O-0009 Second Line Therapy in Hepatocellular Carcinoma (HCC): A Randomized Controlled Phase 2 Trial (RCT) with Tivantinib (ARQ 197)

Abstract

ABSTRACT Introduction Tivantinib is a selective, oral inhibitor of c-MET, the tyrosine kinase receptor for hepatocyte growth factor involved in tumor cell migration, invasion, proliferation and angiogenesis. Tivantinib has shown promising results in HCC in phase 1 studies as monotherapy and in combination with sorafenib. Methods This multi-center RCT enrolled patients with: unresectable HCC, failure to 1 systemic therapy, ECOG PS Results Of 107 enrolled HCC patients, 71 received tivantinib (TA: 38 TB: 33), 36 placebo. Main characteristics of patients on tivantinib vs placebo were: 82% vs 78% male; median age 70 vs 68; PS 0 58% vs 58% VI 21% vs 36% Met+ 22 vs 15; Met- 27 vs 13; HCV+ 51% vs 39% HBV+ 23% vs 14% HBV-HCV- 34% vs 47%. TA was reduced to TB in all patients due to G > 3 neutropenia rate. Major advantage of tivantinib vs placebo was observed in Met+ patients, with median TTP: 2.7 vs 1.4 months (HR 0.43, 95% CI 0.19-0.97; P = 0.03); PFS: 2.2 vs 1.4 months (HR 0.45, 95%CI 0.21-0.95, P = 0.02); DCR (95%CI): 50% (28–72%) vs 20% (4–48%). A preliminary OS trend (HR 0.47) favoring tivantinib is being followed for updates. In ITT, tivantinib vs placebo results are: TTP: 1.6 vs 1.4 months (HR 0.64, 90%CI 0.43-0.94; P = 0.04); PFS: 1.5 vs 1.4 months (HR 0.67, 95%CI 0.44-1.04; P = 0.06); DCR (95% CI): 44% (31-56%) vs 31% (16-48%). In HCV+ patients, median TTP for patients on Tivantinib vs Placebo was: 2.7 vs 1.4 months (HR = 0.395, P = 0.012); in HBV+ patients median TTP was: 1.4 vs 1.4 (HR 1.24, P = 0.68). No relationship between cMet and viral status was observed. The most common AEs in tivantinib were asthenia (26.8%), neutropenia (25.4%), low appetite (25.4%); the most common drug-related AEs were neutropenia (25.4%), anemia (15.5%). The most frequent drug-related serious AE was neutropenic sepsis (4.2%). Efficacy was independent of dose, with less frequent G > 3 neutropenia in TB (21.1% vs 6.1%). Additional data on secondary endpoints will be presented. Conclusion Tivantinib was shown to be effective as second-line therapy in HCC when compared to placebo. This advantage is more evident in Met + patients. The safety profile of tivantinib at 240 mg BID was manageable.