Safety and Efficacy of Tigatuzumab Plus Sorafenib As First-Line Therapy

Research Article

Safety and efﬁcacy of tigatuzumab plus sorafenib as ﬁrst-line therapy in subjects with advanced hepatocellular carcinoma: A phase 2 randomized study

⇑ Ann-Lii Cheng1, , Yoon-Koo Kang2, Aiwu Ruth He3, Ho Yeong Lim4, Baek-Yeol Ryoo2, Chao-Hung Hung5, I-Shyan Sheen6, Namiki Izumi7, TaShara Austin8, Qiang Wang9, Jonathan Greenberg9, Shinichi Shiratori9, Robert A. Beckman10,11, Masatoshi Kudo12, and the Investigators’ Study Group

1Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; 2Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC, USA; 4Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea; 5Chang Gung Medical Foundation- Kaohsiung, Kaohsiung, Taiwan; 6Chang Gung Medical Foundation-Linkuo, Taoyaun, Taiwan; 7Japan Red Cross Musashino Hospital, Tokyo, Japan; 8Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 9Daiichi Sankyo Pharma Development, Edison, NJ, USA; 10Department of Oncology, Lombardi Comprehensive Cancer Center and Innovation Center for Biomedical Informatics, Georgetown University MedicalCenter,Washington,DC,USA;11Department of Biostatistics, Bioinformatics, and Biomathematics, Lombardi Comprehensive Cancer Center and Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA; 12Kinki University Hospital, Osaka, Japan

Background & Aims: Tigatuzumab is a humanized monoclonal tigatuzumab (6 mg/kg loading, 6 mg/kg/week maintenance) plus antibody that acts as a death receptor-5 agonist and exerts sorafenib 400 mg twice daily; or sorafenib 400 mg twice daily. tumour necrosis factor-related apoptosis-inducing ligand-like The primary end point was time to progression. Secondary end activity. In this phase II study, safety and tolerability of the com- points included overall survival and safety. bination of tigatuzumab and sorafenib was evaluated in patients Results: 163 subjects were randomized to treatment. Median with advanced hepatocellular carcinoma. time to progression was 3.0 months in the tigatuzumab Methods: Adults with advanced hepatocellular carcinoma, mea- 6/2 mg/kg combination group (p = 0.988 vs. sorafenib), surable disease, and an Eastern Cooperative Oncology Group per- 3.9 months in the tigatuzumab 6/6 mg/kg combination group formance score 6 1 were enrolled. Eligible subjects were (p = 0.586 vs. sorafenib), and 2.8 months in the sorafenib alone randomly assigned 1:1:1 to tigatuzumab (6 mg/kg loading, group. Median overall survival was 12.2 months in the tigatuzu- 2 mg/kg/week maintenance) plus sorafenib 400 mg twice daily; mab 6/6 mg/kg combination group (p = 0.659 vs. sorafenib), vs. 8.2 months in both other treatment groups (p = 0.303, tigatuzumab 6/2 mg/kg combination vs. sorafenib). The most common treatment–emergent adverse events were palmar–plan- Keywords: Advanced hepatocellular carcinoma; Combination therapy; CS-1008; Monoclonal antibody; Sorafenib; Tigatuzumab. tar erythrodysesthesia syndrome, diarrhea, and decreased Received 8 July 2014; received in revised form 21 April 2015; accepted 2 June 2015; appetite. available online 10 June 2015 Conclusions: Tigatuzumab combined with sorafenib vs. sorafenib ⇑ Corresponding author. Address: National Taiwan University Hospital, No. 7, alone in adults with advanced hepatocellular carcinoma did not Chung-Shan South Road, Taipei City 10002, Taiwan. Tel.: +886 2 231 meet its primary efﬁcacy end point, although tigatuzumab plus 23456x6725; fax: +886 2 237 11174. E-mail address: [email protected] (A.-L. Cheng). sorafenib is well tolerated in hepatocellular carcinoma. Abbreviations: HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, Ó 2015 European Association for the Study of the Liver. Published hepatitis C virus; RT, radiotherapy; SHARP, a phase III study of Sorafenib in by Elsevier B.V. All rights reserved. patients with advanced HCC; DR5, death receptor 5; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; BID, twice daily; ECOG, Eastern Cooperative Oncology Group; ICH, International Conference On Harmonisation; GCP, Good Introduction Clinical Practice; TTP, time to progression; ORR, objective response rate; OS, overall survival; AEs, adverse events; PD, disease progression; CI, conﬁdence interval; NCI CTCAE, National Cancer Institute’s Common Terminology Criteria for Hepatocellular carcinoma (HCC) remains one of the most com- Adverse Events; SAE, serious AE; AFP, alpha-fetoprotein; TIG, Tigatuzumab; SOR, mon malignancies worldwide and is a major global cause of Sorafenib; HR, hazard ratio; SD, standard deviation; TEAE, treatment–emergent cancer-related deaths [1]. Studies have shown that although the AE; PPE, palmar–plantar erythrodysesthesia; AST, aspartate aminotransferase; incidence of HCC has plateaued or is declining in Asian countries HAHA, human antihuman antibody; BRISK-PS, Brivanib study in HCC patients at risk post Sorafenib. such as China and Japan [2,3], countries such as USA are

Journal of Hepatology 2015 vol. 63 j 896–904 JOURNAL OF HEPATOLOGY experiencing an acceleration of cases [3,4]. The risk factors for maintenance) plus sorafenib 400 mg BID; or iii) sorafenib 400 mg BID. these HCC cases include infection with hepatitis B or C virus Tigatuzumab did not reach an MTD in its single agent phase I study, and the tigatuzumab low dosage was based on a population PK model derived from data from (HBV, HCV), non-alcoholic fatty liver disease, and alcoholic liver this phase I study [14]. The low dose level was predicted to produce serum trough disease [5]. levels in excess of the levels corresponding to maximal efficacy in preclinical Common therapies for HCC are resection, transcatheter arte- xenograft models (data not shown). To assess dose dependency of the efficacy rial chemoembolization, radioembolization, partial hepatectomy, in patients in a phase II study, the higher dose level, previously shown to be safe cryoablation, percutaneous alcohol injection, microwave therapy, in phase I, was added in case a higher dose level was required clinically to uni- formly penetrate the intra-tumoural space. Human tumours are larger and have stereotactic body radiotherapy, or external body radiotherapy. higher interstitial pressure than murine tumours, which may impede the uniform Systemic chemotherapy and radiotherapy (RT) have no clear sur- biodistribution of antibodies [20]. In some instances, higher doses may provide a vival benefit and excessive toxicity [6–8]. Patients with sufficient concentration gradient to allow more uniform penetration of tumours, advanced-stage disease have unsatisfactory long-term survival potentially providing more complete target coverage and tumour cell death [21]. Disease assessments were performed at screening/baseline and at the end of outcomes, often owing to underlying liver disease, with high every two treatment cycles (six weeks) (Fig. 1B). There was no limit to the num- rates of tumour recurrence [9]. There is thus a substantial need ber of treatment cycles that could be administered. for novel treatments for advanced disease. Tigatuzumab was administered intravenously over 30 ± 10 min before a dose Sorafenib is a multi-kinase inhibitor with antiangiogenic, of sorafenib on day one of each week. Sorafenib was to be taken 61 h before or pro-apoptotic, and Raf kinase inhibitory activity [10]. Sorafenib P2 h after meals. An interactive web response system was used to enrol/randomize subjects. showed a survival benefit over placebo in the SHARP (A phase Subjects were provided with a subject identification number when they were III Study of Sorafenib in Patients with Advanced HCC) and the enrolled/randomized, and were randomized to one of three treatments according Asian-Pacific pivotal studies in patients with advanced HCC to a randomization schedule. This schedule was computer generated before the [11,12], and is now the standard of care for this indication. randomized portion of the study began by the clinical research organization (ICON Clinical Research, North Wales, PA, USA), under the direction of the spon- Tigatuzumab is a humanized monoclonal antibody that acts as sor’s biostatistics department. Randomization was stratified by Eastern a death receptor 5 (DR5) agonist, exerting tumour necrosis Cooperative Oncology Group (ECOG) performance status (0 vs. 1); extrahepatic factor-related apoptosis-inducing ligand (TRAIL)-like activity metastasis and/or macrovessel invasion (yes vs. no), and region (USA, Japan, [13]. In a phase I, single agent study in 17 patients with meta- and Asia [Taiwan and South Korea]). The time between randomization and initi- 6 static solid tumours or lymphomas, tigatuzumab showed evi- ation of treatment was to be 7 days. The study was conducted in compliance with the protocol, the ethical princi- dence of preliminary anticancer effects, including 26 months of ples set forth in the Declaration of Helsinki, International Conference on stable disease in a patient with advanced HCC, and a favourable Harmonisation (ICH) Guideline E6 for Good Clinical Practice (GCP), and applicable toxicity profile [14]. regulatory requirement(s). In preclinical studies, sorafenib overcame TRAIL resistance in HCC cells and enhances tigatuzumab-induced apoptosis [15]. Participants Several reports have shown the cytotoxic synergy of sorafenib in combination with TRAIL receptor antibodies in various types The key inclusion criteria were: subjects aged P18 years; histologically or cyto- of cancer cells [16–19]. According to these reports, sorafenib logically confirmed HCC or clinical diagnosis of HCC; advanced disease; measur- able disease based on RECIST criteria (version 1.1) [22] of P1 untreated target may downregulate Mcl-1, a key molecule playing a critical role lesion that can be measured in one dimension; ECOG performance status 0 or in the resistance to TRAIL-induced apoptosis. Thus, administra- 1; Child-Pugh class A; life expectancy of P12 weeks; and adequate organ and tion of tigatuzumab in combination with sorafenib may have syn- bone marrow function. ergistic effects for treating HCC. This phase II study aimed to Key exclusion criteria included: any prior systemic therapy for HCC; RT, assess the safety and efficacy of tigatuzumab in combination with major surgical procedure, or use of any investigational agent within four weeks and minor surgical procedures within two weeks of the first dose of study treat- sorafenib in adult subjects with advanced HCC from Asia and ment; anticipation of need for RT or a major surgical procedure during the study; USA. history of organ transplantation; or clinically significant, severe, active infection requiring intravenous antibiotics.

Outcomes Patients and methods

The primary endpoint was time to progression (TTP). Secondary endpoints were Study design objective response rate (ORR), overall survival (OS), and safety (adverse events [AEs] and clinical laboratory evaluations). This was a phase II, multi-centre, open-label, randomized study, conducted at 28 study sites in Japan, South Korea, Taiwan, and the USA. All therapies were admin- Assessments istered on an outpatient basis, with each treatment cycle lasting three weeks (21 days). As the clinical safety of the proposed weekly regimen of tigatuzumab with daily sorafenib was not established, this trial started with safety cohorts Efficacy assessments were based on tumour measurements obtained from serial receiving sequentially escalating maintenance doses of tigatuzumab, to gradually radiographs and clinical measurements (e.g., CT scans) performed at baseline reach steady-state levels with repeated dosing, plus regular doses of sorafenib. then after the end of every two treatment cycles, and survival status. Tumour The loading dose of tigatuzumab 6 mg/kg and the weekly tigatuzumab dosing measurements, disease progression (PD), ORR, and variables based on response schedule were largely based on data derived from the phase I dose-escalation to treatment were assessed in accordance with RECIST (version 1.1) [22]. An inde- study [14]. pendent radiological review of tumour measurements and independent review of The dosing schedule for the three safety cohorts is shown in Fig. 1A. response rates was also carried out at Columbia University, NY, USA. Dose-limiting toxicity (DLT) in three subjects in a cohort would halt dose progres- TTP was defined as the time from the date of registration/randomization until sion, and the prior dose level would be designated the maximum tolerated dose PD according to RECIST criteria (version 1.1) [22] or symptomatic progression (MTD) (Fig. 1A). If 6 mg/kg/week tigatuzumab was determined not to be above (defined as deterioration to ECOG performance status 4). the MTD, the randomized portion of the study would be initiated as planned. All clinical AEs occurring 630 days after the last dose of study medication In the randomized portion of the study, 150 eligible subjects were randomly were recorded. After discontinuation from study treatment, subjects were to be assigned 1:1:1 to; i) tigatuzumab (6 mg/kg loading [or MTD as determined], contacted every three months, until death or for up to 16 months after last sub- 2 mg/kg/week maintenance) plus sorafenib 400 mg twice daily (BID); ii) tigatuzu- ject randomization, to obtain information concerning subsequent treatments and mab (6 mg/kg loading [or MTD as determined], 6 mg/kg/week [or MTD] survival status.

Journal of Hepatology 2015 vol. 63 j 896–904 897 Research Article AB

Fig. 1. Study design. (A) Safety cohort and (B) randomized portion. DLTs, any of the following considered related to tigatuzumab: Grade 3/4 non-hematologic toxicities (except alopecia, fatigue, anorexia, nausea/diarrhoea, fever without neutropenia); failure to recover to baseline toxicity (except alopecia) after delaying next dose by >3 weeks; Grade 3/4 neutropenia complicated by fever/infection or Grade 4 neutropenia P7 days; Grade 3 thrombocytopenia complicated by hemorrhage/Grade 4 thrombocytopenia. BID, twice daily; CR, complete response; DLT, dose-limiting toxicity; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; IV, intravenous; MTD, maximum tolerated dose; PO, oral; PD, disease progression; PR, partial response; PS, performance status; QW, weekly; SD, stable disease.

Statistical methods Enrolled, n = 172

The primary efficacy analysis was performed on the full analysis set, which com- Safety cohort, prised all subjects in the randomized portion of the study who received P1 dose n = 9 Randomized, of study drug. The safety analysis set comprised all subjects, in both the safety n = 163 cohort and randomized portion, who received any amount of study drug (tigatuzumab or sorafenib) and had P1 safety assessment. For sample size planning in the randomized portion, based on the primary endpoint of TTP, 150 subjects randomized with a 1:1:1 ratio to one of the three Tigatuzumab 6/2 mg/kg + Tigatuzumab 6/6 mg/kg + Sorafenib, sorafenib, sorafenib, treatment groups was considered to provide reasonable precision for the estima- n = 55 n = 53 n = 55 tion of the hazard ratio (HR) between treatment groups. A Cox proportional hazards model was employed to estimate the HR (and 95% Discontinued, n = 50 Discontinued, n = 53 Discontinued, n = 49 confidence interval [CI]) between treatment groups. The model included, as fac- (94.3%) (96.4%) (89.1%) tors, treatment groups and stratification factors used in randomization • AE/SAE, n = 8 (15.1%) • AE/SAE, n = 6 (10.9%) • AE/SAE, n = 10 (18.2%) (Fig. 1B). Other important pre-specified prognostic variables such as age and • Withdrew consent, n = 9 • Withdrew consent, n = 2 • Deaths, n = 2 (3.6%) HBV/HCV infection status were also explored and included in the model as appro- (17.0%) (3.6%) • Withdrew consent, n = 2 priate. In addition, a stratified log-rank test was employed to assess whether • PD, n = 32 (60.4%) • PD, n = 41 (74.5%) (3.6%) there was a difference between sorafenib treatment alone and sorafenib in com- • Other, n = 1 (1.9%) • Investigator discr./other, • PD, n = 35 (63.6%) n = 4 (7.2%) bination with tigatuzumab 6/2 or 6/6 mg/kg per week (both separately and combined), with p values presented for the comparisons. Kaplan–Meier product limit Full analysis set, n = 53 Full analysis set, n = 54 Full analysis set, n = 55 estimates for TTP and OS were calculated and plotted for each treatment group, and the estimate of median TTP and OS provided, along with the 95% CI. AEs were coded using the Medical Dictionary for Regulatory Activities and Fig. 2. Subject disposition (as of primary analysis cut-off date, 13 July 2012). assigned grades based on National Cancer Institute’s Common Terminology AE, adverse event; PD, disease progression; SAE, serious AE. Criteria for Adverse Events (NCI CTCAE), Version 4.0. There was no formal safety and data monitoring board. Toxicity was assessed by the sponsor/ICON medical monitor and investigator. all nine subjects discontinued from the study: 7 (77.8%) due to PD, 1 (11.1%) due to a serious AE (SAE) or AE, and 1 (11.1%) due to withdrawal of consent. Results No DLTs were observed in the safety cohort and the MTD of tigatuzumab was not reached. Therefore, the randomized portion The first subject enrolled in the study on 9 July 2010 and the last of the study was conducted using the tigatuzumab loading dose subject completed on 9 September 2013. of 6 mg/kg.

Safety cohort Randomized portion Nine subjects were enrolled in the safety cohort (n = 3 per tigatuzumab 2, 4, or 6 mg/kg weekly maintenance dosing group). Patients Median (range) age was 49 (37–81) years, six (66.7%) subjects In total, 163 subjects were randomized to treatment (Fig. 2). The were men, and all nine were Asian. Two-thirds (66.7%) of subjects median (range) age was 63 (27–84) years, 134 (82.7%) subjects had an ECOG performance status of 0. All had received prior can- were men and the majority (159 [98.1%]) were Asian. Baseline cer therapy. As of the primary analysis cut-off date (13 July 2012), demographics and clinical characteristics for randomized

898 Journal of Hepatology 2015 vol. 63 j 896–904 JOURNAL OF HEPATOLOGY

Table 1. Patient baseline demographics and clinical characteristics (full analysis set).

Randomized portion Tigatuzumab 6/2 Tigatuzumab 6/6 Sorafenib Total mg/kga + mg/kgb + (n = 55) (N = 162) sorafenib sorafenib (n = 53) (n = 54) Median age, years (range) 63 (27-82) 62.5 (39-84) 66 (39-84) 63 (27-84) Sex, n (%) Male 45 (84.9) 45 (83.3) 44 (80.0) 134 (82.7) Race, n (%) Asian 52 (98.1) 53 (98.1) 54 (98.2) 159 (98.1) ECOG performance status, n (%) 0 32 (60.4) 31 (57.4) 30 (54.5) 93 (57.4) 1 21 (39.6) 23 (42.6) 25 (45.5) 69 (42.6) Missing 0 0 1 (1.8) 0 Tumor staging at diagnosis, n (%) I 5 (9.4) 4 (7.4) 6 (10.9) 15 (9.3) II 8 (15.1) 4 (7.4) 11 (20.0) 23 (14.2) IIIA 7 (13.2) 7 (13.0) 9 (16.4) 23 (14.2) IIIB 8 (15.1) 5 (9.3) 2 (3.6) 15 (9.3) IIIC 1 (1.9) 1 (1.9) 5 (9.1) 7 (4.3) IV 9 (17.0) 17 (31.5) 14 (25.5) 40 (24.7) Other 15 (28.3) 15 (27.8) 7 (12.7) 37 (22.8) Missing 0 1 (1.9) 1 (1.8) 2 (1.2) Contributing cause of disease, n (%) HBV 32 (60.4) 24 (44.4) 25 (45.5) 81 (50.0) HCV 16 (30.2) 20 (37.0) 19 (34.5) 55 (34.0) HBV/HCV 1 (1.9) 1 (1.9) 0 2 (1.2) Alcohol use 3 (5.7) 5 (9.3) 7 (12.7) 15 (9.3) Alcohol use/HBV 0 1 (1.9) 0 1 (0.6) Missing 1 (1.9) 3 (5.6) 4 (7.3) 8 (4.9) Prior cancer therapyc, n (%) 34 (64.2) 34 (63.0) 36 (65.5) 104 (64.2) Prior radiation therapy, n (%) 9 (17.0) 9 (16.7) 7 (12.7) 25 (15.4) Prior cancer surgery, n (%) 24 (45.3) 25 (46.3) 26 (47.3) 75 (46.3) Prior locoregional therapy, n (%) 33 (62.3) 32 (59.3) 30 (54.5) 95 (58.6) Median AFP, IU/ml (range) 3291 (1.54-851,200) 297 (1.96-746,400) 1366 (0.97-694,600) --

AFP, alpha-fetoprotein; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus. a6 mg/kg loading dose followed by 2 mg/kg maintenance dose. b6 mg/kg loading dose followed by 6 mg/kg maintenance dose. cCytostatics, chemotherapeutics, biologics and small molecules.

subjects are summarized in Table 1. Baseline alpha-fetoprotein Efficacy (AFP) was not well balanced, with low AFP favouring the tigatu- HRs for comparisons of TTP were 1.12 (95% CI 0.69–1.80) for TIG zumab high-dose arm. As this was a randomized trial with no 6/2 mg/kg + SOR vs. SOR alone (p =0.657), and 1.15 (95% CI 0.73– stratification of baseline AFP, this observation is a random effect, 1.81) for TIG 6/6 mg/kg + SOR vs. SOR alone (p =0.548). Median as no evidence of other factors are noted for this imbalance. (95% CI) TTP was 3.0 (2.6–5.5) months in the TIG Within the efficacy analysis set, the number of subjects with nor- 6/2 mg/kg + SOR group, 3.9 (2.7–5.3) months in the TIG mal AFP 6200 IU/ml in sorafenib (SOR) alone, tigatuzumab (TIG) 6/6 mg/kg + SOR group, and 2.8 (1.5–6.6) months in the SOR 6/2 mg/kg + SOR, and TIG 6/6 mg/kg + SOR groups is 23 (41.8%), alone group. Neither of the treatment differences for the compar- 19 (35.8%), and 25 (46.3%), respectively; the number of subjects ison with SOR alone were statistically significant (Fig. 3A). The with baseline AFP >200 IU/ml is 32 (58.2%), 34 (64.2%), and 28 combined p value for both TIG + SOR groups vs. SOR alone was (51.9%), respectively; and the number of subjects with baseline 0.794. AFP >400 IU/ml is 31 (56.4%), 32 (60.4%), and 23 (42.6%) respec- TTP as assessed by independent radiological review showed tively. As of the primary analysis cut-off date, 11 of the 163 ran- similar results, especially in the higher dose TIG and SOR alone domized subjects remained in the study and 152 had groups: median TTP (95% CI) of 4.0 (2.8–5.4) months with TIG discontinued, mostly due to PD (Fig. 2). In total, 162 were 6/2 mg/kg + SOR (p = 0.898 vs. SOR alone), 4.1 (2.7–5.7) months included in the full analysis set, which included the originally with TIG 6/6 mg/kg + SOR (p = 0.868 vs. SOR alone), and 2.8 assigned groups. All subjects had discontinued from the study (1.6–5.6) months with SOR alone. The combined p value for both as of 9 September 2013. TIG + SOR groups vs. SOR alone was 0.790.

Journal of Hepatology 2015 vol. 63 j 896–904 899 Research Article

A 100 SOR TIG 6/2 mg/kg + SOR TIG 6/6 mg/kg + SOR

75 Median TIG 6/2 mg/kg + SOR = 3.0 (95% Cl 2.6-5.5) months (p = 0.988 vs. SOR) Median TIG 6/6 mg/kg + SOR = 3.9 (95% Cl 2.7-5.3) months (p = 0.586 vs. SOR) Median SOR = 2.8 (95% Cl 1.5-6.6) months

50 Subjects without progression (%) 25

0 0 8 14 20 26 32 38 Months from randomization Subjects remaining at risk (cumulative events) SOR 55 (0) 28 (19) 22 (25) 18 (28) 13 (30)10 (33) 9 (34) TIG 6/2 mg/kg + SOR 53 (0) 29 (13) 18 (22) 12 (25) 9 (28) 7 (30) 5 (32) TIG 6/6 mg/kg + SOR 54 (0) 35 (13) 22 (24) 17 (29) 14 (31) 10 (34) 10 (34)

B 100 SOR TIG 6/2 mg/kg + SOR TIG 6/6 mg/kg + SOR

Median TIG 6/2 mg/kg + SOR = 8.2 (95% Cl 5.7-10.4) months (p = 0.303 vs. SOR) 75 Median TIG 6/6 mg/kg + SOR = 12.2 (95% Cl 9.0-15.0) months (p = 0.659 vs. SOR) Median SOR = 8.2 (95% Cl 4.9-13.4) months

50 Subjects surviving (%)

0 0 3 6 9 12 18 Months from randomization Subjects remaining at risk (cumulative events) SOR 55 (0) 44 (9) 30 (22) 23 (29) 20 (32) 11 (34) TIG 6/2 mg/kg + SOR 53 (0) 41 (5) 27 (16) 20 (23) 11 (32) 5 (35) TIG 6/6 mg/kg + SOR 54 (0) 45 (5) 38 (11) 31 (18) 25 (24) 7 (33)

Fig. 3. Efﬁcacy outcomes (full analysis set): (A) Time to tumour progression and (B) overall survival at the OS update. Censored observations indicated by a circle, triangle, or square. TIG, Tigatuzumab; SOR, Sorafenib.

900 Journal of Hepatology 2015 vol. 63 j 896–904 JOURNAL OF HEPATOLOGY We examined the effect of hepatitis viral infection status on Pre-specified subgroup analyses performed to identify charac- the efficacy results. The median TTP in patients with HCV in the teristics potentially predictive of a longer TTP following study SOR alone, TIG 6/2 mg/kg + SOR, and TIG 6/6 mg/kg + SOR groups treatment showed that there were no significant interactions was 4.2 months, 3.0 months, and 6.0 months, respectively; and in between treatment and any of the subgroup classification factors patients with HBV, 2.6 months, 4.0 months, and 2.7 months, (Fig. 4). respectively. The median OS in patients with HCV in the SOR alone, TIG 6/2 mg/kg + SOR, and TIG 6/6 mg/kg + SOR groups Exploratory and HCV groups was 9.2 months, 7.6 months, and 13.9 months, respectively; and in patients with HBV, 6.2 months, 9.3 months, An exploratory analysis was performed with the Cox proportional and 9.0 months, respectively. hazards model of OS incorporating baseline AFP level, as this was The effect of country of origin on efficacy was also evaluated. imbalanced at baseline. At the final OS update, the HR (95% CI) for The median TTP in patients in Taiwan in the SOR alone, TIG the comparison between TIG 6/2 mg/kg + SOR and SOR treatment 6/2 mg/kg + SOR, and TIG 6/6 mg/kg + SOR groups was alone was 1.24 (0.77–1.99) (p = 0.372), and 0.84 (0.52–1.35) for 2.3 months, 5.4 months, and 2.7 months, respectively; in South the comparison between TIG 6/6 mg/kg + SOR and SOR treatment Korea 2.0 months, 5.5 months, and 2.8 months, respectively; alone (p = 0.466). After incorporating logarithm of baseline AFP and in Japan, 8.3 months, 2,9 months, and 7.2 months, respec- level as a covariate in the exploratory analysis, the HR (95% CI) tively. The median OS in patients in Taiwan in the SOR alone, estimates were 1.27 (0.79–2.05) and 0.93 (0.58–1.50), respec- TIG 6/2 mg/kg + SOR, and TIG 6/6 mg/kg + SOR groups was tively (p = 0.321 and 0.760, respectively). 4.9 months, 9.4 months, and 11.1 months, respectively; in South Korea, 7.6 months, 9.3 months, and 9.7 months, respectively; Safety (includes safety cohort) and in Japan, NA, 7.6 months, and 15.0 months, respectively. Three patients were enrolled from the United States, insufficient In total, 171 (99.4%) subjects were included in the safety analysis data for a separate evaluation of efficacy in that region. set, which included the originally assigned groups. Mean dura- The sample sizes and numbers of events in each of these sub- tion of treatment ranged from 15.6 to 19.1 weeks for tigatuzu- groups are small to moderate, and the associated confidence mab, and 15.4 to 18.9 weeks for sorafenib across all treatment intervals of median PFS/OS are wide and overlapping between groups. Mean (SD) dose intensity of tigatuzumab was 3.96 treatment groups. Additionally, Cox regression model analysis (1.70) mg/kg/week. does not suggest an interaction between the treatment groups Safety data are based on the primary analysis. Most subjects and any of the following factors: HBV infection status, HCV infec- experienced P 1 treatment–emergent AE (TEAE) assessed as tion status, and region. Grade 3 or higher (Supplementary Table 1). In total, 75.9% At study end, the number of subjects with radiographic pro- (88/116) of tigatuzumab-treated subjects experienced P1 TEAE gression or symptomatic progression was 34 (64.2%), 41 that was considered related to tigatuzumab, and 98.3% (75.9%), and 37 (67.3%) in the TIG 6/2 mg/kg + SOR, TIG 6/6 mg/kg + SOR, and SOR alone groups, respectively. These pro- p value† for portions were notably lower in all treatment groups following interaction between independent radiological review: 54.7%, 53.7%, and 58.2%. Covariate Hazard ratio (95% Cl) treatment and subgroup class At the final OS update, median (95% CI) OS was highest in the HBV infaction status vs 1.685 (0.875-3.242) group receiving TIG 6/6 mg/kg + SOR (12.2 [9.0–15.0] months). In (yes . no) 0.110 HBV infaction status comparison, median OS was 8.2 months in the TIG (TIG vs. SOR) 1.195 (0.671-2.128) 6/2 mg/kg + SOR (95% CI, 5.7–10.4) and the SOR alone groups Region (Taiwan vs. Japan) 2.387 (0.951-5.993) (95% CI, 4.9–13.4). Neither of the treatment differences for the Region 3.460 (1.392-8.599) 0.057 comparison with SOR alone were statistically significant (South Korea vs. Japan) Region (Fig. 3B). The combined p value for both TIG + SOR groups vs. (TIG vs. SOR) 2.091 (0.898-4.865) Baseline ECOG SOR alone was 0.737. vs 2.478 (1.266-4.849) (1 . 0) 0.091 No subjects achieved a complete response. A partial response Baseline ECOG (TIG vs. SOR) 1.633 (0.923-2.891) was confirmed in 5.7% of subjects in the TIG 6/2 mg/kg + SOR Extrahepatic metastasis* vs. group, 14.8% in the TIG 6/6 mg/kg + SOR group, and 10.9% in (yes no) 0.909 (0.427-1.936) 0.651 Extrahepatic metastasis* the SOR alone group. In subjects with a partial response, the (TIG vs. SOR) 0.919 (0.401-2.104) mean (SD) duration of response was 27.8 (13.5) weeks for sub- HCV infection status vs. 0.757 (0.371-1.542) (yes no) 0.062 jects in the TIG 6/2 mg/kg + SOR group (n = 3), 14.0 (10.6) weeks HCV infection status for those in the TIG 6/6 mg/kg + SOR group (n = 8), and 31.4 (TIG vs. SOR) 1.211 (0.743-1.972) Locoregional therapy (18.8) weeks in the SOR alone group (n = 6). Stable disease was vs (yes . no) 1.257 (0.650-2.430) 0.481 observed in 49.1% of subjects receiving TIG 6/2 mg/kg + SOR, Locoregional therapy (TIG vs. SOR) 1.416 (0.774-2.593) 53.7% receiving TIG 6/6 mg/kg + SOR, and 43.6% receiving SOR 0 123 456 7 8 9 alone. In subjects with stable disease, the mean (SD) duration Hazard ratio (95% Cl) of response was 21.6 (13.0) weeks with TIG 6/2 mg/kg + SOR treatment (n = 26), 24.5 (16.6) weeks with TIG 6/6 mg/kg + SOR Fig. 4. Cox proportional hazards model analysis of time to tumour progres- (n = 29), and 23.3 (14.6) weeks with SOR alone (n = 24). sion, including interaction between treatment and subgroup classification factor (full analysis set). ECOG, Eastern Cooperative Oncology Group; HBV, Response rates as assessed by independent review showed simi- hepatitis B virus; HCV, hepatitis C virus; SOR, sorafenib; TIG, tigatuzumab. lar results (data not shown). ⁄Includes microvessel invasion. Wald test.

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Table 2. TEAEs experienced by P20% of subjects in the ‘All Tigatuzumab’ group (safety analysis set).

Randomized portion System organ class Safety cohort Tigatuzumab 6/2 mg/kga + Tigatuzumab 6/6 Sorafenib All tigatuzumab preferred term, n (%) portion sorafenib mg/kgb + sorafenib (n = 55) (N = 116) (n = 9) (n = 52) (n = 55) Gastrointestinal disorders Abdominal pain 3 (33.3) 14 (26.9) 17 (30.9) 12 (21.8) 34 (29.3) Abdominal pain 3 (33.3) 10 (19.2) 13 (23.6) 3 (5.5) 26 (22.4) upper Constipation 4 (44.4) 19 (36.5) 13 (23.6) 9 (16.4) 36 (31.0) Diarrhea 6 (66.7) 23 (44.2) 36 (65.5) 27 (49.1) 65 (56.0) Nausea 4 (44.4) 10 (19.2) 11 (20.0) 8 (14.5) 25 (21.6) General disorders and administration site conditions Fatigue 3 (33.3) 13 (25.0) 14 (25.5) 17 (30.9) 30 (25.9) Edema peripheral 2 (22.2) 14 (26.9) 10 (18.2) 11 (20.0) 26 (22.4) Fever 4 (44.4) 16 (30.8) 15 (27.3) 9 (16.4) 35 (30.2) Investigations ALT increased 4 (44.4) 14 (26.9) 15 (27.3) 14 (25.5) 33 (28.4) AST increased 5 (55.6) 20 (38.5) 21 (38.2) 24 (43.6) 46 (39.7) Blood amylase 2 (22.2) 12 (23.1) 11 (20.0) 8 (14.5) 25 (21.6) increased Blood bilirubin 3 (33.3) 12 (23.1) 9 (16.4) 13 (23.6) 24 (20.7) increased Lipase increased 5 (55.6) 17 (32.7) 17 (30.9) 19 (34.5) 39 (33.6) Platelet count 2 (22.2) 8 (15.4) 15 (27.3) 14 (25.5) 25 (21.6) decreased Metabolism and nutrition disorders Decreased appetite 5 (55.6) 25 (48.1) 26 (47.3) 25 (45.5) 56 (48.3) Hypoalbuminemia 2 (22.2) 12 (23.1) 12 (21.8) 13 (23.6) 26 (22.4) Hypophosphatemia 2 (22.2) 17 (32.7) 17 (30.9) 14 (25.5) 36 (31.0) Respiratory, thoracic, and mediastinal disorders Cough 6 (66.7) 7 (13.5) 11 (20.0) 7 (12.7) 24 (20.7) Dysphonia 1 (11.1) 14 (26.9) 14 (25.5) 14 (25.5) 29 (25.0) Skin and subcutaneous tissue disorders Alopecia 4 (44.4) 19 (36.5) 18 (32.7) 16 (29.1) 41 (35.3) Palmar-plantar 7 (77.8) 37 (71.2) 42 (76.4) 35 (63.6) 86 (74.1) erythrodysesthesia syndrome Vascular disorders Hypertension 4 (44.4) 13 (25.0) 19 (34.5) 20 (36.4) 36 (31.0)

ALT, alanine aminotransferase; AST, aspartate aminotransferase. a6 mg/kg loading dose followed by 2 mg/kg maintenance dose. b6 mg/kg loading dose followed by 6 mg/kg maintenance dose.

(114/116) experienced P1 TEAE that was considered related to (Supplementary Table 1). In total, 12.1% and 14.7% discontinued sorafenib. The most common tigatuzumab-related TEAE was tigatuzumab or sorafenib, respectively, due to TEAEs. decreased appetite (27.6% of all tigatuzumab-treated subjects), Discontinuation of sorafenib due to TEAEs ranged from 11.1% to and the most common sorafenib-related TEAE was diarrhoea 32.7% across all treatment groups. The percentage of subjects (40.0–66.7% of subjects across all treatment groups). with TEAEs leading to death ranged from 10.9% to 20.0% across Among all tigatuzumab-treated subjects, the most common all treatment groups; none of these TEAEs were considered TEAEs were palmar-plantar erythrodysesthesia (PPE) syndrome, related to tigatuzumab. The percentage of subjects who died dur- diarrhoea, decreased appetite, increased aspartate aminotrans- ing the study or follow-up ranged from 44.4% (safety cohort) to ferase (AST), and alopecia (Table 2), and the most common 61.8% (randomized to sorafenib alone). Grade 3–5 TEAEs were increased AST, increased lipase, hypophos- The most common treatment-emergent SAEs were ascites in phatemia, PPE syndrome and hypertension (Supplementary tigatuzumab-treated subjects (n = 5), and hepatic encephalopa- Table 1). During the randomized portion of the study, Grade 3– thy in sorafenib-treated subjects (n = 4). 5 TEAEs (most commonly disease progression) occurred with No clinically meaningful mean changes from baseline in similar frequency across all three treatment groups hematology, serum chemistry, or coagulation values were

902 Journal of Hepatology 2015 vol. 63 j 896–904 JOURNAL OF HEPATOLOGY observed. Differences among treatment groups in vital signs were Conclusions clinically non-signiﬁcant. Furthermore, all blood samples assayed for human antihuman antibody (HAHA) were negative. Tigatuzumab in combination with sorafenib vs. sorafenib alone in adults with advanced HCC did not meet its primary efﬁcacy endpoint, although the combination is well tolerated. Discussion

With limited therapeutic options available for advanced HCC, Conflict of interest novel treatments are warranted to improve prognoses. This phase II randomized study was conducted to assess the safety and effi- A-L.C was a consultant for Daiichi Sankyo, Inc.; Merck Serono; cacy of the novel humanized monoclonal antibody tigatuzumab Eisai; Jennerex and Exelixis and received research funding from in combination with the standard of care, sorafenib, in adults Sanofi-Aventis; Chugai and MSD. Y-K.K has received research with advanced HCC from Japan, South Korea, Taiwan, and USA. grants from Bayer and worked as an advisory board member In the safety cohort portion of the study, there were no for Bayer. T.A. is an employee of Novartis Pharmaceuticals observed DLTs for tigatuzumab, up to a dose of 6 mg/kg weekly, Corporation and is an ex-employee of Daiichi Sankyo, Inc. Q.W. and the MTD for the drug was not reached. In the randomized is an employee of Daiichi Sankyo, Inc. J.G. is an employee of portion of the study, no significant differences between the treat- Daiichi Sankyo, Inc. and owns stock in the company. S.S. is an ment groups were observed for the primary efficacy endpoint, employee of Daiichi Sankyo, Co., Ltd. R.A.B. is a stockholder in TTP, or the secondary efficacy endpoints. The independent radio- Johnson & Johnson, Inc. and in Daiichi Sankyo Pharma logical review yielded similar results for TTP, although the data Development (DSPD) and was a full time employee of DSPD at suggested that the proportion of subjects with radiographic or the time of the study. symptomatic progression at study end was notably lower across The remaining authors declared that they do not have any- treatment groups. This is likely due to differences in reviewer thing to disclose regarding funding or conflict of interest with judgment. respect to this manuscript. Generally, the combination of tigatuzumab and sorafenib provided acceptable tolerability in adults with advanced HCC. The most common TEAEs (e.g. PPE syndrome, diarrhoea, decreased Financial support appetite) were consistent with sorafenib use [23] or underlying liver disease [24]. Reassuringly, no TEAEs leading to death were This work was supported with funding from Daiichi Sankyo considered by the investigator to be related to tigatuzumab. Pharma Development, a division of Daiichi Sankyo, Inc. Editorial Although allergic and anaphylactic reactions may occur with assistance was provided by Sola Neunie, therapeutic proteins [25], there were no reports of anaphylactic MSc, of PAREXEL, and was funded by Daiichi Sankyo Pharma reactions or severe hypersensitivity in this study, and there was Development. no evidence of the HAHA antibody. These safety data are consistent with results from prior phase II studies of tigatuzumab in combination with other anticancer therapies, such as gemc- Author’s contributions itabine and carboplatin/paclitaxel [14,26]. This study has a few limitations. There was a large imbalance A-L.C. contributed to the study concept and design, acquisition of between groups in baseline AFP, a prognostic marker for HCC [27] data, analysis and interpretation of data, critical revision of the which favoured the high-dose tigatuzumab group, giving the ini- manuscript for important intellectual content, and study tial impression of a large advantage in OS at the median. Serum supervision. tigatuzumab concentrations increased dose-dependently, and Y-K.K. contributed to the study concept and design, acquisi- for both dose groups exceeded the target concentration derived tion of data, analysis and interpretation of data, and critical revi- from preclinical data (data on file), suggesting that the drug con- sion of the manuscript for important intellectual content. centrations were sufficient to mediate clinical effects. However, A.R.H. contributed to the study concept and design, acquisi- there were imbalances in AFP at baseline between the treatment tion of data, analysis and interpretation of data, and critical revi- groups, and this apparent advantage in OS is not maintained sion of the manuscript for important intellectual content. throughout the Kaplan–Meier curves, as reflected in the OS H.Y.L. contributed to the study concept and design, acquisi- HRs, which are near one; further, adjustment for the imbalance tion of data, analysis and interpretation of data, drafting of the in AFP brings the HR even closer to one. In addition, the use of manuscript, and critical revision of the manuscript for important TTP (as a surrogate of OS) as the standard primary end point in intellectual content. studies assessing primary treatments for HCC, as recommended B-Y.R. contributed to the study concept and design, acquisi- by the American Association for the Study of Liver Diseases tion of data, analysis and interpretation of data, critical revision [28], is currently under question, following results from the of the manuscript for important intellectual content, and study recent phase III BRISK-PS study (Brivanib Study in HCC Patients supervision. at Risk Post sorafenib) of brivanib in advanced HCC, where a ben- C-H.H. contributed to the analysis and interpretation of data efit in TTP, but not in OS, was observed. Thus, appropriate end- and critical revision of the manuscript for important intellectual points for HCC primary treatment studies require further content. investigation and clarification [29]. Finally, HCC biopsy and tissue I-S.S. contributed to the acquisition of data and drafting of the analyses were not performed, as is becoming increasingly impor- manuscript. tant in HCC clinical trials.

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