Second-line tivantinib (ARQ 197) vs placebo in patients (Pts) with MET-high hepatocellular carcinoma (HCC): Results of the METIV-HCC phase III trial

Background: Tivantinib (T), a selective, oral MET inhibitor, improved overall survival (OS) and progression‐free survival (PFS) versus placebo (P) in a phase II study in MET‐High HCC pts. Methods: This randomized, placebo‐controlled phase III trial (NCT01755767) enrolled pts with: advanced HCC; Child Pugh A; ECOG PS ≤1; adequate bone marrow, liver, kidney functions; no liver transplant; radiographic disease progression (PD) after or intolerance to sorafenib; tumor MET‐High (MET ≥2+ in ≥50% of tumor cells) by centralized immunohistochemistry. Pts were randomly assigned 2:1 to oral T or P, stratified by vascular invasion (VI), extrahepatic spread (ES), AFP ( < / > 200ng/mL), treated until PD or unacceptable toxicity. Response (RECIST 1.1) was evaluated by CT / MRI every 8 weeks. Primary endpoint of OS and secondary endpoints including PFS and safety were assessed in the intent‐to‐treat (ITT) population. Results: From Dec 2012 to Dec 2015, 1209 pts were consented in Australia, the Americas, Europe, New Zealand: 589 MET‐High, 43 initially randomized at the dose of 240mg BID, then reduced due to high neutropenia rate, 340 randomized at 120mg BID: 226 to T, 114 to P (ITT population). Characteristics of pts were balanced between arms: 306 (90%) male; median age: 67; PS 0: 207 (61%); VI: 117 (34%); ES: 197 (58%); AFP ≤200: 195 (57%); radiographic PD on sorafenib: 275 (81%). Median OS (95% CI) was 8.4 months (m) (6.8‐10.0) in T, 9.1 m (7.3‐10.4) in P, HR = 0.97 (0.75‐1.25), P = 0.81. Median PFS (95% CI) was 2.1 m (1.9‐3.0) in T, 2.0 m (1.9‐3.6) in P, HR = 0.96 (0.75‐1.22), P = 0.72. No OS difference was seen in pts with VI (HR 1.19, 0.79‐1.79), ES (HR 1.09, 0.78‐1.52), AFP > 200ng/mL (HR 1.00, 0.71‐1.41). Grade (G) > 3 AEs were 55.6% in T, 55.3% in P. In T, most common G > 3 AEs were ascites (7.1%), general deterioration (5.8%), anemia (4.9%); most common serious AE was general deterioration (4.9%). Deaths within 30 days of last dose were 22.1% on T vs 15.8% on P (most common causes: general deterioration 3.5%, hepatic failure 2.6%). Conclusion: Tivantinib at the 120mg BID dose did not improve OS or PFS over placebo in patients with advanced MET‐High HCC who failed previous treatment with sorafenib.