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Activity of Tepotinib in Hepatocellular Carcinoma With High-Level MET Amplification: Preclinical and Clinical Evidence.
JCO Precision Oncology 2024 Februrary
PURPOSE: MET amplification ( MET amp) has been reported in 1%-5% of patients with hepatocellular carcinoma (HCC) and may be sensitive to MET inhibition. Tepotinib, a selective MET inhibitor, has shown promising activity in HCC with MET overexpression. We investigated the preclinical and clinical activity of tepotinib in HCC with MET amp ( MET gene copy number [GCN] ≥5), including high-level MET amp ( MET GCN ≥10).
METHODS: Preclinical antitumor activity of tepotinib 100 mg/kg (orally, days 1-5, every 7 days, 3-5 weeks; 3-12 replicates) was evaluated according to MET amp status, as determined using the nCounter platform (NanoString), in 37 HCC patient-derived xenografts (PDXs) in immunodeficient mice. Clinical outcomes were evaluated in patients with MET amp by fluorescence in situ hybridization who received tepotinib 500 mg (450 mg active moiety) in two phase Ib/II trials in HCC with MET overexpression.
RESULTS: Across the PDX models, tepotinib induced complete or near-complete tumor regression in the only two models with high-level MET amp. Median tumor volume reductions were 100% and 99.8% in models with MET GCN 47.1 and 44.0, respectively. Across the two clinical trials, 15/121 patients had MET amp. Disease control was achieved by 11/15 patients with MET amp (complete response [CR], n = 1; partial response [PR], n = 4; stable disease [SD], n = 6) and 4/4 with high-level MET amp (CR, n = 1; PR, n = 2; SD, n = 1). All three patients with high-level MET amp and objective response received treatment for >1 year, including one patient who received first-line tepotinib for >6 years.
CONCLUSION: High-level MET amp may be an oncogenic driver in HCC that is sensitive to MET inhibitors such as tepotinib.
METHODS: Preclinical antitumor activity of tepotinib 100 mg/kg (orally, days 1-5, every 7 days, 3-5 weeks; 3-12 replicates) was evaluated according to MET amp status, as determined using the nCounter platform (NanoString), in 37 HCC patient-derived xenografts (PDXs) in immunodeficient mice. Clinical outcomes were evaluated in patients with MET amp by fluorescence in situ hybridization who received tepotinib 500 mg (450 mg active moiety) in two phase Ib/II trials in HCC with MET overexpression.
RESULTS: Across the PDX models, tepotinib induced complete or near-complete tumor regression in the only two models with high-level MET amp. Median tumor volume reductions were 100% and 99.8% in models with MET GCN 47.1 and 44.0, respectively. Across the two clinical trials, 15/121 patients had MET amp. Disease control was achieved by 11/15 patients with MET amp (complete response [CR], n = 1; partial response [PR], n = 4; stable disease [SD], n = 6) and 4/4 with high-level MET amp (CR, n = 1; PR, n = 2; SD, n = 1). All three patients with high-level MET amp and objective response received treatment for >1 year, including one patient who received first-line tepotinib for >6 years.
CONCLUSION: High-level MET amp may be an oncogenic driver in HCC that is sensitive to MET inhibitors such as tepotinib.
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