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

Abstract

BACKGROUND:

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.

METHODS:

Eligible 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).

RESULTS:

In 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%).

CONCLUSIONS:

Tepotinib 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 REGISTRATION:

ClinicalTrials.gov: NCT02115373.

• Authors: Thomas Decaens, Carlo Barone, Eric Assenat, Martin Wermke, Angelica Fasolo, Philippe Merle, Jean-Frédéric Blanc, Véronique Grando, Angelo Iacobellis, Erica Villa, Joerg Trojan, Josef Straub, Rolf Bruns, Karin Berghoff, Juergen Scheele, Eric Raymond, Sandrine Faivre
• Journal: British journal of cancer (Br J Cancer) Vol. 125 Issue 2 Pg. 190-199 (07 2021) ISSN: 1532-1827 [Electronic] England
• PMID: 33824476 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Antineoplastic Agents
• Piperidines
• Pyridazines
• Pyrimidines
• tepotinib
• Sorafenib
• MET protein, human
• Proto-Oncogene Proteins c-met

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacology)
• Carcinoma, Hepatocellular (drug therapy, genetics)
• Drug Administration Schedule
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Liver Neoplasms (drug therapy, genetics)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Piperidines (administration & dosage, adverse effects, pharmacology)
• Proto-Oncogene Proteins c-met (genetics)
• Pyridazines (administration & dosage, adverse effects, pharmacology)
• Pyrimidines (administration & dosage, adverse effects, pharmacology)
• Sorafenib (therapeutic use)
• Survival Analysis
• Treatment Outcome
• Up-Regulation (drug effects)
• Young Adult