Tivantinib in Second-Line Treatment of MET-High Advanced Hepatocellular Carcinoma


Key Points

  • No difference in overall survival was observed for tivantinib vs placebo.
  • No difference in progression-free survival was observed. 

In the phase III METIV-HCC trial reported in The Lancet Oncology, Rimassa et al found no improvement in overall survival with the investigational MET inhibitor tivantinib vs placebo in patients with advanced hepatocellular carcinoma with high MET expression previously treated with sorafenib (Nexavar). A randomized phase II study had shown improved progression-free and overall survival with tivantinib vs placebo in this setting.

Study Details

In the double-blind trial, 340 patients from 90 sites in Australia, the Americas, Europe, and New Zealand were randomized 2:1 between December 2012 and December 2015 to receive tivantinib at 120 mg twice daily (n = 226) or placebo (n = 114). The trial initially contained a tivantinib at 240 mg twice daily arm (with randomization of 28 patients to tivantinib and 15 to placebo); enrolment was stopped due to excessive grade ≥ 3 neutropenia in this arm.

MET-high status was defined as a staining intensity score ≥ 2 in ≥ 50% of tumor cells. Patients had to have disease progression after receiving sorafenib-containing systemic therapy.

Randomization was stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentration. The primary endpoint was overall survival in the intention-to-treat population.

Overall Survival

Median follow-up was 18.1 months. Median overall survival was 8.4 months in the tivantinib group vs 9.1 months in the placebo group (hazard ratio = 0.97, P = .81). Median progression-free survival was 2.1 vs 2.0 months (HR = 0.96, P = .72). Median time to progression was 2.4 vs 3.0 months (HR = 0.96, P = .76).

Adverse Events

Grade ≥ 3 adverse events occurred in 56% of the tivantinib group vs 55% of the placebo group, with the most common in the tivantinib group being ascites (7%), anemia (5%), abdominal pain (4%), and neutropenia (4%). Death occurred within 30 days of the last study dose in 22% vs 16% of patients, with the most common causes in the tivantinib group being general deterioration (4%) and hepatic failure (2%). Death was considered treatment-related in 3 patients (1%) in the tivantinib group, with causes consisting of sepsis; anemia and acute renal failure; and acute coronary syndrome.

The investigators concluded, “Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma.”

The study was funded by ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).

Jordi Bruix, MD, of Barcelona Clinic Liver Cancer Group, University of Barcelona, is the corresponding author for The Lancet Oncology article. 

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