Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study

Summary

Background

Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma.

Methods

In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741.

Findings

71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4–2·8]) than placebo (1·4 months [1·4–1·5]; hazard ratio [HR] 0·64, 90% CI 0·43–0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4–8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4–1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19–0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events.

Interpretation

Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily.

Funding

ArQule, Daiichi Sankyo (Daiichi Sankyo Group).

Introduction

At diagnosis, more than 80% of patients with hepatocellular carcinoma present with multicentric tumours and concurrent liver cirrhosis.¹ Sorafenib is the only approved treatment for advanced disease, and provides a median time to progression of 5·5 months and median overall survival of 10·7 months in previously untreated patients with Child-Pugh A disease.2, 3, 4 An equivalent relative treatment benefit was noted in a population from Asia Pacific with advanced hepatocellular carcinoma.5, 6 However, no salvage therapy has shown activity, and effective second-line treatment of advanced hepatocellular carcinoma is an urgent unmet need despite the many biological agents currently in development.7, 8

Accumulating evidence has established the role of the MET receptor tyrosine kinase, encoded by the MET proto-oncogene, in tumour development and metastatic progression.⁹ Binding of HGF to MET activates primarily the RAS-MAPK and PI3K-AKT signalling pathways.¹⁰ Tivantinib (ARQ 197) is a selective, oral, small-molecule MET inhibitor that preferentially inhibits growth and induces apoptosis in human tumour cell lines expressing MET.¹¹ Sensitivity to tivantinib was confirmed in a panel of hepatocellular carcinoma cell lines, and antitumour activity was shown in murine xenograft models in various tumours.11, 12 Tumour biopsy samples taken before and after treatment with tivantinib have also shown a decrease in MET activity and downstream pathways associated with tivantinib.¹³ In addition, preclinical studies have shown additive or synergistic activity with the combination of tivantinib and sorafenib,¹⁴ which was recently confirmed in a phase 1 clinical trial in hepatocellular carcinoma.¹⁵

In a multicentre, single-arm, phase 1b study (NCT00802555) of 21 previously treated patients with cirrhosis (Child-Pugh A or B) and advanced hepatocellular carcinoma, tivantinib monotherapy was associated with disease stabilisation in nine (53%) of 16 assessable patients and a median time to progression of 5·3 months; tivantinib had an acceptable toxicity profile in this population (Santoro A, unpublished data). Based on this evidence, we undertook this phase 2 trial in patients with unresectable hepatocellular carcinoma who had progressed on or were intolerant to previous systemic therapy.