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 ¡Ý2+ in ¡Ý50 % of tumour cells). This study is registered with , number .
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.
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.
ArQule, Daiichi Sankyo (Daiichi Sankyo Group).