Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression

Thomas Decaens,Martin Wermke,Eric Assenat,Angelo Iacobellis,Juergen Scheele,Véronique Grando,Angelica Fasolo,Rolf Bruns,Karin Berghoff,Eric Raymond,Erica Villa,Sandrine Faivre,Joerg Trojan,Carlo Barone,Philippe Merle,Jean-Frédéric Blanc,Josef Straub

doi:10.1038/s41416-021-01334-9

Abstract

BackgroundThis Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression.MethodsEligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b (‘3 + 3’ design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2).ResultsIn Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5–74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%).ConclusionsTepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit–risk balance in sorafenib pretreated aHCC with MET overexpression.Trial RegistrationClinicalTrials.gov: NCT02115373.

Highlights

This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression
The incidence of hepatocellular carcinoma (HCC), which accounts for 90% of primary liver cancers,[2] is still rising, in part driven by high rates of chronic viral hepatitis and increasing obesity-related liver disease.[3]
The options for advanced hepatocellular carcinoma (aHCC) treatment have since expanded: lenvatinib and atezolizumab + bevacizumab are approved for first-line treatment and regorafenib, ramucirumab and cabozantinib are approved for use post-sorafenib in both the US and Europe.[9,10,11,12,13]

Summary

Introduction

This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression. Sorafenib was the only approved systemic targeted therapy for advanced HCC (aHCC).[6] As first-line therapy, sorafenib provides a modest but significant improvement in overall survival (OS), but its activity is almost universally hampered by the development of drug resistance.[7,8] The options for aHCC treatment have since expanded: lenvatinib and atezolizumab + bevacizumab are approved for first-line treatment and regorafenib, ramucirumab (in patients with alphafetoprotein [AFP] elevation) and cabozantinib are approved for use post-sorafenib in both the US and Europe.[9,10,11,12,13] In the US, approvals have been granted for pembrolizumab and nivolumab ± ipilimumab in the second-line setting.[14,15,16,17] Despite the availability of novel therapies, the overall prognosis for aHCC is poor.[18] dependent on the results of ongoing trials and drug approvals, greater use of immunotherapies for upfront therapy may lead to an increased need for effective treatment options for subsequent lines.[6]

Methods

Results

Conclusion