Accepted Manuscript Predictors of Sorafenib Benefit in Patients with Hepatocellular Carcinoma Jordi Bruix, Ann Lii Cheng, Josep Llovet PII: DOI: Reference: S0168-8278(17)32392-9 https://doi.org/10.1016/j.jhep.2017.10.013 JHEPAT 6718 To appear in: Journal of Hepatology Received Date: Accepted Date: 9 October 2017 10 October 2017 Please cite this article as: Bruix, J., Cheng, A.L., Llovet, J., Predictors of Sorafenib Benefit in Patients with Hepatocellular Carcinoma, Journal of Hepatology (2017), doi: https://doi.org/10.1016/j.jhep.2017.10.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Predictors of Sorafenib Benefit in Patients with Hepatocellular Carcinoma Answer to the letter by Jackson et al. We were surprised to receive the letter by Jackson et al. stating that sorafenib does not benefit patients with hepatocellular carcinoma associated to hepatitis B virus infection. This statement is based on an inherently problematic meta-analysis recently published by the same authors (1) and based on an incorrect interpretation of our own study which pooled the databases of the two seminal sorafenib trials in HCC comparing sorafenib vs placebo (2). The two problematic aspects of the metanalysis are as follows: First, it did not include the pivotal trials that demonstrated the benefit of sorafenib vs placebo (3,4), and second, the three phase 3 trials that constituted the basis of the meta-analysis were not placebocontrolled, but had active agents (sunitinib, brivanib and linifanib) that were compared to sorafenib. While these three trials were negative, it cannot be concluded that these agents are equivalent to placebo. Jackson et al neglect the fact that in the RCT of sorafenib vs placebo by Cheng et al (4) the majority of the patients were HBV positive and the results were unequivocally positive. While this Asia-Pacific trial results should be enough to accept the survival benefit of sorafenib in HBV patients, his understanding of the results of our study pooling the two sorafenib vs placebo trials (2) is not correct. We did not explore if sorafenib was effective in a subgroup of patients, but rather if in a given subgroup the results were significantly better using the “p for interaction” statistical test. Thus, we demonstrated that sorafenib was significantly more effective in patients with HCV infection and in those with liver only disease. For HBV patients we did not identify that the benefit was more or less intense than in the global population. We hope that these comments help to explain the flaws of the metanalysis and the letter by Jackson et al and that his misleading suggestions will not prevent the effective treatment with sorafenib for HBV patients that develop hepatocellular carcinoma and are in need of systemic treatment. References.1.- Jackson R, Psarelli EE, Berhane S, et al. Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized Phase III Trials. J Clin Oncol 2017;35:622-628. 2.- Bruix J, Cheng AL, Meinhardt G, et al. Prognostic Factors and Predictors of Sorafenib Benefit in Patients With Hepatocellular Carcinoma: Analysis of Two Phase 3 Studies. J Hepatol 2017. 3.- Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390. 4.- Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34. Jordi Bruix. BCLC Hospital Clínic Barcelona, IDIBAPS, University of Barcelona CIBERehd, Barcelona, Spain. Ann Lii Cheng. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Josep Llovet. BCLC Hospital Clínic Barcelona, IDIBAPS, University of Barcelona CIBERehd, Barcelona, Spain; Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.