Safety and efficacy of sorafenib in Japanese patients with hepatocellular carcinoma in clinical practice: a subgroup analysis of GIDEON

Hepatocellular carcinoma (HCC) is the second-leading cause of cancer-related death in men and the sixth in women worldwide [1, 2]. The major risk factors for HCC are hepatitis C virus (HCV), hepatitis B virus, alcohol consumption, non-alcoholic steatohepatitis and diabetes mellitus [3, 4]. The majority of cases of HCC (70–90 % of cases) develop as a consequence of cirrhosis [5]—consequently, many patients have liver dysfunction and a high comorbidity rate. Not surprisingly, heterogeneity in the etiology, clinical symptoms and behavior of HCC makes it difficult to manage [6].

The mortality rate associated with HCC has declined by 37 %, primarily because of increased patient surveillance [7]; however, there are still many patients with unresectable HCC. Worldwide standards for the treatment of unresectable HCC have only recently been established [7‐9]. Progress made in the understanding of the molecular mechanisms involved in the development and proliferation of tumors has enabled the development of effective therapeutic agents (i.e., targeted molecular therapy) for progressive HCC [10, 11].

Sorafenib is an oral multikinase inhibitor that has an inhibitory effect on tumor growth and angiogenesis [12], and it is a first-line treatment option for unresectable HCC [13]. The effect of sorafenib on prolongation of overall survival (OS) has been demonstrated in two previous phase 3, placebo-controlled, randomized studies [14, 15].

The Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and Of Its Treatment With SorafeNib (GIDEON) was a prospective, global, non-interventional study conducted under the guidance of the European Medicines Agency [16]. The primary objective was to evaluate the safety of sorafenib in patients with unresectable HCC under real-world practice across different geographic regions as well as in a series of subgroups; 3371 patients participated from 39 countries, including Japan. Two interim analyses and a final analysis have been performed, as specified in the protocol [17, 18]. In the first and second interim analyses, 500 and 1500 patients were followed up, respectively, for ≥4 months; in the final analysis, ≥3000 patients were followed up for ≥12 months.

In Japan, GIDEON was conducted as a specific drug use-results survey under the regulation of postmarketing surveillance. Before the start of this study, all-case postmarketing surveillance was conducted separately, as required by the Japanese Ministry of Health, Labour and Welfare [19, 20]. The aim of the all-case postmarketing surveillance was to investigate unexpected drug-related adverse events (AEs), the incidence of drug-related AEs and the factors that might affect drug safety and efficacy. Patient registration was initiated after the completion of the registration for the all-case surveillance.

It is important to assess the safety and efficacy of sorafenib in daily practice and also understand the differences in the characteristics of HCC patients between Japan and other countries.

Here we report the results of the efficacy and safety analyses of sorafenib in 517 Japanese patients who participated in GIDEON.

GIDEON was a large-scale, prospective, noninterventional study with ≥3300 patients from 39 countries evaluating the safety and efficacy of sorafenib and the factors that affect decision making with regard to treatment options. The median treatment duration of sorafenib in patients with Child-Pugh B was shorter than in patients with Child-Pugh A. Although the incidence of all or drug-related AEs was similar between Child-Pugh A and B, the incidence of all or drug-related SAEs, the number of AEs resulting in permanent discontinuation of sorafenib and deaths was higher in patients with Child-Pugh B. The incidence of drug-related AEs of hepatic-related events, such as liver dysfunction, hypoalbuminemia and hepatic encephalopathy, was higher in patients with Child-Pugh B than with Child-Pugh A. The incidence of drug-related AEs was analyzed by patient-year in consideration of the treatment duration of sorafenib. The results showed that drug-related AEs and liver function in patients with Child-Pugh A and Child-Pugh B were 1.59 and 2.67, 0.07 and 0.37 events per patient-year, respectively (data not shown). It is necessary to fully weigh the benefits versus risks associated with sorafenib treatment in patients with Child-Pugh B. Furthermore, when Cox regression analysis was given for parameters used in the Child-Pugh classification (excluding hepatic encephalopathy) at the time of treatment initiation with sorafenib, albumin and bilirubin levels were identified as contributing factors to the OS, with the hazard ratio for bilirubin being the highest (data not shown). The results of global analysis had shown that ascites, albumin and bilirubin levels were factors affecting the OS, which were similar to those of the Japanese subgroup analysis [25].

Before the start of this study in Japan, all-case surveillance was conducted separately under the regulations of postmarketing surveillance [19, 20]. The incidence of drug-related AEs was 90.2 %. Frequently observed drug-related AEs included HSFR (51.4 %), liver dysfunction (26.4 %), diarrhea (25.1 %) and hypertension (21.6 %) [19, 20]. The results of Japanese subgroup analyses showed that drug-related AEs were observed in 87.6 % of patients. Frequently observed drug-related AEs included hand-foot skin reaction (47.8 %), liver dysfunction (4.5 %), diarrhea (35.8 %) and hypertension (24.2 %).

Reasons for the low incidence of liver dysfunction may be that a safety bulletin (liver failure and hepatic encephalopathy) was issued from the Japanese Proper Use Advisory Committee immediately after initiation of registration and that there was routine monitoring (e.g., periodic liver function tests followed by appropriate dose reduction or interruption) during sorafenib treatment.

The incidence of drug-related AEs of liver dysfunction was less than 1 % in the sorafenib arm in the Phase III SHARP and Asia-Pacific trial. In the SHARP trial, times to deterioration of liver function (Child-Pugh classification) were similar between the sorafenib and placebo arm (data not shown).

Compared with other regions, the mean time from the initial diagnosis to death in Japan tended to be longer irrespective of BCLC stage. This difference could be the result of early detection or because patients in Japan had more treatment opportunities than those in other regions. In addition, TTP from the start of sorafenib therapy in Japanese patients was the shortest among patients worldwide; Japan’s early monitoring by imaging appears to be the major reason why Japanese patients have the shortest TTP [26, 27].

The present results also showed that the incidence of AEs resulting to permanent discontinuation of sorafenib in Japanese patients was 41.3 %, a higher rate than seen in other regions. The incidence of HFSR was 4.1 %, which was the second highest rate after liver dysfunction (4.3 %) (data not shown). Although the HFSR itself is not a life-threatening AE, it can decrease patient quality of life, cause infection and pain, limit daily activities and lead to a complex medical situation.

It has been reported that the incidence of HFSR differs between Japanese and non-Japanese patients [28]. The incidence of hand-foot skin reaction in the all-case surveillance and in this study was high: 51.4 and 47.8 %, respectively, higher than for other Asian countries (31.7 % in Korean patients [29]). Although the discontinuation rate due to HFSR is low, the cause is not fully understood, and future studies will be needed.

Incidence of drug-related AEs was highest in Japan, but treatment-emergent death occurring up to 30 days after discontinuation of sorafenib was lowest compared with other regions. Ealier discontinuation of sorafenib treatment may be related to the apparent lower rate of treatment-emergent death.

The number of TACE sessions performed before sorafenib therapy was higher for Japanese patients than for those in other regions. Patients with ≥6 TACE sessions tended to have lower response rates, and there was a higher proportion of Child-Pugh B patients at initiation of sorafenib therapy. TACE failure/refractoriness was defined by the Japan Society of Hepatology in 2010 and revised in 2014 [30, 31], which was after patient registration began in the GIDEON study. In TACE-refractory patients with intermediate-stage HCC, the deterioration of liver function is accelerated when TACE is continued, and conversion to sorafenib significantly improves the median OS [32, 33]. Therefore, in the case of uncontrolled tumors by TACE, TACE should not be repeated and alternative treatments, such as sorafenib, are recommended.

GIDEON did not include a control group or randomization. The number of patients with Child-Pugh B was much smaller than with Child-Pugh A; therefore, the results should be interpreted with caution. Japanese patients were not registered in the Phase III SHARP and the Asia-Pacific trial [14, 15]. Thus, obtaining background information and treatment trends from real-world practice data in Japanese patients may provide a valuable contribution to the future of HCC treatment. In this subgroup analysis of Japanese patients, there was an earlier diagnosis, more frequent treatment with TACE before sorafenib therapy and a tendency toward longer OS irrespective of BCLC stage at the time of initial diagnosis compared with other regions.

In conclusion, sorafenib was well tolerated by Japanese HCC patients in clinical settings. Patients with Child-Pugh B had a shorter duration of treatment and higher incidence of SAEs. Therefore, it is critical to evaluate the patient's benefit and risk before making a decision to treat with sorafenib for patients with Child-Pugh B.