Tivantinib is a small molecule inhibitor of c-Met. A previous phase 2 study suggested a clinical benefit of tivantinib as a second-line therapy for hepatocellular carcinoma (HCC) with high expression of c-Met. This Japanese study aimed to confirm the efficacy and safety of tivantinib in this population (NCT02029157).
Main inclusion criteria were HCC patients refractory or intolerant to a prior sorafenib therapy, Child Pugh A, ECOG PS ≤ 1, at least one measurable lesion according to RECIST 1.1, and diagnosed as c-Met high (regarded as ≥ 2+ in ≥ 50% of tumor cells, by IHC). Enrolled patients were blindly randomized to either tivantinib or placebo group in 2:1 ratio. Stratification factors were vascular invasion (Y/N) and ECOG PS (0/1). Tivantinib (120 mg bid) or placebo was orally administered until discontinuation criteria was met. Primary endpoint was PFS by the independent review committee, based on CT/MRI every 6 weeks. Secondary endpoints included OS and safety. A sample size of 160 patients and 136 PFS events were calculated to detect a HR of 0.6 (improvement in median PFS from 8 to 13.3 weeks), with 10% dropout, 80% power, and log-rank test with 5% two-sided alpha.
From 60 sites in Japan, 386 patients were consented, and 195 patients were randomized (tivantinib; n = 134, placebo; n = 61). As results, median PFS was 2.8 months in the tivantinib group, whereas 2.3 months in the placebo group (HR = 0.72 [95% CI 0.51-1.02], p = 0.065). Median OS at the time of analysis was 9.9 months in the tivantinib group, whereas 8.5 months in the placebo group (HR = 0.85 [95% CI 0.59-1.22]), but additional follow up may be needed to confirm long-term outcome. Grade ≥3 AE occurring ≥5% were neutropenia (31.6%), leukopenia (24.8%), lymphopenia (7.5%), anemia (14.3%) and febrile neutropenia (6.0%) in the tivantinib group, whereas none in the placebo group. New toxic profile was not identified except for known AE in the previous study.
Although favorable survival were observed in the tivantinib group, this study in Japan could not show the significant clinical benefit of tivantinib as a second-line therapy for c-Met high HCC.
Clinical trial identification
Legal entity responsible for the study
Kyowa Hakko Kirin
Kyowa Hakko Kirin
S. Kobayashi: Honoraria: Nippon Kayaku. K. Ueshima: Honoraria, advisory role: Bayer, Eizai, Otsuka, Shionogi, Gilead, Abbvie, Terumo, EA Pharma. N. Izumi: Honoraria, advisory role: Bayer, Shionogi, Otsuka, Gilead, Kowa. T. Chiba: Reseach funding: Bayel. K. Motomura: Honoraria: Olympus. A. Ido: Research funding: Kyowa Hakko Kirin. J. Kinoshita, T. Sato: Employment of Kyowa Hakko Kirin. M. Ikeda: Honoraria, advisory role, research funding: Bayer, BMS, Abbott, Eisai, Taiho, Eli Lilly, Chugai, Nippon Kayaku, Kyowa Hakko Kirin, Ono, Kowa. T. Okusaka: Honoraria, advisory, research fund: Novartis, Taiho, Merck, Lilly, Dainippon, Bayer, Yakult, Nobel, N Kayaku, Baxter, Astellas, F FILM, AZ, Ono, EA Pharm, N Chemi., D Sankyo, Celgene, Chugai, Boehringer, Zeria, Eisai, Kowa, K Kirin, Pfizer, GSK, N Carrier. M. Kudo: Honoraria, advisory role; Chugai, Otsuka, Takeda, Sumitomo Dainippon, Daiichi Sankyo, MSD, Eisai, Bayer, Abbvie, Kowa, BMS, Taiho. K. Tamura: Honoraria: Ono, Eli Lilly, Kyowa Hakko Kirin. J. Furuse: Advisory, research fund: Taiho, Yakult, Lilly, Chugai, Eisai, Ono, D Sankyo, Merck, Bayer, Novartis, Dainippon, Mochida, MSD, AZ, Takeda, Astellas, F Film, K Kirin, Otsuka, Zeria, J-Ph, Boehringer, Shionogi, Sanofy, Sandoz, BMS, Janssen, N carrier, OTS. All other authors have declared no conflicts of interest.