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BIOMARKER:

MET D1228H

i
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
Entrez ID:
Associations
Trials
over1year
Predictive Biomarkers of Response to REGN5093 to Guide Patient Selection in MET-Altered Advanced Non-small Cell Lung Cancer (IASLC-WCLC 2023)
We report biomarkers associated with clinical response and resistance to REGN5093 which may help with screening of aNSCLC pts in future combination studies of REGN5093 with other therapies.
Clinical • Metastases
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • JAK2 (Janus kinase 2)
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EGFR mutation • BRAF mutation • MET amplification • KRAS G12D • PIK3CA H1047R • MET exon 14 mutation • MET overexpression • MET mutation • MET expression • KRAS G12 • JAK2 V617F • TP53 R248Q • EGFR mutation + MET-CEP7 fusion • MET Y1230C • MET D1228H • MET Y1230C
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FoundationOne® CDx • TruSight Oncology 500 Assay
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davutamig (REGN5093)
over1year
Response and acquired resistance to MET inhibitors in de novo MET fusion-positive advanced non-small cell lung cancer. (PubMed, Lung Cancer)
MET fusions occur in a rare subset of patients with NSCLC and represent a promising therapeutic target. MET secondary mutations D1228H/N or D1246N present the potential resistance mechanisms of MET inhibitors in patients with de novo MET fusions.
Preclinical • Journal • Metastases
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TP53 (Tumor protein P53) • STAT3 (Signal Transducer And Activator Of Transcription 3) • EPHB4 (EPH receptor B4)
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TP53 mutation • MET overexpression • MET D1228N • MET fusion • EPHB4 expression • EPHB4 overexpression • MET D1228H
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tivantinib (ARQ 197)
almost2years
Mutations in the MET tyrosine kinase domain and resistance to tyrosine kinase inhibitors in non-small-cell lung cancer. (PubMed, Respir Res)
MET TKD mutations were identified in both baseline and patients treated with TKIs. MET-H1094Y might play an oncogenic role in NSCLC and may confer acquired resistance to EGFR-TKIs. Preliminary data indicates that EGFR-mutated NSCLC patients who acquired MET-V1092I or MET-H1094Y may benefit from combinatorial therapy with EGFR-TKI and MET-TKI, providing insights into personalized medical treatment.
Journal
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MET (MET proto-oncogene, receptor tyrosine kinase)
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EGFR mutation • MET amplification • MET exon 14 mutation • MET mutation • MET H1094Y • MET D1228N • MET D1228H • MET Y1230C
2years
Integrative genomic analysis of drug resistance in MET exon 14 skipping lung cancer using patient-derived xenograft models. (PubMed, Front Oncol)
PDX mice were then treated with MET inhibitors (crizotinib and tepotinib) and EGFR-MET bispecific antibodies (EMB-01 and amivantamab) to evaluate their drug response in vivo. We also established and characterized a pair of METex14 NSCLC PDXs, including the first crizotinib resistant METex14 PDX. And dual inhibition of MET and EGFR might be a therapeutic strategy for EGFR-driven drug resistance METex14 lung cancer.
Preclinical • Journal
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MET (MET proto-oncogene, receptor tyrosine kinase)
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EGFR mutation • EGFR amplification • EGFR overexpression • MET exon 14 mutation • MET D1228H
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Xalkori (crizotinib) • Rybrevant (amivantamab-vmjw) • Tepmetko (tepotinib) • bafisontamab (EMB-01)
2years
Circulating tumour DNA biomarkers in savolitinib-treated patients with non-small cell lung cancer harbouring MET exon 14 skipping alterations: a post hoc analysis of a pivotal phase 2 study. (PubMed, Ther Adv Med Oncol)
Specifically, undetectable baseline METex14 or post-treatment clearance may predict favourable clinical outcomes, while secondary MET mutations and other acquired gene alterations may explain resistance to savolitinib. The trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.
P2 data • Retrospective data • Journal • Circulating tumor DNA
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TP53 (Tumor protein P53) • MET (MET proto-oncogene, receptor tyrosine kinase) • PTEN (Phosphatase and tensin homolog) • POT1 (Protection of telomeres 1) • PI3K (Phosphoinositide 3-kinases)
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TP53 mutation • PTEN mutation • MET exon 14 mutation • POT1 mutation • MET D1228H • MET Y1230C
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Orpathys (savolitinib)
over2years
MET and NF2 alterations confer early resistance to first-line alectinib treatment in ALK-rearranged non-small cell lung cancer (ESMO 2022)
Of these, 52 received first-line alectinib treatment (1L) and 56 received alectinib after crizotinib resistance (2L). Also, NF2-mutant patients only had a median PFS of 4 months, significantly poorer than those without (HR 11.1, 95CI 2.17-50; p<0.001). Conclusions By analyzing different mutational profiles of ALK-rearranged patients after alectinib treatment, we proposed MET and NF2 as putative mechanisms that conferred resistance to early resistance of first-line alectinib, which shone light on future tailored treatment for ALK-positive NSCLCs.
Clinical
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MET (MET proto-oncogene, receptor tyrosine kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF2 (Neurofibromin 2)
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KRAS mutation • BRAF mutation • NRAS mutation • PIK3CA mutation • ALK positive • MET amplification • ALK rearrangement • ALK mutation • MET mutation • ALK G1202R • NF2 mutation • ALK G1269A • ALK I1171N • ALK I1171T • ALK I1171 • ALK L1196M • ALK amplification • ALK V1180L • ALK E1129V • ALK rearrangement + PIK3CA mutation • MET D1228H
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Xalkori (crizotinib) • Alecensa (alectinib)
3years
METex14 ctDNA dynamics & resistance mechanisms detected in liquid biopsy (LBx) from patients (pts) with METex14 skipping NSCLC treated with tepotinib (MTCS 2021)
LBx biomarker analysis from the largest on-treatment data set for a MET inhibitor in MET ex14 skipping NSCLC showed that ctDNA depletion in MET ex14 VAF is associated with improved clinical response in pts treated with tepotinib. Serial LBx could help monitor responses, understand resistance and guide dose-adjustment strategies to improve outcomes and quality of life.
Clinical • Liquid biopsy • Circulating tumor DNA
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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TP53 mutation • KRAS mutation • NRAS mutation • MET D1228H
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Guardant360® CDx
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Tepmetko (tepotinib)
3years
A Large Real-World Study on the Effectiveness of the Combined Inhibition of EGFR and MET in EGFR-Mutant Non-Small-Cell Lung Cancer After Development of EGFR-TKI Resistance. (PubMed, Front Oncol)
Potential acquired resistance mechanisms to EGFR-TKI + crizotinib included EGFR-T790M (n = 2), EGFR-L718Q (n = 1), EGFR-S645C (n = 1), MET-D1228H (n = 1), BRAF-V600E (n = 1), NRAS-Q61H (n = 1), KRAS-amp (n = 1), ERBB2-amp (n = 1), CDK4-amp (n = 1), and MYC-amp (n = 1). Our study provides real-world clinical evidence from a large cohort that simultaneous inhibition of EGFR and MET could be a more effective therapeutic strategy for patients with MET-amp acquired from EGFR-TKI therapy.
Clinical • Journal • Real-world evidence
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • MET (MET proto-oncogene, receptor tyrosine kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • CDK4 (Cyclin-dependent kinase 4)
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TP53 mutation • BRAF V600E • EGFR mutation • BRAF V600 • EGFR T790M • MET mutation • NRAS Q61 • KRAS Q61H • EGFR L718Q • MET D1228H
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Xalkori (crizotinib)
over3years
[VIRTUAL] METex14 ctDNA dynamics & resistance mechanisms detected in liquid biopsy (LBx) from patients (pts) with METex14 skipping NSCLC treated with tepotinib. (ASCO 2021)
LBx biomarker analysis from the largest on-treatment data set for a MET inhibitor in METex14 skipping NSCLC, showed that ctDNA depletion in METex14 VAF is associated with improved clinical response in pts treated with tepotinib . This suggests serial LBx could help us to monitor response/non-response, understand resistance, and guide trials that test escalation/de-escalation strategies to improve outcomes and maximize QOL.
Clinical • Liquid biopsy • Circulating tumor DNA
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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TP53 mutation • KRAS mutation • MET D1228H
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Guardant360® CDx
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Tepmetko (tepotinib)
over3years
[VIRTUAL] A large real-world study on the effectiveness of the combined inhibition of EGFR and MET in EGFR-mutant advanced non-small cell lung cancer (NSCLC). (ASCO 2021)
Our study provides real-world clinical evidence, in the largest cohort to date, that simultaneous inhibition of EGFR and MET improves clinical outcomes of patients with EGFR-mutant NSCLC who acquired MET amplification from prior EGFR-TKI therapy, indicating that combinatorial regimen of EGFR-TKI and MET-TKI could be a more effective therapeutic strategy in this subset of patients.
Clinical • Real-world evidence
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • MET (MET proto-oncogene, receptor tyrosine kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • CDK4 (Cyclin-dependent kinase 4)
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TP53 mutation • BRAF V600E • EGFR mutation • HER-2 amplification • BRAF V600 • MET amplification • EGFR T790M • EGFR amplification • MET mutation • NRAS Q61 • KRAS Q61H • KRAS amplification • EGFR L718Q • MET D1228H
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Xalkori (crizotinib)