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Activity of Tepotinib in Hepatocellular Carcinoma With High-Level MET Amplification: Preclinical and Clinical
Shukui Qin1,2, Hongming Pan3, Jean Frédéric Blanc4
1PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China.
Purpose:
MET amplification (METamp) 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 METamp (MET gene copy number [GCN] ≥5), including high-level METamp (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 METamp 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 METamp 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 METamp. 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 METamp. Disease control was achieved by 11/15 patients with METamp (complete response [CR], n = 1; partial response [PR], n = 4; stable disease [SD], n = 6) and 4/4 with high-level METamp (CR, n = 1; PR, n = 2; SD, n = 1). All three patients with high-level METamp and objective response received treatment for >1 year, including one patient who received first-line tepotinib for >6 years.
Conclusion:
High-level METamp may be an oncogenic driver in HCC that is sensitive to MET inhibitors such as tepotinib.
