ArQule, Inc. and Daiichi Sankyo Co., Ltd. announced final results from a randomized, placebo-controlled, double-blind, phase 2 clinical trial with the selective MET inhibitor tivantinib as a single-agent, investigational, second-line treatment in hepatocellular carcinoma (HCC). 

 The 107 patients in the trial had unresectable HCC and had disease progression after first-line therapy or were unable to tolerate the first-line therapy. Patients were randomized to receive tivantinib at 360 milligrams (mg) twice daily or 240 mg twice daily or placebo (2:1 tivantinib:placebo). The primary endpoint was time to progression (TTP) in the intent to treat (ITT) population. Other study endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS), as well as safety for the ITT population and pre-defined MET-high or MET-low cohorts, as defined by immunohistochemistry. 

A statistically significant 56 percent improvement as compared to placebo was seen in TTP in the ITT population (hazard ratio [HR] = 0.64; 90 percent confidence intervals [CI] = 0.43-0.94; log rank p-value = 0.04). The median TTP in tivantinib arm was 1.6 months and 1.4 months in the placebo arm.

In the MET-high cohort, there were statistically significant improvements in TTP, PFS and OS:

- Median OS in tivantinib arm was 7.2 months and 3.8 months in the placebo arm (HR = 0.38; 95 percent CI = 0.18-0.81; log rank p-value = 0.01)

- Median TTP was 2.9 months in the tivantinib arm and 1.5 months in the placebo arm (HR = 0.43; 95 percent CI = 0.19-0.97; log rank p-value = 0.03)

- Median PFS was 2.4 months in the tivantinib arm and 1.5 months in the placebo arm (HR = 0.45; 95 percent CI = 0.21-0.95; log rank p-value = 0.02).

There was no significant difference in TTP or OS between tivantinib and placebo in the MET-low cohorts.

Adverse events were reported at similar rates in the treatment and placebo arms of the trial, except for a higher incidence of fatigue and hematologic events, including neutropenia and anemia, in tivantinib-treated patients. The incidence of hematologic events decreased following dose reduction of tivantinib from 360 mg twice daily to 240 mg twice daily. Due to increased incidence of neutropenia in the 360 mg treatment group, the tivantinib dose was reduced to 240 mg twice daily for all patients.

"Patients living with this disease need more options to slow progression. The findings from this tivantinib study represent the first randomized data reported in HCC with an investigational MET inhibitor, as single-agent therapy in second-line treatment," said Lorenza Rimassa, Deputy Director, Medical Oncology Unit, Humanitas Cancer Center, Milan, Italy. "The data suggest that patients significantly benefited in time to progression and, importantly, those in a biologically relevant MET-high subgroup had an additional significant advantage in overall survival."

"Research has shown that MET is a signaling pathway associated with poor outcomes in many cancers, including liver cancer and non-small cell lung cancer (NSCLC)," said Glenn Gormley, MD, PhD, Global Head of Research&Development and Senior Executive Officer, Daiichi Sankyo Co., Ltd. "The strong overall survival results among HCC patients in this trial whose tumors were MET-high reinforce this previous research that defines MET as a critical pathway in cancer as well as the activity of tivantinib as a MET inhibitor."

The data was presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) (abstract number 4006).