
      Distinct MET protein localization associated with MET exon 14 mutation types in patients with non-small-cell lung cancer.
      China461Sanger sequencing, IHC, FISH2.0540324
      Zheng
      • Zheng D
      • Wang R
      • Ye T
      • et al.
      MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer.
      China1770IHC, quantitative RT-PCR1.3No informationNo information
      Tong
      • Tong JH
      • Yeung SF
      • Chan AW
      • et al.
      MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis.
      Hong Kong687Sanger sequencing, IHC, FISH2.681035010
      Gow
      • Gow CH
      • Hsieh MS
      • Wu SG
      • Shih JY.
      A comprehensive analysis of clinical outcomes in lung cancer patients harboring a MET exon 14 skipping mutation compared to other driver mutations in an East Asian population.
      Taiwan746RT-PCR, IHC3.6No informationNo information
      Kwon
      • Kwon D
      • Koh J
      • Kim S
      • et al.
      MET exon 14 skipping mutation in triple-negative pulmonary adenocarcinomas and pleomorphic carcinomas: an analysis of intratumoral MET status heterogeneity and clinicopathological characteristics.
      Korea102
      All NSCLC patients were negative for EGFR/KRAS/ALK mutations.
      Quantitative RT-PCR, IHC, FISH8.8No informationNo information
      Lee
      • Lee GD
      • Lee SE
      • Oh DY
      • et al.
      MET exon 14 skipping mutations in lung adenocarcinoma: Clinicopathologic implications and prognostic values.
      Korea795Quantitative RT-PCR, sanger sequencing, IHC2.1754215
      Cheng
      • Cheng T
      • Gu Z
      • Song D
      • et al.
      Genomic and clinical characteristics of MET exon14 alterations in a large cohort of Chinese cancer patients revealed distinct features and a novel resistance mechanism for crizotinib.
      China12848NGS, IHC1.08No informationNo information
      Xu
      • Xu Z
      • Li H
      • Dong Y
      • et al.
      Incidence and PD-L1 expression of MET 14 skipping in Chinese population: A non-selective NSCLC cohort study using RNA-based sequencing.
      China951NGS, RT-PCR, sanger sequencing, IHC1.68No informationNo information
      Izumi
      • Izumi M
      • Suzumura T
      • Ogawa K
      • et al.
      Differences in molecular epidemiology of lung cancer among ethnicities (Asian vs. Caucasian).
      Japan876NGS0.1No informationNo information
      Yang
      • Yang H
      • Zhou Z
      • Lin L
      • et al.
      Characterization of MET exon 14 alteration and association with clinical outcomes of crizotinib in Chinese lung cancers.
      China11242NGS1.1No informationNo information
      ALK = anaplastic lymphoma kinase gene; EGFR = epidermal growth factor receptor; FISH = fluorescence in situ hybridisation; IHC = immunohistochemistry; KRAS = Kirsten rat sarcoma virus gene; NGS = next-generation sequencing; NSCLC = non-small cell lung cancer; RT-PCR = real-time polymerase chain reaction; SAS = splice acceptor site; SDS = splice donor site; w/o = without.
      a All NSCLC patients were negative for EGFR/KRAS/ALK mutations.
      MET amplification denotes an increase in the gene copy number (GCN) of the MET gene, with 5 copies being a commonly adopted threshold. De novo MET amplification has been observed in 1% to 5% of NSCLCs,
      • Drilon A
      • Cappuzzo F
      • Ou SI
      • Camidge DR.
      Targeting MET in Lung Cancer: Will Expectations Finally Be MET?.
      including in patients with EGFR-mutant NSCLC.
      • Lai GGY
      • Lim TH
      • Lim J
      • et al.
      Clonal MET amplification as a determinant of tyrosine kinase inhibitor resistance in epidermal growth factor receptor–mutant non–small-cell lung cancer.
      MET amplifications can also occur in the context of a resistance mechanism to EGFR or other TKIs
      • Drilon A
      • Cappuzzo F
      • Ou SI
      • Camidge DR.
      Targeting MET in Lung Cancer: Will Expectations Finally Be MET?.
      ,
      • Frampton GM
      • Ali SM
      • Rosenzweig M
      • et al.
      Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
      • Schrock AB
      • Frampton GM
      • Suh J
      • et al.
      Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations.
      • Dagogo-Jack I
      • Yoda S
      • Lennerz JK
      • et al.
      MET alterations are a recurring and actionable resistance mechanism in ALK-positive lung cancer.
      ; where up to 15% of patients who experience disease progression whilst receiving treatment with the third-generation EGFR TKI, osimertinib, have MET amplification.
      • Schmid S
      • Li JJN
      • Leighl NB.
      Mechanisms of osimertinib resistance and emerging treatment options.
      MET is now an actionable biomarker in NSCLC with the availability of MET-specific inhibitors, tepotinib and capmatinib, in selected countries in North America, South America, Europe and Asia, and savolitinib in China (Figure 1). However, in Asia, the expert group recognized that there is non-standardised testing for MET alterations and differential accessibility to selective MET inhibitors, which has limited the adoption of this targeted treatment into routine clinical practice. The ATORG group have developed consensus statements to address the importance of MET testing; suggesting potential solutions to address the unmet need regarding availability and affordability of standardised diagnostic tools in APAC; and to provide clinical recommendations regarding appropriate treatment options in the management of MET-driven NSCLC.
      Figure 1
      Figure 1Current Availability of MET Inhibitors in APAC (as of March 2022).
      *Special tepotinib import scheme only applies to Hainan, China.
      Capmatinib approval for MET ex14 skipping positive patients (treatment-naïve or previously treated patients)
      Tepotinib approval for MET ex14 M+ NSCLC
      § Capmatinib approval for 1L and previously treated patients, tepotinib approval for patients with unresectable, advanced/recurrent MET ex14 positive NSCLC.

      Materials and Methods

      The ATORG expert panel consisted of lung cancer physicians from specialities including medical oncology and pathology. A comprehensive search for scientific reviews (including meta-analyses) and APAC-specific clinical trials in NSCLC published from 2017 to 2021 specifically pertaining to the use of MET inhibitors for MET ex14 skipping and MET amplification in EGFR TKI resistance was conducted in PubMed using the following search terms: (Non-Small Cell Lung Cancer [MeSH Terms]) AND ((“c-MET”) OR (“MET Exon 14”) OR (“MET amplification”)). Sixty publications were identified under the article types “Comment, Consensus Development Conference, Guideline, Meta-analysis, Practice Guideline, Review, Systematic Review” and 96 original research papers under the article types “Reports, Clinical Conference, Clinical Study, Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Clinical Trial, Phase IV, Comment, Comparative Study, Consensus Development Conference, Controlled Clinical Trial, Meta-Analysis, Multicenter Study, Observational Study, Randomised Controlled Trial, Systematic Review, Validation Study”. In addition, available clinical guidelines for NSCLC, including those available from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO) and other Asian guidelines were investigated for recommendations pertaining to the use of MET inhibitors. Findings from the literature review were discussed in detail at a consensus meeting on 29 January 2022. Recommendations were made from the perspective of the clinical landscape in APAC, considering the diversity in healthcare factors, including availability, accessibility and affordability of testing and treatments. Consensus statements providing guidance on each of the four key considerations in the management of MET-driven NSCLC in APAC were discussed, developed and agreed upon amongst the panel members at the meeting and in offline consultation. These four considerations are:
      • 1.
        Optimising testing for MET alterations.
      • 2.
        Current treatment landscape of MET exon 14 skipping mutation in NSCLC and guidelines.
      • 3.
        MET amplification in EGFR TKI resistance.
      • 4.
        Access and reimbursement of MET testing and MET inhibitors.

      Results and Discussion

      Optimising Testing for MET Alterations

      Question 1: What is the optimal approach for MET ex14 skipping mutation testing?
      Diverse methods are used for detecting MET ex14 skipping mutation (Table 2). Genetic analysis of DNA from tissue biopsies is commonly used for detecting MET alterations; since many different mutations can result in MET ex14 skipping, next-generation sequencing (NGS) is preferred over single-gene methods.
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      Moreover, NGS can detect the presence of other oncogenic drivers as well. Amongst the commercially available assays, those which are based on hybrid capture technology usually perform better than non-standardised amplicon-based methods.
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      However, recent studies
      • Poirot B
      • Doucet L
      • Benhenda S
      • Champ J
      • Meignin V
      • Lehmann-Che J.
      MET exon 14 alterations and new resistance mutations to tyrosine kinase inhibitors: Risk of inadequate detection with current amplicon-based NGS panels.
      • Descarpentries C
      • Leprêtre F
      • Escande F
      • et al.
      Optimization of routine testing for MET exon 14 splice site mutations in NSCLC patients.
      • Davies KD
      • Lomboy A
      • Lawrence CA
      • et al.
      DNA-based versus RNA-based detection of MET exon 14 skipping events in lung cancer.
      • Jurkiewicz M
      • Saqi A
      • Mansukhani MM
      • et al.
      Efficacy of DNA versus RNA NGS-based Methods in MET Exon 14 skipping mutation detection.
      • Lee JK
      • Madison R
      • Classon A
      • et al.
      Characterization of Non-Small-Cell Lung Cancers With MET Exon 14 Skipping Alterations Detected in Tissue or Liquid: Clinicogenomics and Real-World Treatment Patterns.
      arrived at the same conclusion that DNA is not a sufficient template for testing MET ex14 skipping, due to the diversity of mutations at various genomic locations, which may lead to improper primer or probe binding, or because of artefacts introduced by the specific NGS technology used.
      • Teishikata T
      • Shiraishi K
      • Shinno Y
      • et al.
      An alert to possible false positives with a commercial assay for MET exon 14 skipping.
      Table 2Assays for Detecting MET exon 14 Skipping in NSCLC (adapted from
      • Salgia R
      • Sattler M
      • Scheele J
      • Stroh C
      • Felip E.
      The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping.
      )
      DNADNARNABoth
      Biopsy typeLiquid biopsyTissue biopsy
      Panel nameFoundationOne® Liquid

      Foundation Medicine. Genomic Testing – FOUNDATIONONE®LIQUID. Available at: https://www.foundationmedicine.com/genomic-testing/foundation-one-liquid. Accessed 15 February 2022.

      Archer® LiquidPlex™

      ArcherDX. Products – Liquid Biopsy Tests – LIQUIDPlex™. Available at: https://archerdx.com/liquidplex. Accessed 15 February 2022.

      Guardant360®
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      • Lee SH
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      Prospective feasibility study for using cell-free circulating tumor DNA-guided therapy in refractory metastatic solid cancers: An interim analysis.
      PlasmaSELECT™

      Personal Genome Diagnostics. CAP/CLIA Services. Available at: https://www.personalgenome.com/cap-clia. Accessed 15 February 2022.

      FoundationOne® CDx

      Foundation Medicine. Genomic Testing – FOUNDATIONONE®CDx. Available at: https://www.foundationmedicine.com/genomic-testing/foundation-one-cdx. Accessed 15 February 2022.

      Illumina TruSight Tumor 26 assayArcher® FusionPlex™ Lung

      ArcherDX. Cancer Diagnostics. Available at: https://archerdx.com/diagnostic-products/cancer-diagnostic/. Accessed 17 March 2022.

      Oncomine Focus Assay

      Thermo Fisher Scientific Inc. An approach for establishing Oncomine Focus Assay performance. Available at: http://assets.thermofisher.com/TFS-Assets/LSG/Vector-Information/oncomine-focus-assay-performance-white-paper.pdf. Accessed 17 March 2022.

      Material readCirculating tumour DNACirculating free DNACirculating free DNACirculating tumour DNATumour DNATumour DNATumour mRNATumour DNA or mRNA
      Sample required2 × 8.5 mL blood samples5-10 ng DNA10 mL blood sample for 5-30 ng DNA2 × 10 mL blood samplesFFPE tissue; 50-1000 ng DNAFFPE tissue; 30-300 ngFFPE tissue; 20-250 ngFFPE tissue; 7 uM thick and >5 mm2
      Number of genes interrogated70 genes28 genes73 genes64 genes324 genes26 genes14 genes52 genes
      SensitivityCan detect mutations if present in > 0.5% of sampleCan detect mutations if present in > 1% of sampleCan detect mutations if present in > 0.1% of sampleNot reportedCan detect mutation that represents 2-5 allele frequency100% detection if mutation is >5% allele frequencyNot reported100% detection if mutation is >5% allele frequency
      Turnaround time< 2 weeksNot reported7 daysNot reported< 2 weeks2-3 daysNot reported3 days
      AdvantageDoes not depend on tissue biopsy (especially if tissue is scarce or tissue biopsy is not possible/will take more than 2 weeks to obtain
      • Rolfo C
      • Mack PC
      • Scagliotti GV
      • et al.
      Liquid biopsy for advanced non-small cell lung cancer (NSCLC): A statement paper from the IASLC.
      ); more convenient and less invasive
      • Esagian SM
      • Grigoriadou G
      • Nikas IP
      • et al.
      Comparison of liquid-based to tissue-based biopsy analysis by targeted next generation sequencing in advanced non-small cell lung cancer: a comprehensive systematic review.
      ; high concordance with tissue biopsy results
      • Felip E
      • Garassino MC
      • Hiroshi S
      • et al.
      Tepotinib in patients with MET exon 14 skipping NSCLC as identified by liquid or tissue biopsy.
      Hybridisation-based capture technology (better than amplicon-based) and can detect many gene mutations
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      High-quality DNA easier to extractMore accurate than DNA assay
      • Davies KD
      • Lomboy A
      • Lawrence CA
      • et al.
      DNA-based versus RNA-based detection of MET exon 14 skipping events in lung cancer.
      , especially for novel alterations
      Analyses both DNA and RNA
      DisadvantageDNA only; some tumours do not shed enough DNA to be detected in liquid biopsies; negative result needs to be followed up with tissue-based assay
      • Rolfo C
      • Mack PC
      • Scagliotti GV
      • et al.
      Liquid biopsy for advanced non-small cell lung cancer (NSCLC): A statement paper from the IASLC.
      Amplicon-based technology – allele dropout possible
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      High-quality RNA difficult to extractAmplicon-based technology – allele dropout possible
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      DNA = deoxyribonucleic acid; FFPE = formalin-fixed, paraffin-embedded; mRNA = messenger ribonucleic acid.
      RNA-based methods have been found to be more accurate than DNA-based ones,
      • Davies KD
      • Lomboy A
      • Lawrence CA
      • et al.
      DNA-based versus RNA-based detection of MET exon 14 skipping events in lung cancer.
      and detecting the shortened RNA product is often easier. However, extracting high-quality RNA from tissue biopsies is technically challenging; RNA-based methods can therefore be used to augment DNA-based testing [real-time polymerase chain reaction (RT-PCR)/NGS-based], especially if non-canonical alterations are present. The difference in the performance of small, customised panels versus large NGS panels is yet to be determined.
      In addition, analysis of MET alterations in liquid biopsies (circulating tumour cells or circulating tumour DNA (ctDNA) in plasma) can be used as an adjunctive tool when biopsy samples are scarce or unavailable.
      • Esagian SM
      • Grigoriadou G
      • Nikas IP
      • et al.
      Comparison of liquid-based to tissue-based biopsy analysis by targeted next generation sequencing in advanced non-small cell lung cancer: a comprehensive systematic review.
      This is more convenient and less invasive; however, current recommendations from the International Association for the Study of Lung Cancer (IASLC) state that a negative ctDNA result still needs to be followed by a confirmatory tissue biopsy,
      • Rolfo C
      • Mack PC
      • Scagliotti GV
      • et al.
      Liquid biopsy for advanced non-small cell lung cancer (NSCLC): A statement paper from the IASLC.
      since tumour burden may be too low in certain patients for the MET alteration to be detected in the plasma. ctDNA assays are still being developed as research tools and can be quite sensitive, but no circulating tumour RNA (ctRNA) assays are commercially available. Liquid biopsy assays have also been used for predicting treatment outcome; for example, in the phase II VISION trial of tepotinib in patients with advanced or metastatic NSCLC and confirmed MET ex14 skipping mutations, concordant results were observed using tissue or liquid biopsy assays, in both treatment-naïve and previously treated patients.
      • Paik PK
      • Felip E
      • Veillon R
      • et al.
      Tepotinib in non–small-cell lung cancer with MET exon 14 skipping mutations.
      MET ex14 skipping mutation results in impaired receptor degradation which inevitably causes MET overexpression.
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      For this reason, MET Immunohistochemistry (IHC) would appear to be a good screening method; however, a recent study from a large cancer centre in the United States suggests that IHC is an inefficient screening tool for these alterations. Nearly all MET IHC positive cases in this study were negative for MET ex14 skipping mutations or MET amplification.
      • Guo R
      • Berry LD
      • Aisner DL
      • et al.
      MET IHC is a poor screen for MET amplification or MET exon 14 mutations in lung adenocarcinomas: Data from a tri-institutional cohort of the lung cancer mutation consortium.
      In summary, NGS using RNA is most accurate,
      • Davies KD
      • Lomboy A
      • Lawrence CA
      • et al.
      DNA-based versus RNA-based detection of MET exon 14 skipping events in lung cancer.
      but analysis of DNA derived from tissue biopsies may be more practical and easily accessible for detection of MET ex14 skipping in NSCLC
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      ; additionally, analysis of liquid biopsies (ctDNA in plasma) is being increasingly adopted, especially when tissue sample is inadequate or not available, and is more convenient and less invasive.
      • Esagian SM
      • Grigoriadou G
      • Nikas IP
      • et al.
      Comparison of liquid-based to tissue-based biopsy analysis by targeted next generation sequencing in advanced non-small cell lung cancer: a comprehensive systematic review.
      Due to the limitations of currently available assays, depending on the patient profile, availability of different testing options and costs, it may be useful to order orthogonal tests to reduce the possibility of false positive or false negative MET ex14 detection, and consequently potentially ineffective treatment being given to these patients with advanced NSCLC.

      ATORG Consensus

      Testing for MET ex14 skipping of patients with advanced NSCLC is recommended. Owing to the ongoing development of various platforms and technologies, and pragmatic considerations around tissue availability and test access in the respective clinical setting, the optimal method of testing is not prescribed and should be based on test availability, test characteristics, patients’ demographics (ie likelihood of a positive), the disease status as well as the treatments available. MET ex14 testing is preferred within multi-gene panels for detecting targetable driver mutations in NSCLC. It may be useful to order orthogonal tests, depending on patient profile.
      Question 2: What is the optimal approach to testing MET amplification?
      Increase in copy number of the MET gene can occur via both polyploidy (duplication of chromosomes) and amplification (duplication of local or regional genes); polyploidy is not an oncogenic driver, but amplification is an important resistance mechanism to EGFR TKIs.
      • Wang Q
      • Yang S
      • Wang K
      • Sun SY.
      MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer.
      Fluorescence in-situ hybridisation (FISH) is commonly used to detect MET amplification,
      • Wang Q
      • Yang S
      • Wang K
      • Sun SY.
      MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer.
      as it is less technically challenging than NGS, and can be used to distinguish between polyploidy and amplification (the ratio of MET to centromere protein on chromosome 7 [MET/CEP7] values do not change in polyploidy, but a change is observed for local amplification). In ongoing clinical trials, the cut-off for MET amplification is usually set as MET GCN ≥ 5 or MET/CEP7 ≥ 2.2 for medium level of amplification.
      • Wang Q
      • Yang S
      • Wang K
      • Sun SY.
      MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer.
      Nonetheless, the cut-off for amplification may vary from assay to assay, and the threshold for benefit from MET inhibitors is not clearly defined; a single standardised FISH test has not been adopted in clinical trials and the clinical community.
      Multiplex NGS panels are gaining popularity for detecting MET amplification.
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      However, these platforms are limited in that data quality is highly dependent on the platform used, and low copy number gains (especially if neoplastic cell number is low) may not be detected.
      • Eijkelenboom A
      • Tops BBJ
      • van den Berg A
      • et al.
      Recommendations for the clinical interpretation and reporting of copy number gains using gene panel NGS analysis in routine diagnostics.
      The cut-offs used for defining MET amplification are quite heterogeneous, although a > 3-to-5-fold cut-off (for MET GCN greater than 3 or 5) has been used in several studies.
      • Clavé S
      • Salido M
      • Rocha P
      • et al.
      Identification of MET gene amplifications using next-generation sequencing in non-small cell lung cancer patients.
      ,
      • Peng LX
      • Jie GL
      • Li AN
      • et al.
      MET amplification identified by next-generation sequencing and its clinical relevance for MET inhibitors.
      Standardisation among the assays will be needed, similar to the attempt on tumour mutation burden.
      • Sholl LM
      • Hirsch FR
      • Hwang D
      • et al.
      The promises and challenges of tumor mutation burden as an immunotherapy biomarker: A perspective from the international association for the study of lung cancer pathology committee.
      It is still not entirely clear if the results obtained from FISH and NGS for MET amplification are concordant, particularly for low level amplification. A study using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay, a hybrid capture-based NGS assay interrogating the coding regions of 410 cancer-related genes, showed good concordance between IHC/FISH and NGS.
      • Ross DS
      • Zehir A
      • Cheng DT
      • et al.
      Next-generation assessment of human epidermal growth factor receptor 2 (ERBB2) amplification status: Clinical validation in the context of a hybrid capture-based, comprehensive solid tumor genomic profiling assay.
      In contrast, a more recent study showed poor concordance between NGS and FISH.
      • Schubart C
      • Stöhr R
      • Tögel L
      • et al.
      MET amplification in non-small cell lung cancer (NSCLC)-A consecutive evaluation using next-generation sequencing (NGS) in a real-world setting.
      The concordance rate among FISH and NGS was only 62.5% (25/40) in another study, and MET amplification identified by NGS failed to distinguish significant clinical outcomes.
      • Peng LX
      • Jie GL
      • Li AN
      • et al.
      MET amplification identified by next-generation sequencing and its clinical relevance for MET inhibitors.
      Analysis of MET protein overexpression using IHC is also commonly used as a biomarker for MET dysregulation,
      • Wang Q
      • Yang S
      • Wang K
      • Sun SY.
      MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer.
      as it is much cheaper and easier to perform, especially for enrolment of patients in clinical trials. IHC scores of 2+ or 3+ are usually taken to be indicative of MET amplification.
      • Wang Q
      • Yang S
      • Wang K
      • Sun SY.
      MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer.
      Semi-quantitative H-scores are also used to show the percentage of cancer cells showing none, weak, moderate, or strong staining and calculated as the sum of the percentage staining multiplied by an ordinal value corresponding to the four intensity levels (0 = none, 1 = weak, 2 = moderate, 3 = strong); the resulting score ranges from 0 (no staining in the tumour) to 300 (diffuse intense staining of the tumour).
      • Bhargava R
      • Striebel J
      • Beriwal S
      • et al.
      Prevalence, morphologic features and proliferation indices of breast carcinoma molecular classes using immunohistochemical surrogate markers.
      A novel approach using a combined EGFR+MET H-score by IHC (EGFR/MET overexpression defined as a H-score of >400) was recently shown to be predictive of treatment response in a combination trial of amivantamab (an EGFR/c-MET bispecific antibody) and lazertinib (a third-generation EGFR TKI)
      • Bauml J
      • Cho BC
      • Park K
      • et al.
      Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response.
      ; this biomarker still needs further validation. Notwithstanding this information, IHC assays have proven inaccurate in detecting MET amplification, and thus FISH and NGS are still the preferred detection methods.
      • Guo R
      • Berry LD
      • Aisner DL
      • et al.
      MET IHC is a poor screen for MET amplification or MET exon 14 mutations in lung adenocarcinomas: Data from a tri-institutional cohort of the lung cancer mutation consortium.
      More recently, liquid biopsies are being used to detect MET amplification. These assays have the same limitations as described for MET ex14 detection but can be useful when tissue biopsy is unavailable.
      • Ikeda S
      • Schwaederle M
      • Mohindra M
      • Fontes Jardim DL
      • Kurzrock R
      MET alterations detected in blood-derived circulating tumor DNA correlate with bone metastases and poor prognosis.
      For example, the INSIGHT 2 study
      • Yang JCH
      • Ellers-Lenz B
      • Straub J
      • Johne A
      • Wu YL.
      INSIGHT 2: Tepotinib plus osimertinib in patients with EGFR-mutant NSCLC having acquired resistance to EGFR TKIs due to MET-amplification: A phase II trial in progress study.
      (tepotinib combined with osimertinib) accepts patients with MET amplification detected by FISH or a liquid biopsy-based NGS test.
      • Smit EF
      • Dooms C
      • Raskin J
      • et al.
      INSIGHT 2: a phase II study of tepotinib plus osimertinib in MET-amplified NSCLC and first-line osimertinib resistance.
      In the CHRYSALIS study,
      • Bauml J
      • Cho BC
      • Park K
      • et al.
      Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response.
      NGS in either ctDNA (plasma samples) or tumour biopsy samples was used to identify EGFR/MET mutations and amplification, respectively, but IHC for EGFR/MET expression was also explored as a potential biomarker.

      ATORG Consensus

      The current gold standard for detecting MET amplification is FISH. However, new technologies are evolving and becoming increasingly available, such as NGS focusing on MET GCN, using tissue biopsy or ctDNA in plasma samples (liquid biopsy).
      • Ikeda S
      • Schwaederle M
      • Mohindra M
      • Fontes Jardim DL
      • Kurzrock R
      MET alterations detected in blood-derived circulating tumor DNA correlate with bone metastases and poor prognosis.

      Current Treatment Landscape of MET exon 14 Skipping Mutation in NSCLC and Guidelines

      Question 3: What is the current availability of MET inhibitors and what differentiating features inform treatment decisions?
      Three MET-specific inhibitors have recently been approved for patients with MET ex14 skipping in metastatic NSCLC in selected Asian countries – tepotinib, capmatinib, and savolitinib.
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      ,
      • Lu S
      • Fang J
      • Li X
      • et al.
      Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study.

      Tepotinib

      Tepotinib is an oral, selective small-molecule MET kinase inhibitor, given once daily (QD).
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      It is approved for use in the US, Canada, Argentina, Brazil, European Union, Great Britain, Switzerland and Israel; in APAC, it is approved for use in Japan, South Korea, Hong Kong, Australia, Singapore, and Taiwan, as well as in Hainan province in China.
      The VISION trial
      • Felip E
      • Garassino MC
      • Hiroshi S
      • et al.
      Tepotinib in patients with MET exon 14 skipping NSCLC as identified by liquid or tissue biopsy.
      (NCT02864992) is a prospective, non-randomised, open-label phase II trial investigating tepotinib in patients with MET ex14 skipping or MET-amplified advanced and metastatic NSCLC; tepotinib showed good clinical activity in patients with MET ex14 skipping mutations, although the median duration of response (mDoR) was longer in treatment-naïve compared to pretreated patients (32.7 vs 10.1 months, for the patient population evaluated by tissue biopsy), with a tolerable safety profile (Table 3). The results from an Asian-specific population
      • Yang JC-H
      • Ahn M-J
      • Sakai H
      • et al.
      Tepotinib in Asian patients with advanced NSCLC with MET exon 14 (METex14) skipping.
      demonstrate similar results; for first-line treatment (n = 20), overall response rate (ORR) was 70.0% (45.7, 88.1) with an 83% 12-month DoR rate, while in the second line (n = 37), ORR was 51.4% (34.4, 68.1) and mDoR was 8.3 months. Overall, ORR was 54.4%, mDoR was 18.5 months, median progression-free survival (mPFS) was 12.1 months, and median overall survival (mOS) was 20.4 months (n = 79). The most common adverse events (AEs) were peripheral oedema, elevated serum creatinine, and diarrhoea. Overall, 29.5% of patients had grade ≥ 3 treatment-related adverse events (TRAEs), leading to permanent discontinuation in 14.8% of patients. Systemic response to tepotinib was robust and durable in patients with brain metastases at baseline.
      • Patel JD
      • Le X
      • Veillon R
      • et al.
      Intracranial activity of tepotinib in patients (pts) with MET exon 14 (METex14) skipping NSCLC enrolled in VISION.
      Table 3Current Therapeutic Landscape of MET exon 14 Skipping Mutations – Available Drugs
      Tepotinib
      • Felip E
      • Garassino MC
      • Hiroshi S
      • et al.
      Tepotinib in patients with MET exon 14 skipping NSCLC as identified by liquid or tissue biopsy.
      (Merck)
      Capmatinib
      • Wolf J
      • Seto T
      • Han JY
      • et al.
      Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer.
      (Novartis)
      Savolitinib
      • Lu S
      • Fang J
      • Li X
      • et al.
      Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study.
      (Hutchmed)
      Crizotinib
      • Drilon A
      • Clark JW
      • Weiss J
      • et al.
      Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration.
      (Pfizer)
      MoAHighly potent and selectiveHighly potent and selectiveHighly potent and selectiveMulti-kinase inhibitor, but potent
      CNS endpoints and brain penetrationTumour shrinkage in patients with brain metastases with 86.6% intracranial disease control and 71.4% intracranial control
      • Thomas M
      • Reinmuth N
      • Wermke M
      • et al.
      Tepotinib in patients with MET exon 14 skipping non-small cell lung cancer: Interim analysis of VISION Cohorts A and C.
      Tumour shrinkage in patients with brain metastases with 54% intracranial responseNot availableNot available
      Dosing
      • 2 tablets/day, QD
      • One-step dose reduction schedule
      • 4 tablets/day, BID
      • Two-step dose reduction schedule (requiring different tablets and a new prescription)
      400 or 600 mg orally, once daily250 mg BID
      TestingLiquid (NGS – DNA) and tissue biopsy (NGS)Tissue biopsy only – NGS/RT-PCR1Tissue biopsy only – Sanger/NGSLiquid (NGS – DNA) and tissue biopsy – NGS (DNA/RNA)
      Efficacy 1LORRVISION trial
      Results shown are for the patients enrolled based on tissue biopsy.
      54.7%
      VISION Asian sub-group
      Results shown are for the patients enrolled based on tissue biopsy.
      • Yang JC-H
      • Ahn M-J
      • Sakai H
      • et al.
      Tepotinib in Asian patients with advanced NSCLC with MET exon 14 (METex14) skipping.
      : 70.0%
      GEOMETRY Mono-1 trial 68%
      • Wolf J
      • Seto T
      • Han JY
      • et al.
      Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer.
      46.4%PROFILE 1001 trial 25%
      mDoR32.7 months
      Results shown are for the patients enrolled based on tissue biopsy.
      83% 12-month DoR rate
      Results shown are for the patients enrolled based on tissue biopsy.
      12.6 months5.6 months9.1 months
      No sub-group analysis was done. Data not stratified for first- and second-line treatments, this data is for both lines of treatment.
      mPFS/mOSmPFS 15.3 months
      Results shown are for the patients enrolled based on tissue biopsy.
      ; mOS 29.7 monthsa
      74% 12-month PFS rate
      Results shown are for the patients enrolled based on tissue biopsy.
      ; 67% 24-month OS rate
      Results shown are for the patients enrolled based on tissue biopsy.
      mPFS 12.4 monthsmPFS 6.9 months, mOS 19.4 months
      • Lu S
      • Fang J
      • Li X
      • et al.
      Final OS results and subgroup analysis of savolitinib in patients with MET exon 14 skipping mutations (METex14+) NSCLC.
      7.3 months
      No sub-group analysis was done. Data not stratified for first- and second-line treatments, this data is for both lines of treatment.
      Efficacy 2L+ORR47.7%
      Results shown are for the patients enrolled based on tissue biopsy.
      51.4%
      Results shown are for the patients enrolled based on tissue biopsy.
      41.0%40.5%36.6%
      mDoR10.1 months
      Results shown are for the patients enrolled based on tissue biopsy.
      8.3 months
      Results shown are for the patients enrolled based on tissue biopsy.
      9.7 months9.7 months9.1 months
      No sub-group analysis was done. Data not stratified for first- and second-line treatments, this data is for both lines of treatment.
      mPFS/mOSmPFS 11.1 months
      Results shown are for the patients enrolled based on tissue biopsy.
      ; mOS 22.3 months
      Results shown are for the patients enrolled based on tissue biopsy.
      • Felip E
      • Garassino MC
      • Hiroshi S
      • et al.
      Tepotinib in patients with MET exon 14 skipping NSCLC as identified by liquid or tissue biopsy.
      mPFS 11.1 months
      Results shown are for the patients enrolled based on tissue biopsy.
      ; mOS 26.8 months
      Results shown are for the patients enrolled based on tissue biopsy.
      mPFS 5.4 monthsmPFS 6.9 months, mOS 10.9 months
      • Lu S
      • Fang J
      • Li X
      • et al.
      Final OS results and subgroup analysis of savolitinib in patients with MET exon 14 skipping mutations (METex14+) NSCLC.
      7.3 months
      No sub-group analysis was done. Data not stratified for first- and second-line treatments, this data is for both lines of treatment.
      SafetyOedema, nausea, diarrhoea, increased blood creatinine, hypoalbuminemia; manageable AEs, especially grade 3+ (29.6%) with a lower rate of discontinuations due to AEs (14.1%)
      • Thomas M
      • Reinmuth N
      • Wermke M
      • et al.
      Tepotinib in patients with MET exon 14 skipping non-small cell lung cancer: Interim analysis of VISION Cohorts A and C.
      Peripheral oedema, creatinine increase, diarrhoea; 29.5% with Grade 3+ AEs; leading to dose reduction (29.5%) and permanent discontinuation (14.8%)Peripheral oedema, nausea, vomiting, increased blood creatinine, dyspnoea, fatigue and decreased appetite; 67% had grade 3+ AEs, managed with dose reduction (23%) or discontinuation (11%)Peripheral oedema, nausea, increased AST/ALT, vomiting and hypoalbuminemia; 46% had grade 3+ TRAEs – managed with dose reduction or discontinuationOedema, vision disorder, nausea, diarrhoea, vomiting, fatigue and constipation; less grade 3 TRAEs (4% elevated transaminases and 4% dyspnoea); only 3 grade 4 AEs – managed with dose reduction (38%) or discontinuation (7%)
      1L = first line; 2L = second line; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate transaminase; BID = twice daily; CNS = central nervous system; DNA = deoxyribonucleic acid; DoR = duration of response; MET/c-MET = mesenchymal-epithelial transition; MoA = mechanism of action; mOS = median overall survival; mPFS = median progression-free survival; N/A = not applicable; NGS = next-generation sequencing; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; QD = once daily; RT-PCR = real-time polymerase chain reaction; TRAE = treatment-related adverse event.
      a Results shown are for the patients enrolled based on tissue biopsy.
      b No sub-group analysis was done. Data not stratified for first- and second-line treatments, this data is for both lines of treatment.
      The trial used both liquid biopsy (Guardant360 NGS panel or Archer DX MET Variant Test on the Reveal DX Assay) and RNA from tissue biopsy (Oncomine Focus Assay® or Archer DX® MET Variant Test on the Reveal DX Assay), to detect MET ex14 skipping, and both were found to be concordant for predicting treatment outcome.

      Capmatinib

      Capmatinib is also an oral selective MET inhibitor but is given twice daily (BID).
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      ,
      • Wolf J
      • Seto T
      • Han JY
      • et al.
      Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer.
      It was the first US Food and Drug Administration-approved targeted therapy for MET ex14 metastatic NSCLC and is now approved in Asia in Japan, Korea, Taiwan, Thailand, Hong Kong, and India.
      The GEOMETRY mono-1 trial
      • Wolf J
      • Seto T
      • Han JY
      • et al.
      Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer.
      for capmatinib was also a prospective, non-randomised, open-label phase II study that recruited patients with advanced or metastatic MET dysregulated NSCLC. Patients receiving first-line treatment had higher ORR, mPFS and DoR compared with those receiving second- and third-line treatments. The reason for this difference is not well understood and is still being investigated. Capmatinib also showed some signal of activity in patients with MET GCN ≥ 10; the ORR of treatment-naïve versus previously treated patients was 40% and 29%, respectively. The common AEs were similar to tepotinib and included peripheral oedema, nausea and vomiting; 67% of patients had grade ≥ 3 AEs and the treatment-related discontinuation rate was 11%. Limited data were available on central nervous system activity (n = 13); 54% had an intracranial response.
      • Wolf J
      • Seto T
      • Han JY
      • et al.
      Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer.
      MET ex14 skipping was detected by RT-PCR on tissue biopsy-derived RNA and retrospectively validated with the Foundation One Companion diagnostics (CDx) NGS (DNA) assay.
      • Socinski MA
      • Pennell NA
      • Davies KD.
      MET exon 14 skipping mutations in non-small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations.
      Liquid biopsy was not used. Regardless of type of mutation and coexisting conditions, no trend toward using a secondary biomarker to predict for likely responders was observed.

      Savolitinib

      Savolitinib is the third selective oral MET kinase inhibitor currently available, administered QD.
      • Lu S
      • Fang J
      • Li X
      • et al.
      Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study.
      It is currently only approved in China for patients with NSCLC and MET ex14 skipping mutations who have progressive disease following prior systematic therapy or who are unable to receive chemotherapy.
      The single-arm phase II study for savolitinib (NCT02897479) demonstrated an ORR of 46.4% and 40.55% for first-line and second-line treatment, respectively. The most common TRAEs were peripheral oedema, nausea, increased aspartate transaminase (AST)/alanine transaminase (ALT), vomiting, and hypoalbuminemia; 46% of patients of patients had grade ≥ 3 TRAEs.
      MET ex14 skipping was detected using single-gene sequencing or NGS (Geneseeq Tetradecan panel) from tissue biopsies.

      Crizotinib

      Crizotinib is a multi-TKI approved for the treatment of anaplastic lymphoma kinase (ALK) or ROS1-rearranged advanced NSCLCs in 2011 and 2016, respectively, and is now available in many countries. It was originally developed to target MET
      • Sahu A
      • Prabhash K
      • Noronha V
      • Joshi A
      • Desai S.
      Crizotinib: A comprehensive review.
      since it has potent activity against c-MET and has been used off-label for patients with MET ex14 skipping.
      • Frampton GM
      • Ali SM
      • Rosenzweig M
      • et al.
      Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
      ,
      • Drilon A
      • Clark JW
      • Weiss J
      • et al.
      Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration.
      • Paik PK
      • Drilon A
      • Fan PD
      • et al.
      Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.
      • Camidge DR
      • Otterson GA
      • Clark JW
      • et al.
      Crizotinib in patients with MET-amplified NSCLC.
      • Yang X
      • Li Y
      • Duan Q
      • Zhang Q
      • He M.
      Identification of a novel MET exon 14 skipping variant in lung adenocarcinoma sensitive to crizotinib treatment.
      • Wang SXY
      • Zhang BM
      • Wakelee HA
      • et al.
      Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib.
      The PROFILE 1001 trial in advanced NSCLC
      • Drilon A
      • Clark JW
      • Weiss J
      • et al.
      Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration.
      has the most data among the MET inhibitors, and although the efficacy of crizotinib is not as high as MET-specific inhibitors (ORR of 32%, DoR of 9.1 months and mPFS of 7.3 months), it may be considered as an alternative if MET-specific inhibitors are not available.

      Guidelines

      Amongst international guidelines for MET inhibitors, the ASCO guidelines are the most current and recommend MET-targeted therapy with capmatinib or tepotinib for patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 for first-line treatment of MET ex14 skipping stage IV NSCLC.
      • Hanna NH
      • Robinson AG
      • Temin S
      • et al.
      Therapy for stage IV non–small-cell lung cancer with driver alterations: ASCO and OH (CCO) joint guideline update.

      Summary

      Small-molecule MET inhibitors (tepotinib, capmatinib, and savolitinib) are now available in a few Asian countries. There is no direct head-to-head clinical trial comparing any of these small-molecule MET inhibitors against crizotinib and such studies are unlikely to be feasible. For all three MET-specific inhibitors, efficacy appears to be higher in treatment-naïve patients than in previously treated patients
      • Lu S
      • Fang J
      • Li X
      • et al.
      Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study.
      ,
      • Felip E
      • Garassino MC
      • Hiroshi S
      • et al.
      Tepotinib in patients with MET exon 14 skipping NSCLC as identified by liquid or tissue biopsy.
      ,
      • Wolf J
      • Seto T
      • Han JY
      • et al.
      Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer.
      ; though the reason for this difference is still being studied and needs further validation. The AE profile is similar between all agents, but grade 3 and higher AEs appear to be less frequent with tepotinib
      • Lu S
      • Fang J
      • Li X
      • et al.
      Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study.
      ,
      • Felip E
      • Garassino MC
      • Hiroshi S
      • et al.
      Tepotinib in patients with MET exon 14 skipping NSCLC as identified by liquid or tissue biopsy.
      ,
      • Wolf J
      • Seto T
      • Han JY
      • et al.
      Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer.
      ; moreover, since tepotinib is given QD, a 1-step dose reduction scheme is available if AE management is required (Table 3).
      These drugs can be considered for first-line or second- or subsequent lines of treatment in metastatic NSCLC. Many patients often receive a few cycles of standard of care (SOC) therapy (usually chemotherapy +/- immune checkpoint inhibitors) before specific MET inhibitors are given, due to a delay in receiving molecular test results for MET ex14 skipping. The Thoracic Oncology Group of Australasia's ASPiRATION study (ACTRN12621000221853)

      ASPiRATION - An observational cohort study assessing the clinical impact of comprehensive genomic profiling in people with newly diagnosed metastatic lung cancer. Available at: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000221853. Accessed 8 April 2022.

      is an ongoing study evaluating upfront comprehensive genomic profiling (CGP) in all new diagnosed patients with advanced non-squamous NSCLC. The ASPiRATION and Molecular Screening and Therapeutics (MoST) platform tepotinib phase II substudy, is currently enrolling newly diagnosed patients with MET ex14 skipping mutations to evaluate the treatment benefit of the MET inhibitor tepotinib (MoST 17: ACTRN12621000811808)

      Cancer Molecular Screening and Therapeutics (MoST) Program. Available at:: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000811808. Accessed 12 April 2022.

      in Australia, and results are only expected to be available in 2024. The ASPiRATION study allows commencement of SOC therapy for two cycles while awaiting CGP results.
      Other agents being investigated include antibodies and antibody drug conjugates (ADCs); data on their safety and efficacy is still being evaluated (Table 4). Another candidate in the pipeline is REGN5093, which is a bispecific antibody in phase I/II trials (NCT04077099); results from this trial are also awaited.
      Table 4Current Therapeutic Landscape of MET exon 14 Skipping Mutations – Pipeline Drugs
      Amivantamab
      • Spira A
      • Krebs M
      • Cho BC
      • et al.
      OA15.03 Amivantamab in non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METex14) mutation: Initial results from CHRYSALIS.
      (J&J)
      Telisotuzumab vedotin
      • Camidge DR
      • Morgensztern D
      • Heist RS
      • et al.
      Phase I study of 2- or 3-week dosing of Telisotuzumab vedotin, an antibody-drug conjugate targeting c-Met, monotherapy in patients with advanced non-small cell lung carcinoma.
      (AbbVie)
      Sym015
      • Camidge DR
      • Janku F
      • Martinez-Bueno A
      • et al.
      Safety and preliminary clinical activity of the MET antibody mixture, Sym015 in advanced non-small cell lung cancer (NSCLC) patients with MET amplification/exon 14 deletion (METAmp/Ex14∆).
      (Symphogen)
      MoABispecific antibody – against EGF and MET receptorsADC – Against MET/TubulinMixture of two antibodies – helps to overcome resistance to MET inhibitors
      CNS endpoints and brain penetrationNot availableNot availableNot available
      Dosing1050 mg (< 80 kg) or 1400 mg (> 80 kg) Cycle 1 QW, cycle 2 + Q2W1.9 mg/kg Q2W and 2.7 mg/kg Q3W18 mg/kg on Cycle 1 Day 1 followed by 12 mg/kg Q2W
      TestingTissue – NGS (DNA)Tissue – lab reportedLiquid biopsy (concordant with tissue for MET ex14 skipping) and tissue
      Efficacy 1LORR--50% (n = 3 MET ex14 deletion), DCR = 100%
      DoR---
      PFS/OS--6.5 months
      Efficacy 2L+ORRCHRYSALIS – MET ex14 skipping NSCLC - 14 evaluable patients: 1L (1/2) and +2L (8/12) - previously treated with MET inhibitors (4/7) 64% PRs
      • Spira A
      • Krebs M
      • Cho BC
      • et al.
      OA15.03 Amivantamab in non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METex14) mutation: Initial results from CHRYSALIS.
      NSCLC having c-MET membrane H-score ≥150 with MET ex14 skipping mutation – only 1 in efficacy cohort – non-responder (progressive disease)Only minor responses (n = 10 MET ex14 deletion), DCR = 60%
      DoR6.5 months (range 4.3-12.2 months) 11/14 patients still on treatment--
      PFS/OS--5.4 months
      SafetyCommon AE: diarrhoea, nausea, pruritus, rash, anaemia, vomiting, dermatitis acneiform, and fatigue
      • Spira A
      • Ramalingam S
      • Neal J
      • et al.
      OA15.01 Mobocertinib in EGFR exon 20 insertion–positive metastatic NSCLC patients with disease control on prior EGFR TKI therapy.
      Common AE: fatigue, peripheral neuropathy (higher in biweekly dosing), dizziness and nausea; 65% had grade 3 AEsCommon AE: peripheral oedema, fatigue, 6 out of 45 patients in safety cohort experienced grade 3 AEs
      1L = first line; 2L = second line; ADC = antibody-drug conjugate; AE = adverse event; CNS = central nervous system; DCR = disease control rate; DoR = duration of response; EGF = epidermal growth factor; MET/c-MET = mesenchymal epithelial transition; MoA = mechanism of action; N/A = not applicable; NGS = next-generation sequencing; NSCLC = non-small cell lung cancer; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; QW = once weekly; Q2W = once every 2 weeks.

      ATORG Consensus

      Tepotinib and capmatinib (as well as savolitinib in China) can be considered in the first-line or second- or subsequent lines of treatment in patients with metastatic NSCLC harbouring MET ex14 skipping alterations. Patients can still receive SOC chemotherapy while the result from molecular testing is awaited. If MET-selective inhibitors are not accessible, crizotinib may be considered in the second-line and beyond setting.
      Question 4: Which line of treatment would you consider appropriate for MET inhibitors (first-line vs second-line and beyond), especially for NSCLC patients with mixed biomarker phenotypes e.g. PD-L1 high and MET ex14 skipping?

      ATORG Consensus

      For patients with mixed phenotypes (ie patients whose tumours harbour two actionable biomarkers e.g. PD-L1 and MET ex14 skipping, or mixed histologies), there is no comparative data (RCTs) to evaluate outcomes to targeted therapy with MET inhibitors vs SOC (chemotherapy and/or immunotherapy); thus, chemo-immunotherapy remains the standard of care, especially in the first line setting. While retrospective data have suggested elevated PD-L1 expression in MET ex14 altered patients, responses do not appear to correlate with PD-L1 expression, which is consistent with low median tumour mutation burden (TMB).
      • Sabari JK
      • Leonardi GC
      • Shu CA
      • et al.
      PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers.
      ,
      • Negrao MV
      • Skoulidis F
      • Montesion M
      • et al.
      Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer.
      More clinical data is needed before any definitive recommendations are made. In second line, targeted MET inhibitor therapy should be considered where available. At the time of disease progression, a repeat biopsy and molecular testing may be considered to determine the predominant molecular profile to guide therapy.

      MET Amplification in EGFR TKI Resistance

      Question 5: What is the role of MET amplification in EGFR TKI resistance?
      MET amplification is associated with resistance to EGFR TKIs in patients with EGFR-mutant NSCLC, and thus, concomitant inhibition of both EGFR and MET would be required to overcome resistance to EGFR TKIs.
      • Wang Q
      • Yang S
      • Wang K
      • Sun SY.
      MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer.
      Patients with NSCLC and EGFR mutations will experience disease progression with first- or second-generation TKIs due to acquired mutations that confer resistance to these drugs; 15% of patients who progress following second-line treatment with the third-generation EGFR TKI, osimertinib, have MET amplification.
      • Schmid S
      • Früh M
      • Peters S.
      Targeting MET in EGFR resistance in non-small-cell lung cancer—ready for daily practice?.
      Preliminary data have also shown that MET amplification is the most common resistance mechanism following first-line osimertinib treatment; in the FLAURA trial, 15% of patients had MET amplification.
      • Ramalingam SS
      • Cheng Y
      • Zhou C
      • et al.
      Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study.
      Several EGFR TKIs and MET inhibitor (eg tepotinib, capmatinib, savolitinib, amivantamab, and crizotinib) combinations are being explored to address acquired MET amplification (Table 5).
      Table 5EGFR TKI and MET inhibitor Combination in EGFR-Mutant NSCLC with MET Dysregulation
      RegimenPrior EGFR TKICriteria of MET DysregulationnORRmPFSmDoR
      Gefitinib + capmatinib
      • Wu Y-L
      • Zhang L
      • Kim D-W
      • et al.
      Phase Ib/II study of capmatinib (INC280) plus gefitinib after failure of epidermal growth factor receptor (EGFR) inhibitor therapy in patients with EGFR-mutated, MET factor–dysregulated non–small-cell lung cancer.
      : NCT01610336
      GefitinibIHC 3+ > 50% tumour cells or MET GCN ≥ 436

      78
      47%: GCN ≥ 6

      32%: IHC 3+
      5.49 m: GCN ≥ 6

      5.45 m: IHC 3+
      N/A
      Gefitinib + tepotinib
      • Wu Y-L
      • Cheng Y
      • Zhou J
      • et al.
      Tepotinib plus gefitinib in patients with EGFR mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial.
      (INSIGHT): NCT01982955
      1/2 G TKIIHC 2+ or 3+ and/or FISH + (GCN≥5 or MET/CEP7≥2)19

      MET amplified
      67%

      MET amplified
      16.6 m

      MET amplified
      19.9 m

      MET amplified
      Osimertinib + tepotinib (INSIGHT 2)14: NCT039407033 G TKI (first-line)FISH (GCN ≥ 5 or MET/CEP7 ≥ 2)
      • Smit EF
      • Dooms C
      • Raskin J
      • et al.
      INSIGHT 2: a phase II study of tepotinib plus osimertinib in MET-amplified NSCLC and first-line osimertinib resistance.
      For the patients enrolled based on tissue biopsy.
      90N/AN/AN/A
      Gefitinib + savolitinib
      • Yang J-J
      • Fang J
      • Shu Y-Q
      • et al.
      A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer.
      NCT02374645
      1/2/3 G TKIFISH (GCN ≥ 5 or MET/CEP7 ≥ 2)5131%4.0 months

      (EGFR T790M-negative: 4.2 m)
      5.6 months

      (EGFR T790M-negative: 7.2 m)
      Osimertinib + savolitinib (TATTON)60: NCT021434661/2 G TKI, EGFR T790M-negativeIHC 3+

      FISH (GCN ≥ 5 or MET/CEP7 ≥ 2)

      NGS(GCN ≥5)
      • Sequist LV
      • Han J-Y
      • Ahn M-J
      • et al.
      Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study.
      4262%9.0 m8.0 m
      Analysis for 36 patients.
      Osimertinib + savolitinib (TATTON)60: NCT021434663 G TKI (any line)IHC 3+

      FISH (GCN ≥ 5 or MET/CEP7 ≥ 2)

      NGS(GCN ≥5)
      • Sequist LV
      • Han J-Y
      • Ahn M-J
      • et al.
      Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study.
      6933%5.5 m7.9 m
      Osimertinib + savolitinib
      • Yu H
      • Goldberg S
      • Le X
      • et al.
      P2.01-22 ORCHARD: A phase II platform study in patients with advanced NSCLC who have progressed on first-line osimertinib therapy.
      ,
      • Yu HA
      • Ambrose H
      • Baik C
      • et al.
      ORCHARD osimertinib + savolitinib interim analysis: a biomarker-directed phase II platform study in patients (pts) with advanced non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib.
      (ORCHARD): NCT03944772
      3 G TKI (first-line)NGS

      (GCN

      7 -

      68)
      • Smit EF
      • Dooms C
      • Raskin J
      • et al.
      INSIGHT 2: a phase II study of tepotinib plus osimertinib in MET-amplified NSCLC and first-line osimertinib resistance.
      ,
      • Yu HA
      • Goldberg SB
      • Le X
      • et al.
      Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD).
      17

      MET amplified
      41%N/AN/A
      Lazertinib + amivantamab
      • Bauml J
      • Cho BC
      • Park K
      • et al.
      Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response.
      (CHRYSALIS): NCT02609776
      3 G TKI (any line)Tissue/liquid NGS

      EGFR/MET- based resistance
      1636%

      47% (IHC for EGFR/MET)
      4.9 m

      6.7 m (IHC for EGFR/MET)
      Not reached
      EGFR = epidermal growth factor receptor; FISH = fluorescence in situ hybridisation; G = generation; IHC = immunohistochemistry; GCN = gene copy number; m = months; MET = Mesenchymal Epithelial Transition; N/A = not applicable; NGS = next-generation sequencing; TKI = tyrosine kinase inhibitor.
      a For the patients enrolled based on tissue biopsy.
      b Analysis for 36 patients.
      The INSIGHT study
      • Wu Y-L
      • Cheng Y
      • Zhou J
      • et al.
      Tepotinib plus gefitinib in patients with EGFR mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial.
      was an open-label randomised trial that evaluated tepotinib in combination with gefitinib in patients with NSCLC and prior EGFR TKI resistance, versus pemetrexed and cisplatin or carboplatin. mPFS was 16.6 months (vs. 4.4 months for the chemotherapy arm) in patients with MET amplification, which appeared promising. The INSIGHT 2 study is evaluating the combination of tepotinib and osimertinib
      • Smit EF
      • Dooms C
      • Raskin J
      • et al.
      INSIGHT 2: a phase II study of tepotinib plus osimertinib in MET-amplified NSCLC and first-line osimertinib resistance.
      in treating EGFR-mutant NSCLC with acquired resistance to first-line osimertinib due to MET amplification.
      The combination of capmatinib plus gefitinib in EGFR TKI resistant, MET-dysregulated NSCLC was investigated
      • Wu Y-L
      • Zhang L
      • Kim D-W
      • et al.
      Phase Ib/II study of capmatinib (INC280) plus gefitinib after failure of epidermal growth factor receptor (EGFR) inhibitor therapy in patients with EGFR-mutated, MET factor–dysregulated non–small-cell lung cancer.
      and the best observed ORR was highest (47%) in MET-positive patients (defined as GCN ≥ 6), while the best observed ORR was 32% in patients with IHC 3+ tumours.
      Savolitinib was investigated in combination with gefitinib in patients with EGFR-mutated, MET-amplified advanced NSCLC; the overall ORRs in EGFR T790M-negative, -positive, and unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively.
      • Yang J-J
      • Fang J
      • Shu Y-Q
      • et al.
      A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer.
      In the TATTON study,
      • Han J
      • Sequist L
      • Ahn M
      • et al.
      FP14.03 Osimertinib + savolitinib in pts with EGFRm MET-amplified/overexpressed NSCLC: Phase Ib TATTON parts B and D final analysis.
      the combination of osimertinib and savolitinib in patients who progressed on EGFR TKI (first- or second- generation) and who had T790M-negative NSCLC demonstrated an ORR of 62% in 42 patients using IHC/FISH and NGS positive biomarkers. In another cohort of TATTON that evaluated the same combination in third-generation EGFR TKI-resistant NSCLC patients, the ORR was 33%.
      • Han J
      • Sequist L
      • Ahn M
      • et al.
      FP14.03 Osimertinib + savolitinib in pts with EGFRm MET-amplified/overexpressed NSCLC: Phase Ib TATTON parts B and D final analysis.
      These results are being followed up in the SAVANNAH trial,
      • Ahn M
      • Cantarini M
      • Frewer P
      • et al.
      P1.01-134 SAVANNAH: Phase II trial of osimertinib + savolitinib in EGFR-mutant, MET-driven advanced NSCLC, following prior osimertinib.
      which is currently investigating the combination of osimertinib and savolitinib in patients with EGFR-mutant NSCLC who have progressed on prior osimertinib. The ORCHARD trial
      • Yu H
      • Goldberg S
      • Le X
      • et al.
      P2.01-22 ORCHARD: A phase II platform study in patients with advanced NSCLC who have progressed on first-line osimertinib therapy.
      is also a phase II study of savolitinib in patients with EGFR-mutant NSCLC following progression with first-line osimertinib. Only 17 patients were included in the interim analysis, and ORR was 41%.
      • Yu HA
      • Ambrose H
      • Baik C
      • et al.
      ORCHARD osimertinib + savolitinib interim analysis: a biomarker-directed phase II platform study in patients (pts) with advanced non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib.
      Larger, longer-term investigations are needed for follow-up.
      CHRYSALIS is a phase I study of amivantamab and lazertinib for patients with EGFR-mutant NSCLC post-osimertinib.
      • Bauml J
      • Cho BC
      • Park K
      • et al.
      Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response.
      The biomarker used was IHC positive for EGFR/MET with a combined H-score of over 400. The results were encouraging – among 45 patients, ORR was 36%, and mPFS was 4.9 months; for patients positive for the EGFR/MET resistance biomarker, the ORR was higher (47%) and the mPFS was longer (6.7 months). The IHC analysis suggests high EGFR/MET expression may be an alternative approach to identify potential responders, but this biomarker needs further validation.
      In summary, MET amplification is a common resistance mechanism associated with EGFR TKI treatment, and the combination of MET inhibitors and EGFR TKIs has shown promising results in patients with EGFR-mutant NSCLC who failed prior EGFR TKIs due to MET amplification. EGFR TKIs and a MET inhibitor combination in EGFR-mutant NSCLC patients with MET dysregulation usually show a 30% to 50% ORR and mDoR of 10 months.

      ATORG Consensus

      EGFR TKIs are standard first-line treatments for advanced EGFR-mutated NSCLC. Data are emerging showing activity for various MET inhibitors combined with EGFR TKIs in patients progressing after first-line EGFR TKIs due to acquired MET amplification. However, until more comparative data emerge, and drugs become specifically available for use in this clinical setting, current SOC for patients with EGFR-mutant NSCLC that have MET amplification (causing EGFR TKI resistance) is chemotherapy. This may be handled on a case-by-case basis based on toxicity and patient preference.
      The ATORG recommendation is to enrol patients into clinical trials investigating the combination of selective MET inhibitors and EGFR TKIs for patients with EGFR-mutant NSCLC, such that robust clinical data can be obtained.
      Question 6: What is the appropriate selection biomarker in clinical trials done to date?
      The criteria for defining MET amplification varies between different assays and the cut-off threshold for observing benefits from MET inhibitors is not yet well-defined. Definitive cut-off values of MET amplification using FISH and NGS are still to be implemented, and more validation is needed of the potential biomarker for EGFR/MET by IHC which has been used in the amivantamab and lazertinib combination study.

      ATORG Consensus

      Clinical studies investigating the combination of EGFR TKIs and MET inhibitors to date are largely phase I or II and MET FISH testing should be done primarily for consideration for enrolment into clinical trials. FISH can be used for detecting MET amplification; and NGS may have a broader role in detecting MET alterations through accurate inferences for the MET GCN and through its applicability in testing for multiple resistance mechanisms. The recommendation is to exclude testing for MET amplification in patients with T790M-positive EGFR-mutant NSCLC progressing after first-line EGFR TKIs. However, for EGFR-mutant NSCLC patients with the EGFR T790M mutation receiving osimertinib as second-line therapy, MET amplification can also be acquired upon the disease progression,
      • York ER
      • Varella-Garcia M
      • Bang TJ
      • Aisner DL
      • Camidge DR.
      Tolerable and effective combination of full-dose crizotinib and osimertinib targeting MET amplification sequentially emerging after T790M positivity in EGFR-mutant non-small cell lung cancer.
      and thus this subgroup should be tested for MET amplification.

      Access and Reimbursement of MET Testing and MET Inhibitors

      There is considerable heterogeneity in APAC regarding access and testing for MET alterations, as well as availability of MET inhibitors.
      Question 7: What is the availability of routine MET testing in APAC?
      With respect to diagnostic testing, selected countries in APAC utilize commercial NGS panels for NSCLC mutation testing (including Singapore, Japan, China, Australia, Korea, and Malaysia), although this is reimbursed only in Korea and Japan. Only a small proportion of clinics have access to the newer liquid biopsy-based methodologies. Customised RNA/DNA panels for MET ex14 skipping testing are used in countries like the Philippines. However, not all customised panels currently include MET as a standard gene for testing. For MET amplification, testing is even more heterogeneous with different countries using FISH, IHC, and NGS on liquid and tissue biopsies. In Vietnam, tests for detecting MET ex14 skipping and MET amplification are only available in ongoing clinical trials.

      ATORG Consensus

      The diagnostic challenges associated with MET testing include the lack of standardisation, no national funded programmes, choice of tests based on local test availability and institutional and vendor-biased access programmes, and some through clinical trials. The group recommends that MET ex14 testing should be part of a multiplex gene panel testing for key actionable alterations using a locally validated test.
      Question 8: Are selective MET inhibitors accessible in APAC, and are these eligible for medical reimbursement?
      Selective MET inhibitors are approved for clinical use in only a few APAC countries (Figure 1). Tepotinib is available in Australia, Japan, Korea, Hong Kong, Singapore, China, and Taiwan, but is reimbursed only in Japan, while in Singapore patients can obtain subsidies through national programmes. Capmatinib is approved in Hong Kong, Japan, Korea, Singapore, Taiwan, and Thailand, but reimbursement is provided only in Japan; in Singapore patients can obtain subsidies through national programmes. Savolitinib is only approved in China. Some of these inhibitors, as well as new agents such as amivantamab, are available through ongoing clinical trials or via compassionate use programmes in countries such as Malaysia and the Philippines.

      ATORG Consensus

      There is considerable heterogeneity in the region with regards to access and reimbursement of selective MET inhibitors. Given the emerging clinical benefits of these drugs in the treatment of patients with NSCLC with this specific oncogenic driver, the group believes that this consensus publication will help improve scientific awareness and eventual access to these targeted treatments in the APAC region.

      Conclusions

      The ATORG group recommends testing for MET mutations (MET ex14 skipping) in patients with advanced and metastatic NSCLC as a part of multiplex gene panel for detecting oncogenic driver mutations. Patients with MET ex14 skipping, should be considered for MET-specific inhibitors in the first-line or as salvage therapy following progression of first-line therapy. The group also encourages patient enrolment in clinical trials investigating the combination of selective MET inhibitors and EGFR TKIs (such as the INSIGHT214 and SAVANNAH
      • Ahn M
      • Cantarini M
      • Frewer P
      • et al.
      P1.01-134 SAVANNAH: Phase II trial of osimertinib + savolitinib in EGFR-mutant, MET-driven advanced NSCLC, following prior osimertinib.
      trials) for EGFR-mutant NSCLC who are identified to have acquired MET amplification.
      The ATORG group believes that these consensus recommendations will improve awareness of best practice, as MET-specific inhibitors become available for clinical use in different countries. Moreover, ATORG believes that this position statement could potentially help with implementation of standardised testing for MET within broader panels for molecular profiling of actionable biomarkers in NSCLC and access to MET-specific targeted therapies within countries in this region.

      Authors’ contribution

      M-JA: Conceptualization, Writing - review & editing; MJLM: Conceptualization, Writing - review & editing; NP: Conceptualization, Writing - review & editing; TK: Conceptualization, Writing - review & editing; RAS: Conceptualization, Writing - review & editing; D-WK: Conceptualization, Writing - review & editing; CKL: Conceptualization, Writing - review & editing; T-CH: Conceptualization, Writing - review & editing; CKL: Conceptualization, Writing - review & editing; TR: Conceptualization, Writing - review & editing; SG: Conceptualization, Writing - review & editing; OSHC: Conceptualization, Writing - review & editing; NP: Conceptualization, Writing - review & editing; BJS: Conceptualization, Writing - review & editing; TTHN: Conceptualization, Writing - review & editing; TK: Conceptualization, Writing - review & editing; JC-HY: Conceptualization, Writing - review & editing; Y-LW: Conceptualization, Writing - review & editing; TSKM: Conceptualization, Writing - review & editing; DSWT: Conceptualization, Funding acquisition, Writing - original draft, Writing - review & editing; YY: Conceptualization, Writing - review & editing.

      Acknowledgments

      Independent medical writing support was provided by Radhika Das Chakraborty, PhD and Isabelle Zhu, of MediTech Media Singapore. The consensus meeting and manuscript was funded via a medical writing grant from Merck KGaA. Authors maintained full control and the funder was not involved in the writing of this article or the decision to submit it for publication.

      Disclosure

      Myung-Ju Ahn has received consulting fees from AstraZeneca, Eli Lilly, MSD, Merck, Amgen, Takeda, Daichi Sankyo, Yuhan, Alpha pharmaceuticals, Novartis, Arcus and Pfizer, and honoraria from AstraZeneca, Eli Lilly, MSD, Merck, Amgen, Takeda, Ono and Yuhan. She has also participated in advisory board meetings for Arcus. Marvin Jonne L. Mendoza has received an honorarium from the Department of Health and Asia Pacific Center for Evidence Based Healthcare, Inc. Nick Pavlakis has received grants/research support from Bayer, Pfizer and Roche, and consulting fees from Novartis, Boehringer Ingelheim, Roche, Takeda, MSD, Merck, BMS, Amgen, Beigene, ALLVascular, Pfizer and AstraZeneca. He has also received honoraria from Boehringer Ingelheim, Roche, Takeda and Pierre-Fabre. Terufumi Kato has received grants from AbbVie, Amgen, AstraZeneca, Blueprint, Chugai, Eli Lilly, Haihe, Merck Biopharma, MSD, Novartis, Pfizer, Regeneron and Takeda. He has also received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Merck Biopharma, MSD, Novartis, Ono, Pfizer and Roche. Ross A. Soo has participated in advisory boards for Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Janssen, Eli Lilly, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Taiho, Takeda, Yuhan, and has received grants/research support from AstraZeneca and Boehringer Ingelheim. Dong-Wan Kim has received grants/research support from Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiichi-Sankyo, GSK, Hanmi, Janssen, Merck, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery and Yuhan, and honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Daiichi-Sankyo, GSK, Pfizer, MSD, Merck, Novartis, Roche, Takeda and Yuhan for medical writing assistance. He has participated in advisory board meetings for Amgen, AstraZeneca, BMS/Ono Pharmaceuticals, Daiichi-Sankyo, GSK, Janssen, Merck, MSD, Pfizer, SK Biopharm and Takeda, and has received support for attending these meetings from Amgen and Daiichi-Sankyo. Chong Kin Liam has received grants/research support from AstraZeneca and Boehringer Ingelheim and honoraria from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Zuellig Pharma. He has participated in advisory board meetings for AstraZeneca, Boehringer Ingelheim, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Zuellig Pharma, and has received support for attending these meetings from AstraZeneca, Boehringer Ingelheim and Merck. Te-Chun Hsia has received an honorarium from Merck and also participated in advisory board meetings for Merck. Chee Khoon Lee has received research support from AstraZeneca, Roche and Merck. He has also received honoraria from AstraZeneca, Pfizer, Amgen, Takeda, Yuhan, Boehringer Ingelheim, Roche, MSD, GSK, Novartis, Merck, and has provided consulting or advisory services to Novartis, Boehringer Ingelheim, Takeda, AstraZeneca, Yuhan and Amgen. Thanyanan Reungwetwattana has received honoraria from AstraZeneca, Roche, Pfizer, Novartis, MSD and BMS. She has received payments associated with expert testimonies provided at advisory boards meetings for AstraZeneca, Roche, Novartis, Pfizer, MSD, BMS, Yuhan, Amgen, Zuellig and Boehringer Ingelheim. She also received research grants from AstraZeneca, Roche, Novartis, MSD and Yuhan. Sarayut Geater has received honoraria from Novartis, AstraZeneca, Merck and Roche. Siu Hong Oscar Chan has received honoraria from AstraZeneca, Bristol-Myers Squibb, Novartis, Takeda and Merck, and support for attending advisory board meetings for Takeda. He has participated in advisory board meetings for Merck Serono, Pfizer and Takeda. Naiyarat Prasongsook has received honoraria from AstraZeneca, Novartis and Roche, and has attended advisory board meetings for Roche, Merck and Novartis. Benjamin J. Solomon has received consulting fees from AstraZeneca, Pfizer, Roche (Genentech), Novartis, BeiGene and Eli Lilly, Amgen, Merck Serono, MSD and Takeda, and has received honoraria from AstraZeneca, Pfizer, Roche (Genentech), Novartis, BeiGene, Eli Lilly, Amgen, Merck Serono, MSD and Takeda. Toshiyuki Kozuki has received grants/research support from Daiichi-Sankyo, Chugai, AstraZeneca, Taiho, Eli Lilly, Bristol-Myers Squibb, Ono, MSD, Kyowa Hakko Kirin, Merck, AbbVie, Amgen, Sanofi, Eisai and Labcorp, and honoraria from Chugai, Ono, AstraZeneca, Eli Lilly, Taiho, Bristol-Myers Squibb, MSD, Nippon Kayaku, Nippon, Boehringer Ingelheim, Merck, Pfizer, Takeda, Kyowa Hakko Kirin, Novartis, Daiichi-Sankyo, AbbVie, Bayer and Sawai. James Chih-Hsin Yang has received personal and institutional fees from Daiichi-Sankyo, Merck, MSD, Novartis, Roche (Genentech), Takeda and Yuhan, and has received institutional fees from Eli Lilly, JNJ, Puma Technology, Gilead and GSK, and personal fees from Ono Pharmaceuticals and Pfizer. Yi-Long Wu has received grants/research support from AstraZeneca, BMS and Pfizer, and honoraria from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Hengrui, Merck Sharp & Dohme, Pfizer, Sanofi and Roche. Tony Shu Kam Mok has received grants from AstraZeneca, BMS, G1 Therapeutics, F. Hoffman-La Roche, MSD, Merck Serono, Novartis, SFJ Pharmaceuticals, Pfizer, Takeda and Xcovery. He has received consulting fees from AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines Corporation, BMS, CStone Pharmaceuticals, Curio Science, Daiichi Sankyo, Eisai, Fishawack Facilitate, Gritstone Oncology Inc, Guardant Health, Hengrui Therapeutics Inc, Ignyta Inc, Incyte Corporation, Inivata, IQVIA, Janssen, Eli Lilly, Loxo-Oncology, Lunit USA Inc, Merck Serono, MSD, Mirati Therapeutics Inc, MoreHealth, Novartis, OrigiMed, Pfizer, Puma Biotechnology Inc, Qiming Development (Hong Kong), Roche/Genentech, Sanofi-Aventis, SFJ Pharmaceuticals, Takeda, Vertex Pharmaceuticals, Yuhan, D3 Bio, C4 Therapeutics, Gilead, G1 Therapeutics. He has also received honoraria from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Daiichi Sankyo, Fishawack Facilitate, InMed Medical Communication, Eli Lilly, MD Health Brazil, Medscape LLC, MSD, Novartis, OrigiMed, P. Permanyer SL, PeerVoice, Physicians’ Education Resource, Pfizer, PrIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics, FoundationOne, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting, Liangyihui Network Technology, Taiho, Takeda Oncology, touchIME, Lucence Health and Daz Group. He held compensated leadership roles in AstraZeneca PLC, HutchMed, Lunit USA, Aurora Tele-Oncology and ACT Genomics-Sanomics Group and uncompensated roles in American Society of Clinical Oncology (ASCO), Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), International Association for the Study of Lung Cancer (IASLC), St. Stephen's College & Prep. School. He is also a stock shareholder of Aurora Tele-Oncology, HutchMed, ACT Genomics-Sanomics Group and holds stock options from Lunit USA and Loxo-Oncology. Daniel Shao-Weng Tan has received grants/research support from Amgen, Novartis, GlaxoSmithKline, AstraZeneca and Pfizer; consulting fees from Novartis, Bayer, Boehringer Ingelheim, AstraZeneca, Eli Lilly, MSD, GlaxoSmithKline and LOXO, as well as honoraria from Takeda, Novartis, Roche, Pfizer, Merck and Boehringer Ingelheim. Yasushi Yatabe has received grants/research support from ArcherDx, Chugai-Pharma, Thermo Fisher Science and Konika Minolta; honoraria from AbbVie Inc., Amgen, Bayer, Ono-Pharma, Daiichi-Sankyo, Eli-Lilly, Merck Bio-Pharma, Pfizer, Merck Sharp & Dohme, Novartis, AstraZeneca, Agilent/Dako, ArcherDx, Sysmex, Chugai-Pharma, Boehringer Ingelheim, Yansen-Pharma, Roche/Ventana, Thermo Fisher Science and Takeda; and has participated in advisory board meetings for Merck Sharp & Dohme, Chugai-Pharma, AstraZeneca, Novartis, Amgen, Takeda and Daiichi-Sankyo.
      Thi Thai Hoa Nguyen has no conflicts of interest to declare.

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