Abstract
BackgroundThis open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression.MethodsIn Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP).ResultsIn Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26–0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib.ConclusionsTepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression.Trial registrationClinicalTrials.gov NCT01988493.
Highlights
This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma with MET overexpression
The 300 mg cohort comprised six patients who received tepotinib in the dose-escalation phase and one patient enrolled in mainland China
A further two patients were enrolled at 500 mg to replace patients not evaluable for dose-limiting toxicities (DLTs)
Summary
This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression. Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. CONCLUSIONS: Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression. The only approved targeted systemic therapy for advanced HCC was the nonselective multikinase inhibitor sorafenib.[2,3] This agent provides only a modest improvement in overall survival (OS) and may not be as well tolerated by Asian patients compared with those of other ethnicities.[4,5] Newer first-line treatment options include the multikinase inhibitor lenvatinib and the immunotherapy atezolizumab (in combination bevacizumab), which have been approved following positive data from randomised Phase 3 trials versus sorafenib.[3,6,7,8]. These patients may derive therapeutic benefit from selective MET inhibition.[9,11] In vitro, MET inhibitors can reduce the growth of MET-positive HCC cell linederived xenograft models.[11]
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