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BIOMARKER:

MET amplification

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Other names: DFNB97, AUTS9, RCCP2, C-Met, HGFR, HGF Receptor, Met Proto-Oncogene, HGF/SF Receptor, Proto-Oncogene C-Met, Scatter Factor Receptor, Tyrosine-Protein Kinase Met, Hepatocyte Growth Factor Receptor, MET, MET Proto-Oncogene, Receptor Tyrosine Kinase
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Entrez ID:
1d
Asian Thoracic Oncology Research Group (ATORG) Expert Consensus Statement on MET Alterations in NSCLC: Diagnostic and Therapeutic Considerations. (PubMed, Clin Lung Cancer)
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.
Review • Journal
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EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase)
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EGFR mutation • MET amplification • MET exon 14 mutation
2d
Optimal Treatments for NSCLC Patients Harboring Primary or Acquired MET Amplification. (PubMed, Technol Cancer Res Treat)
In our cohort of patients harboring primary MET amplification, crizotinib displayed better efficacy than immunotherapy and chemotherapy, as demonstrated both in first-line (P = .0378) and second-line treatment regimens (P = .0181). MET-TKIs might be an optional treatment with worth-expecting efficacy. However, chemotherapy plus bevacizumab could benefit the subpopulation of patients harboring acquired MET amplification after the failure of EGFR-TKIs.
Journal • PD(L)-1 Biomarker • IO biomarker
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EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • MET (MET proto-oncogene, receptor tyrosine kinase)
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PD-L1 expression • PD-L1 overexpression • MET amplification • MET mutation • MET expression
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Avastin (bevacizumab) • Xalkori (crizotinib)
2d
Mutational Landscape and Expression of PD-L1 in Patients with Non-Small Cell Lung Cancer Harboring Genomic Alterations of the MET gene. (PubMed, Target Oncol)
We demonstrated that MET exon 14 skipping alterations and MET amplification are not mutually exclusive to other oncogenic co-mutations, and report the association of genomic MET alterations with PD-L1 expression. Since genomic MET alterations are emerging targets requiring upfront treatment, optimal understanding of the co-mutational landscape for this patient population is needed.
Journal • PD(L)-1 Biomarker • IO biomarker
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EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • MET (MET proto-oncogene, receptor tyrosine kinase) • CDK4 (Cyclin-dependent kinase 4)
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PD-L1 expression • TP53 mutation • KRAS mutation • EGFR mutation • BRAF mutation • MET amplification • MET exon 14 mutation • MET mutation • MET expression • MET D1228N
2d
Response to osimertinib plus trametinib in a heavily treated epidermal growth factor receptor (EGFR)-positive NSCLC harboring a rare, acquired rapidly accelerated fibrosarcoma B-type (BRAF) p.D594N mutation: a case report. (PubMed, Anticancer Drugs)
Herein, we present a case in which an EGFR-positive, MET-amplified nonsmall cell lung cancer (NSCLC) patient acquired BRAF p.D594N mutation on third-line osimertinib plus crizotinib and responded to seventh-line treatment with osimertinib plus MEK inhibitor trametinib. To the best of our knowledge, our case is the first to provide clinical evidence that trametinib plus osimertinib was effective for EGFR-mutant NSCLC patients with acquired BRAF p.D594N mutation. More supporting data and systematic validation studies are needed for comprehensive understanding of this therapy strategy and future applications.
Journal
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EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • MET (MET proto-oncogene, receptor tyrosine kinase)
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EGFR mutation • BRAF mutation • MET amplification • EGFR positive • BRAF D594N
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Xalkori (crizotinib) • Mekinist (trametinib) • Tagrisso (osimertinib)
3d
Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multicentric Retrospective French Study. (PubMed, Target Oncol)
We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation-positive NSCLC. At progression, the most frequent histomolecular alterations were MET amplification and EGFR C797S mutation.
Retrospective data • Journal
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EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • CCDC6 (Coiled-Coil Domain Containing 6)
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EGFR mutation • MET amplification • RET fusion • EGFR C797S • CCDC6-RET fusion
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Tagrisso (osimertinib)
4d
Dual inhibition of BCL2L1 and MCL1 is highly effective against RET fusion-positive or MET exon 14 skipping mutation-positive lung adenocarcinoma cells. (PubMed, Biochem Biophys Res Commun)
Moreover, we found that most LUAD cell lines and tissues expressed high levels of BCL2L1 and MCL1 mRNA but extremely low levels of BCL2. Together, these findings suggest that inhibiting BCL2L1 plus MCL1 may represent a new approach to treating LUAD cells irrespective of their driver mutations.
Journal • IO biomarker
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MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • BCL2 (B-cell CLL/lymphoma 2) • CCDC6 (Coiled-Coil Domain Containing 6) • BCL2L1 (BCL2-like 1)
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MET amplification • RET fusion • MET exon 14 mutation • RET mutation • CCDC6-RET fusion • BCL2 expression • MCL1 expression • RET positive
6d
Genotyping of cerebrospinal fluid in lung cancer patients with leptomeningeal metastasis. (PubMed, Thorac Cancer)
In conclusion, CSF could be superior to plasma in providing a more comprehensive genetic landscape of LM to find out drug resistance mechanisms and guide subsequent treatments.
Retrospective data • Journal
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EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • RB1 (RB Transcriptional Corepressor 1)
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EGFR mutation • MET amplification • EGFR amplification • ALK rearrangement • ROS1 fusion • MET mutation • RB1 mutation
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Tagrisso (osimertinib)
6d
Refining patient selection of MET-activated non-small cell lung cancer through biomarker precision. (PubMed, Cancer Treat Rev)
MET exon 14 skipping mutation (METex14) was established as a strong predictor of response to selective MET tyrosine kinase inhibitors (TKIs), and clinical trial results in patients with non-small cell lung cancer (NSCLC) harboring METex14 led to the approval of capmatinib and tepotinib by regulatory agencies worldwide. This review summarizes the current methods used for the detection of METex14, MET amplification and MET overexpression, and discusses the evidence for the use of MET-TKIs in patients with NSCLC with MET dysregulation. We discuss the practical challenges that impact the use of METex14 in the clinic and the evidence gaps that need to be addressed to validate additional genomic markers for MET-dependent cancers.
Review • Journal
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MET (MET proto-oncogene, receptor tyrosine kinase)
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MET amplification • MET exon 14 mutation • MET overexpression • MET amplification + MET overexpression
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Tabrecta (capmatinib) • Tepmetko (tepotinib)
11d
MET gene amplification is a mechanism of resistance to entrectinib in ROS1+ NSCLC. (PubMed, Thorac Cancer)
Treatment with ROS1-selective inhibitors may lead to MET-mediated resistance. The discovery of ecDNA MET amplification is noteworthy, as ecDNA is associated with more aggressive cancers. Following progression on ROS1-selective inhibitors, MET gene testing and treatments targeting MET should be explored to overcome MET-driven resistance.
Journal
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MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CD74 (CD74 Molecule) • TPM3 (Tropomyosin 3)
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MET amplification • MET exon 14 mutation • ROS1 fusion • MET mutation • ROS1 mutation
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Rozlytrek (entrectinib)
13d
Tepotinib + Gefitinib in Patients with EGFR-Mutant NSCLC with MET Amplification (METamp): Final Analysis of INSIGHT (IASLC-NACLC 2022)
19/55 randomized patients (34.5%) had METamp (MET IHC 3+, n=17; median age: 60.4 years; never-smokers: 68.4%; prior EGFR inhibitors: gefitinib [57.9%], afatinib [21.1%], erlotinib [10.5%], and icotinib [10.5%]). Tepotinib + gefitinib greatly improved PFS and OS versus chemotherapy in patients with EGFR-mutant NSCLC with METamp.
Clinical
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EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase)
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EGFR mutation • EGFR T790M • MET amplification • MET overexpression • MET mutation • EGFR T790M negative
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erlotinib • Gilotrif (afatinib) • gefitinib • Conmana (icotinib) • Tepmetko (tepotinib)
13d
Clinical Response to Tepotinib According to Circulating Tumor (ct)DNA Biomarkers in Patients with Advanced/Metastatic NSCLC with High-level MET Amplification (METamp) Detected by Liquid Biopsy (LBx) (IASLC-NACLC 2022)
Tepotinib showed meaningful activity, especially in first line, in the first trial of a MET inhibitor in EGFR WT NSCLC with high-level METamp to enroll based on a convenient LBx assay. Serial LBx could monitor molecular response and evaluate resistance.
Clinical • Liquid biopsy • Circulating tumor DNA
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EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RB1 (RB Transcriptional Corepressor 1)
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MET amplification • EGFR wild-type • MET exon 14 mutation • RB1 mutation
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Guardant360® CDx
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Tepmetko (tepotinib)
13d
Nivolumab, Cabozantinib S-Malate, and Ipilimumab in Treating Patients With Recurrent Stage IV Non-small Cell Lung Cancer (clinicaltrials.gov)
P2, N=3, Active, not recruiting, National Cancer Institute (NCI) | N=169 --> 3 | Trial completion date: Dec 2022 --> Sep 2023 | Trial primary completion date: Dec 2022 --> May 2022
Enrollment change • Trial completion date • Trial primary completion date
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EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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EGFR L858R • EGFR exon 19 deletion • MET amplification • ALK rearrangement • MET exon 14 mutation • EGFR L861Q • RET rearrangement • EGFR G719X • EGFR negative • MET-H
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Opdivo (nivolumab) • Yervoy (ipilimumab) • Cabometyx (cabozantinib tablet) • Cometriq (cabozantinib capsule)
14d
Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing. (PubMed, JTO Clin Res Rep)
METex14 splicing alterations and MET co-amplification translated to higher and synergistic MET expression at the transcriptomic level. High frequencies of MDM2 and CDK4 co-amplifications and association with multiple immunosuppressive checkpoints and angiogenic pathways provide insight into potential actionable targets for combination strategies in METex14 NSCLC.
Journal • Tumor Mutational Burden • PD(L)-1 Biomarker
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PD-L1 (Programmed death ligand 1) • TMB (Tumor Mutational Burden) • MET (MET proto-oncogene, receptor tyrosine kinase) • MDM2 (E3 ubiquitin protein ligase) • CDK4 (Cyclin-dependent kinase 4) • HMGA2 (High mobility group AT-hook 2)
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TMB-H • MET amplification • MET exon 14 mutation • MET mutation • CDK4 amplification • MET expression
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MI Tumor Seek™
16d
Chlorpromazine cooperatively induces apoptosis with tyrosine kinase inhibitors in EGFR-mutated lung cancer cell lines and restores the sensitivity to gefitinib in T790M-harboring resistant cells. (PubMed, Biochem Biophys Res Commun)
When utilized in combination with trametinib (a MEK inhibitor), dabrafenib (an RAF inhibitor), and everolimus (an mTOR inhibitor), CPZ suppressed the growth of PC9ZD cells cooperatively with everolimus but not with trametinib or dabrafenib. However, after CPZ treatment, EGFR was unevenly distributed in the cells, and colocalization with the early endosome marker Rab5 and EEA1 became more apparent, indicating that CPZ disrupted the intracellular transport of EGFR. These results suggest that CPZ has therapeutic potential for NSCLC with mutated EGFR by a novel mechanism different from conventional TKIs alone or in combination with other agents.
Preclinical • Journal
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EGFR (Epidermal growth factor receptor) • FLT3 (Fms-related tyrosine kinase 3) • MET (MET proto-oncogene, receptor tyrosine kinase) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • RAB5A (Ras-related protein Rab-5A)
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EGFR mutation • FLT3-ITD mutation • EGFR exon 19 deletion • EGFR T790M • MET amplification • KIT D816V
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Mekinist (trametinib) • Tafinlar (dabrafenib) • gefitinib • everolimus • chlorpromazine
18d
MOLECULAR SCREENING OF ADVANCED SARCOMAS THROUGH NEXT-GENERATION SEQUENCING IN A TERTIARY UNIVERSITY HOSPITAL (CTOS 2022)
One patient with a BRAF-mutated MPNST was treated with BRAF/MEK inhibitors encorafenib and binimetinib, reaching partial response and a progression free survival of 7 months...Crizotinib was used in two heavily pretreated patients (one ROS1-rearranged liposarcoma and one ALK-rearranged liposarcoma), with disappointing outcomes... Nowadays, cytotoxic chemotherapy still remains the front-line therapy in most locally advanced and metastatic unresectable sarcomas. Considering the low response rates to standard treatment, the fact that effective therapeutic alternatives are scarce, and the young age of many of these patients, there is an urgent need for the development of novel therapies. A profound understanding of the molecular mechanisms of sarcomagenesis is essential to propel the era of personalized medicine in advanced sarcomas.
Clinical • Next-generation sequencing
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ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B)
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BRAF V600E • BRAF V600 • PIK3CA mutation • MET amplification • ALK rearrangement • ROS1 rearrangement • ALK rearrangement + PIK3CA mutation
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Xalkori (crizotinib) • Braftovi (encorafenib) • Mektovi (binimetinib)
18d
CoC: A Study Comparing Savolitinib Plus Osimertinib vs Savolitinib Plus Placebo in Patients With EGFRm+ and MET Amplified Advanced NSCLC (clinicaltrials.gov)
P2, N=30, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | N=56 --> 30 | Trial completion date: Feb 2024 --> Dec 2024
Enrollment closed • Enrollment change • Trial completion date • Combination therapy
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EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase)
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EGFR mutation • EGFR L858R • EGFR exon 19 deletion • MET amplification
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Tagrisso (osimertinib) • Orpathys (savolitinib)
18d
Efficacy and potential resistance mechanisms of afatinib in advanced non-small cell lung cancer patients with EGFR G719X/L861Q/S768I. (PubMed, Cancer)
The present study elucidated the differential benefits of afatinib within different mutation genotypes and first revealed the spectrum of potential resistance mechanisms in patients with EGFR G719X/L861Q/S768I. The results of this study may provide practical clinical information that can guide optimal treatment in this setting.
Journal
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • FGFR1 (Fibroblast growth factor receptor 1) • CDK4 (Cyclin-dependent kinase 4)
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TP53 mutation • EGFR mutation • HER-2 amplification • BRAF mutation • PIK3CA mutation • HER-2 mutation • EGFR T790M • MET amplification • RET fusion • TP53 wild-type • FGFR1 amplification • EGFR L861Q • PIK3CA amplification • EGFR G719X • CDK4 amplification • EGFR S768I • BRAF amplification
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Gilotrif (afatinib)
19d
MET-induced CD73 restrains STING-mediated immunogenicity of EGFR-mutant lung cancer. (PubMed, Cancer Res)
Pemetrexed (PEM), which is commonly used following EGFR-TKI treatment failure, was identified as an effective potentiator of STING-dependent TBK1-IRF3-STAT1 signaling in MET-amplified, EGFR TKI-resistant cells...Using a physiologic antigen recognition model, inactivation of CD73 significantly increased antigen-specific CD8+ T-cell immunogenicity following PEM treatment. These data reveal that combined PEM and CD73 inhibition can co-opt tumor cell STING induction in TKI resistant EGFR-mutated lung cancers and promote immunogenicity.
Journal • IO biomarker
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EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase) • CD8 (cluster of differentiation 8) • STING (stimulator of interferon response cGAMP interactor 1) • STAT1 (Signal Transducer And Activator Of Transcription 1)
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EGFR mutation • MET amplification
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pemetrexed
19d
Acquired Genomic Alterations on First-Line Chemotherapy With Cetuximab in Advanced Colorectal Cancer: Circulating Tumor DNA Analysis of the CALGB/SWOG-80405 Trial (Alliance). (PubMed, J Clin Oncol)
We performed next-generation sequencing (Guardant360) on circulating tumor DNA obtained from paired plasma samples (pretreatment and postprogression) from the CALGB/SWOG-80405 trial, which randomly assigned patients with mCRC between first-line chemotherapy with cetuximab (anti-EGFR-chemotherapy) or bevacizumab (anti-VEGF-chemotherapy). Acq-GAs, classically associated with anti-EGFR-antibody resistance in later lines (RAS, BRAF, and EGFR-ectodomain mutations; ERBB2 and MET amplifications), were rare with up-front use of anti-EGFR-chemotherapy indicating divergent resistance mechanisms. These findings have critical translational relevance to timing and value of circulating tumor DNA-guided anti-EGFR rechallenge in patients with mCRC, especially those treated with anti-EGFR therapy upfront.
Journal • Circulating tumor DNA
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HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • MET (MET proto-oncogene, receptor tyrosine kinase)
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HER-2 amplification • BRAF mutation • HER-2 mutation • MET amplification • MET mutation
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Guardant360® CDx
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Avastin (bevacizumab) • Erbitux (cetuximab)
23d
Clinical • P2 data
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MET (MET proto-oncogene, receptor tyrosine kinase)
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MET amplification
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Tabrecta (capmatinib)
25d
Bioinformatically-expanded next-generation sequencing analysis optimizes identification of therapeutically relevant MET copy number alterations in >50,000 tumors. (PubMed, Clin Cancer Res)
Leveraging our integrated bioinformatic approach, targeted therapy benefit was observed across diverse MET amplification contexts.
Journal • Next-generation sequencing
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MET (MET proto-oncogene, receptor tyrosine kinase)
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MET amplification
26d
Journal
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EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase) • MGMT (6-O-methylguanine-DNA methyltransferase)
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MET amplification • EGFR amplification • MGMT promoter methylation • IDH wild-type
26d
Research Progress of Acquired Resistance Mediated by MET Amplification in Advanced Non-small Cell Lung Cancer (PubMed, Zhongguo Fei Ai Za Zhi)
Emerging data also demonstrate MET amplification as a resistance driver to TKIs-treated anaplastic lymphoma kinase (ALK)-, RET-, and ROS1-fusion NSCLC. Here, we review the literature on recent research progress of MET amplification as a resistance driver to targeted therapy in oncogene-driven NSCLC and summarize the progress of clinical strategies to overcome the resistance mechanism..
Preclinical • Journal
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EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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EGFR mutation • MET amplification • ROS1 fusion • ALK-ROS1 fusion
30d
Comprehensive Analysis of Genomic Alterations in Hepatoid Adenocarcinoma of the Stomach and Identification of Clinically Actionable Alterations. (PubMed, Cancers (Basel))
A total of 10.53% of HAS patients harbored TMB > 10 muts/Mb. These findings improve our understanding of the genomic features of HAS and provide potential therapeutic targets.
Journal • BRCA Biomarker
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • MET (MET proto-oncogene, receptor tyrosine kinase) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • FGFR1 (Fibroblast growth factor receptor 1) • MDM2 (E3 ubiquitin protein ligase) • CDK4 (Cyclin-dependent kinase 4) • TNFA (Tumor Necrosis Factor-Alpha)
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TP53 mutation • BRCA2 mutation • BRCA1 mutation • HER-2 amplification • MET amplification • FGFR1 amplification • MDM2 amplification • MDM2 mutation • BRCA2 amplification
1m
New P2 trial
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MET (MET proto-oncogene, receptor tyrosine kinase)
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MET amplification
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telisotuzumab vedotin (ABBV-399)
1m
IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells. (PubMed, Sci Signal)
Similar drug sensitization was seen in gefitinib-resistant, EGFR-mutant PC9GR lung cancer cells treated with recombinant IGFBPs. Cells that were osimertinib resistant and had MET amplification or showed epithelial-to-mesenchymal transition also displayed residual sensitivity to IGFBPs. Thus, CAFs promote or reduce drug resistance in a context-dependent manner, and deciphering the relationship between the differential content of CAF secretomes and the signaling dependencies of the tumor may reveal effective combination treatment strategies.
Journal
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MET (MET proto-oncogene, receptor tyrosine kinase) • IGFBP5 (Insulin Like Growth Factor Binding Protein 5) • IGFBP6 (Insulin Like Growth Factor Binding Protein 6)
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EGFR mutation • MET amplification
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Tagrisso (osimertinib) • gefitinib
1m
Journal
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BRAF (B-raf proto-oncogene) • MET (MET proto-oncogene, receptor tyrosine kinase)
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BRAF V600E • BRAF V600 • MET amplification • BRAF amplification
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Erbitux (cetuximab) • Braftovi (encorafenib)
1m
Pulmonary Adenocarcinoma: RET mutation in cfDNA NGS interpretation - case report (ECP 2022)
Erlotinib induced partial response; May 2021 started osimertinib therapy. RET fusion occurs in 1–2% of NSCLC, particularly in younger non‐smokers and high risk for brain metastasis is established. MEN2B/MEN1/MEN2A germline mutations have to be considered when RET mutations present low allele frequency; tumoral heterogeneity will always be considered if RET mutations in follow up with higher frequency. NGS cfDNA potentiality for actionable RET mutations, identification, as well as resistance mechanisms after initial response/resistence rearranged RET.
Clinical • Next-generation sequencing
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • NKX2-1 (NK2 Homeobox 1)
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MET amplification • RET fusion • RET mutation • KRAS A59T
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Tagrisso (osimertinib) • erlotinib
1m
Adenosquamous carcinoma of the lung - biopsy: MET exon 14 skipping mutation (ECP 2022)
MET-TKIs, capmatinib and tepotinib, for NSCLCs with METex14 marked a new step of MET-targeted therapy. METex14 alterations - point mutations/deletions/insertions/com-plex mutations lead to MET receptor decreased degradation, fol-lowed by MET signalling and tumourigenesis. The evaluation methods for METex14 include differential MET exon expression, quantitative reverse transcription polymerase chain reaction (qRT-PCR) or direct RNA sequencing.
MET (MET proto-oncogene, receptor tyrosine kinase) • NKX2-1 (NK2 Homeobox 1) • TTF1 (Transcription Termination Factor 1)
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MET amplification • MET exon 14 mutation • MET mutation • MET expression
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Idylla™ GeneFusion Assay • Oncomine Precision Assay
|
Tabrecta (capmatinib) • Tepmetko (tepotinib)
1m
Evaluation of MET amplification in lung cancer via Idylla™ GeneFusion cartridges (ECP 2022)
This study showed that the IdyllaTM GeneFusion Assay might be a promising screening tool for top level MET amplification assessment in lung cancer samples. Nevertheless, even after threshold adjustment both specificity and sensitivity within different levels of MET amplification remained lower than 90%. Therefore, this test with our proposed cut-off is not suited to identify MET amplification at lower thresholds.
EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase) • KEAP1 (Kelch Like ECH Associated Protein 1)
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MET amplification
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Idylla™ GeneFusion Assay
1m
Oncogene Overlap Analysis of Circulating Cell-free Tumor DNA to Explore the Appropriate Criteria for Defining MET Copy Number-Driven Lung Cancer. (PubMed, Clin Lung Cancer)
We propose that a high MET pCN and/or ApCN, together with the absence of overlapping oncogenic drivers and small MET amplicon size, will enrich for patients most likely to derive benefit from MET targeted therapy.
Journal • Circulating tumor DNA
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MET (MET proto-oncogene, receptor tyrosine kinase)
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MET amplification • MET mutation • MET-H
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Guardant360® CDx
1m
Clinical validation of companion diagnostics for the selection of patients with non-small cell lung cancer tumors harboring epidermal growth factor receptor exon 20 insertion mutations for treatment with amivantamab. (PubMed, J Mol Diagn)
Overall response rates were comparable between the CHRYSALIS, Guardant360 CDx, and ODxT Test populations. Both plasma-based and tissue-based diagnostic tests provided accurate, comprehensive, and complementary approaches to identifying patients with EGFR ex20ins who could benefit from amivantamab therapy.
Journal • Companion diagnostic • EGFR exon 20
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EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase)
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EGFR mutation • MET amplification • EGFR exon 20 insertion • MET mutation • EGFR exon 20 mutation
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Guardant360® CDx • Oncomine™ Dx Target Test
|
Rybrevant (amivantamab-vmjw)
1m
Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK-rearranged non-small cell lung cancer. (PubMed, Cancer Sci)
Ceritinib is a second-generation ALK-TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib, a first-generation ALK-TKI, refractory ALK-rearranged NSCLC. Amplified cMET counter-activated EGFR and/or Her3, and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be able to overcome by identifying precise resistance mechanisms.
Journal
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EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • FGFR3 (Fibroblast growth factor receptor 3) • EML4 (EMAP Like 4) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3)
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MET amplification • ALK positive • ALK rearrangement • ALK mutation • FGFR3 overexpression
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Xalkori (crizotinib) • Zykadia (ceritinib)
1m
Savolitinib monotherapy exerted significant benefit in a non-small cell lung cancer patient with osimertinib resistance harboring primary EGFR L858R mutation and MET amplification: a case report. (PubMed, Anticancer Drugs)
Here, we described a case of a 64-year-old male with lung adenocarcinoma presented primary resistance on osimertinib combined with bevacizumab and platinum-based chemotherapy, next-generation sequencing revealed EGFR exon 21 L858R mutation and MET gene amplification. Our case highlights that EGFR-TKIs may be not the optimal choice for lung adenocarcinoma with primary EGFR-sensitive mutation with MET amplification simultaneously, whereas MET inhibitor alone may be an effective treatment option. In clinical practice, we should fully consider the possibility of primary resistance in EGFR-TKIs administration.
Journal
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EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase)
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EGFR mutation • EGFR L858R • MET amplification • MET mutation • EGFR positive • EGFR mutation + MET amplification
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Avastin (bevacizumab) • Tagrisso (osimertinib) • Orpathys (savolitinib)
2ms
L718Q/V mutation in exon 18 of EGFR mediates resistance to osimertinib: clinical features and treatment. (PubMed, Discov Oncol)
The second-generation TKI afatinib was found to provide a high disease control rate (DCR) (85.7%, 6/7) and relatively low objective response rate (ORR) (42/9%, 3/7). The patients failed to benefit from chemotherapy combined with immunotherapy or other TKI medications. Due to the limited number of cases considered in this study, future studies should explore drugs that more precisely target the L718Q/V mutation of EGFR exon 18.
Journal • IO biomarker
|
EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase)
|
EGFR mutation • EGFR L858R • MET amplification • EGFR C797S • EGFR exon 18 mutation • EGFR L718Q
|
Tagrisso (osimertinib) • Gilotrif (afatinib)
2ms
SAVANNAH: Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib (clinicaltrials.gov)
P2, N=360, Recruiting, AstraZeneca | Active, not recruiting --> Recruiting | Trial completion date: Sep 2022 --> Feb 2025 | Trial primary completion date: Sep 2022 --> May 2024
Enrollment open • Trial completion date • Trial primary completion date • Combination therapy
|
EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase)
|
EGFR mutation • EGFR L858R • EGFR exon 19 deletion • MET amplification • EGFR amplification • MET overexpression
|
Tagrisso (osimertinib) • Orpathys (savolitinib)
2ms
Analysis of actionable genetic alterations in lung carcinoma from the VA National Precision Oncology Program. (PubMed, Semin Oncol)
In this study, 27.5% of Veterans with lung adenocarcinoma have actionable genetic alterations eligible for FDA approved targeted therapies, a frequency only slightly lower than other published datasets despite higher smoking rates in Veterans. Genomic sequencing should be performed in all Veterans with advanced LUAD and LUOT.
Journal
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK (Neurotrophic receptor tyrosine kinase)
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BRAF V600E • KRAS mutation • EGFR mutation • BRAF V600 • KRAS G12C • MET amplification • ALK rearrangement • EGFR exon 20 insertion • MET exon 14 mutation • RET mutation • ROS1 rearrangement • MET mutation • RET rearrangement • EGFR exon 20 mutation • KRAS G12
2ms
Responses to the Tepotinib in Gastric Cancers with MET Amplification or MET Exon 14 Skipping Mutations and High Expression of Both PD-L1 and CD44. (PubMed, Cancers (Basel))
Tepotinib may have therapeutic effects on c-MET-amplified GC, a high expression of both PD-L1 and CD44, and METex14SM. Clinical studies are needed to confirm these therapeutic effects.
Journal • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • MET (MET proto-oncogene, receptor tyrosine kinase) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • KDR (Kinase insert domain receptor) • CD44
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MET amplification • MET exon 14 mutation • MYC expression • MET expression • KDR expression • CD44 expression
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Tepmetko (tepotinib)
2ms
HER2 copy number variation in non-small cell lung cancer (NSCLC) (ESMO 2022)
As further line of treatment, 5 patients received trastuzumab: 4 in combination with chemotherapy and 1 as monotherapy, with 1 stabilization of disease as best response. 3 patients received nivolumab (1 partial response and 1 stable disease) and 3 a targeted therapy (anti ALK, EGFR, BRAF). Conclusions Increased HER2 GCN was found in 9% of patients with unresectable NSCLC, was not correlated to particular clinical characteristics, but frequently occurred with other molecular alterations. Its clinical actionability and the correlation with protein expression deserve further characterization.
PD(L)-1 Biomarker
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • FGFR1 (Fibroblast growth factor receptor 1)
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BRAF V600E • KRAS mutation • EGFR mutation • BRAF V600 • KRAS G12C • EGFR exon 19 deletion • HER-2 mutation • MET amplification • KRAS G12D • ALK rearrangement • FGFR1 amplification • HER-2 exon 20 insertion • MET mutation • KRAS G12 • HER-2 exon 20 mutation • FGFR1 rearrangement • HER-2 exon 23 mutation • KRAS G61 • KRAS G61H
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Opdivo (nivolumab) • Herceptin (trastuzumab)
2ms
Mechanisms of primary and secondary resistance to RET inhibitors in patients with RET-positive advanced NSCLC (ESMO 2022)
55 patients received pralsetinib, 36 selpercatinib, 4 other RETi. Secondary RET mutations, novel RET rearrangements and MET/MYC amplifications were identified after treatment with RETi. More than half of pts had insufficient ctDNA at PD, making tissue biopsy essential to identify resistance mechanisms.
Clinical
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4)
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TP53 mutation • KRAS mutation • MET amplification • RET fusion • KRAS G12V • MYC amplification • RET mutation • MET mutation • RET rearrangement • SMARCA4 mutation • KRAS G12 • KRAS mutation + SMARCA4 mutation • RET positive
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Gavreto (pralsetinib) • Retevmo (selpercatinib)
2ms
The MET inhibitor ABN401 in combination with the third-generation EGFR-TKI is effective MET-amplified and EGFR-mutant NSCLC with acquired resistance to third-generation EGFR-TKI in preclinical models (ESMO 2022)
Methods The signal transduction inhibition and cytotoxic response of ABN401 in combination with Lazertinib were tested in vitro against Osimertinib-resistance NSCLC cell lines (HCC827-AR) and patient-derived organoid (YUO-010), analyzed by western blot and Cell Titer-Glo assay. Notably, in MET gene amplification (PDX model YHIM-1035, gefitinib/Osimertinib resistant), ABN401 alone showed a potent therapeutic effect. Conclusions Our findings suggest that the clinical application of ABN401 in combination with a third-generation EGFR-TKI to NSCLC patients with MET gene amplification can provide a promising therapeutic strategy for overcoming acquired resistance to EGFR-TKIs.
Preclinical • Combination therapy
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EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase)
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EGFR mutation • EGFR exon 19 deletion • EGFR T790M • MET amplification • MET mutation • MET amplification + EGFR mutation
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Tagrisso (osimertinib) • gefitinib • Leclaza (lazertinib) • ABN401