619O - JET-HCC: A phase 3 randomized, double-blind, placebo-controlled study of tivantinib as a second-line therapy in patients with c-Met high hepatocell...

Date 10 September 2017
Event ESMO 2017 Congress
Session Gastrointestinal tumours, non-colorectal 2
Topics Anti-Cancer Agents & Biologic Therapy
Hepatobiliary Cancers
Gastrointestinal Cancers
Presenter Satoshi Kobayashi
Citation Annals of Oncology (2017) 28 (suppl_5): v209-v268. 10.1093/annonc/mdx369
Authors S. Kobayashi1, K. Ueshima2, M. Moriguchi3, T. Takayama4, N. Izumi5, H. Yoshiji6, K. Hino7, T. Oikawa8, T. Chiba9, K. Motomura10, J. Kato11, K. Yasuchika12, A. Ido13, J. Kinoshita14, T. Sato15, M. Ikeda16, T. Okusaka17, M. Kudo2, K. Tamura18, J. Furuse19
  • 1Department Of Gastroenterology, Hepatobiliary And Pancreatic Medical Oncology Division, Kanagawa cancer center, 2418515 - Yokohama/JP
  • 2Department Of Gastroenterology And Hepatology, Kindai University Faculty of Medicine, Sayama/JP
  • 3Department Of Gastroenterology And Hepatology, Kyoto Prefectural University of Medicine, Kyoto/JP
  • 4Department Of Gastroenterology And Oncology, Tokushima University, Graduate School of Biomedical Sciences, Tokushima/JP
  • 5Department Of Gastroenterology And Hepatology, Musashino Red Cross Hospital, Musashino/JP
  • 6Third Department Of Internal Medicine, Nara Medical University, Kashihara/JP
  • 7Department Of Hepatology And Pancreatology, Kawasaki Medical School, Kurashiki/JP
  • 8Division Of Hepatology,department Of Internal Medicine, Iwate Medical University, Morioka/JP
  • 9Department Of Gastroenterology And Nephrology, Graduate School of Medicine, Chiba University, Chiba/JP
  • 10Department Of Hepatology, Aso Iizuka Hospital, Iizuka/JP
  • 11Department Of Gastroenterology, Juntendo University School of Medicine, Bunkyo/JP
  • 12Division Of Hepatobiliary Pancreatic Surgery And Transplantation, Department Of Surgery, Kyoto University Graduate School of Medicine, Sakyo/JP
  • 13Department Of Gastroenterology, Kagoshima University Hospital, Kagoshima/JP
  • 14Clinical Development Center, Kyowa Hakko Kirin, Chiyoda/JP
  • 15Oncology R&d Management Office, Kyowa Hakko Kirin, Chiyoda/JP
  • 16Department Of Hepatobiliary And Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa/JP
  • 17Department Of Hepatobiliary And Pancreatic Oncology, National Cancer Center Hospital, Chuo/JP
  • 18General Medical Research Center, Fukuoka University Faculty of Medicine, Fukuoka/JP
  • 19Department Of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka/JP

Abstract

Background

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).

Methods

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.

Results

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.

Conclusions

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

NCT02029157

Legal entity responsible for the study

Kyowa Hakko Kirin

Funding

Kyowa Hakko Kirin

Disclosure

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.