Safety and effectiveness of sorafenib in Japanese patients with hepatocellular carcinoma in daily medical practice: interim analysis of a prospective postmarketing all-patient surveillance study

Abstract

Background: Sorafenib was approved for treatment of unresectable hepatocellular carcinoma (HCC) in Japan in 2009. A prospective postmarketing all-patient surveillance (PMS) study was requested by Japanese authorities to confirm safety and effectiveness of sorafenib in Japanese HCC population.

Methods: Patients with unresectable HCC treated with sorafenib were followed up for 12 months. Data on patient demographic characteristics, treatment status, clinical outcome, and adverse events (AEs) were collected.

Results: This interim analysis included 1109 and 1065 patients evaluable for safety and effectiveness, respectively. Most patients (83.4 %) received the recommended initial dose of 400 mg twice daily. After a follow-up of 12-months, 89.8 % had discontinued treatment, most because of AEs (44.5 %) or progression (33.8 %). The most common drug-related adverse events (DRAE) were hand-foot skin reaction (51.4 %), liver dysfunction (26.4 %), diarrhea (25.1 %), and hypertension (21.6 %). The median overall survival (OS) was 348 days [95 % confidence interval (CI) 299-389 days], and the median duration of treatment was 87 days (95 % CI 78-98 days). Multivariate analyses identified baseline prognostic factors for longer OS, including female sex, low Child-Pugh score, Eastern Cooperative Oncology Group performance status 0, tumor stage I/II/III, low aspartate aminotransferase level, high hemoglobin level, hepatitis C and history of surgical resection.

Conclusions: In general, the safety and effectiveness findings in this PMS were consistent with findings from previous clinical studies. Sorafenib was well tolerated and clinically useful for Japanese patients.

Clinical trial registration number: NCT01411436.

Keywords: Hepatocellular carcinoma; Japanese; Molecular targeted therapy; Postmarketing surveillance; Sorafenib.

Conflict of interest statement

Compliance with ethical standard Conflict of interest Shuichi Kaneko has received research grants from Bayer Yakuhin and Nippon Shinyaku, and grants from Chugai Pharmaceutical, MSD, Kowa, Mitsubishi Tanabe Pharma, Bristol-Myers Squibb, Eli Lilly, Boehringer Ingelheim Japan, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Eisai, Daiichi Sankyo, AstraZeneca, Novartis Pharma, Astellas Pharma, Teijin Pharma, Zeria Pharmaceutical, Sanofi, Toray Industries, Shionogi, Novo Nordisk Pharma, and Pfizer Japan. Kenji Ikeda has received lecture fees from Sumitomo Dainippon Pharma and Eisai. Yasushi Matsuzaki has received research grants from Mitsubishi Tanabe Pharma, MSD, Ajinomoto Pharmaceuticals, Eisai, Sumitomo Dainippon Pharma, AbbVie, Daiichi Sankyo, Toray Industries, Minophagen Pharmaceutical, Otsuka Pharmaceutical and Kyowa Hakko Kirin, and lecture fees from Mitsubishi Tanabe Pharma, MSD, Ajinomoto Pharmaceuticals, Bristol-Myers Squibb and Janssen Pharmaceutical. Junji Furuse has received research grants from Taiho Pharma, Ono Pharmaceutical, OncoTherapy Science, Merck Serono, Zeria Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Yakuhin, GlaxoSmithKline and Yakult, and lecture fees from Taiho Pharma, Chugai Pharmaceutical, Yakult and Kyowa Hakko Kirin. Hironobu Minami has received research grants from Kyowa Hakko Kirin, Chugai Pharmaceutical, Taiho Pharma and Bristol-Myers Squibb. Yutaka Okayama, Toshiyuki Sunaya, Yuichiro Ito and Lyo Inuyama are employees of Bayer Yakuhin, Ltd. The other authors declare that they have no conflicts of interest.

Figures

Fig. 1

Time course of onset of drug-related adverse events (DRAE) evaluated based on the ratio of cumulative incidence rate at day 30 to that at day 365 using the Kaplan–Meier method: a DRAE occurring in the early stage of treatment (ratio ≥ 0.6); b intermediate DRAE (ratio ≥0.4 to <0.6); c DRAE occurring over the entire period (ratio <0.4). *Clinically similar terms of MedDRA were combined in one DRAE. MedDRA Medical Dictionary for Regulatory Activities

Fig. 2

Kaplan–Meier analyses of OS (effectiveness-analysis set): a OS of overall population of patients; b OS by baseline Child-Pugh class (CP A and CP B); c OS by baseline Child-Pugh score (A5, A6, B7, and ≥B8); d OS by baseline ECOG PS (PS 0, 1, and ≥2); and e OS by etiology. OS overall survival, CP Child-Pugh, ECOG PS Eastern Cooperative Oncology Group performance status, NASH nonalcoholic steatohepatitis

Fig. 3

Overall survival of patient subgroups according to baseline prognostic factors. Evaluated 887 patients (83.3 %) available for this analysis in the effectiveness-analysis set of 1065 patients. *Median value. CI confidence interval, ECOG PS Eastern Cooperative Oncology Group performance status, AST aspartate aminotransferase