Activity of Tepotinib in Hepatocellular Carcinoma With High-Level <i>MET</i> Amplification: Preclinical and Clinical Evidence.

Abstract

<i>MET</i> amplification (<i>MET</i>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 <i>MET</i>amp (<i>MET</i> gene copy number [GCN] ≥5), including high-level <i>MET</i>amp (<i>MET</i> GCN ≥10). 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 <i>MET</i>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 <i>MET</i>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. Across the PDX models, tepotinib induced complete or near-complete tumor regression in the only two models with high-level <i>MET</i>amp. Median tumor volume reductions were 100% and 99.8% in models with <i>MET</i> GCN 47.1 and 44.0, respectively. Across the two clinical trials, 15/121 patients had <i>MET</i>amp. Disease control was achieved by 11/15 patients with <i>MET</i>amp (complete response [CR], n = 1; partial response [PR], n = 4; stable disease [SD], n = 6) and 4/4 with high-level <i>MET</i>amp (CR, n = 1; PR, n = 2; SD, n = 1). All three patients with high-level <i>MET</i>amp and objective response received treatment for >1 year, including one patient who received first-line tepotinib for >6 years. High-level <i>MET</i>amp may be an oncogenic driver in HCC that is sensitive to MET inhibitors such as tepotinib.