Survival Trends in Sorafenib for Advanced Hepatocellular Carcinoma: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Trials.

Background: Emerging data suggest that outcomes for advanced hepatocellular carcinoma (HCC) treated with sorafenib may have improved over time. We aimed to provide robust, time-to-event estimates of survival outcomes for sorafenib in advanced HCC.
Summary: In this systematic review and individual patient data meta-analysis of randomized-controlled trials (RCTs), we searched MEDLINE and Embase from inception till September 2022 for RCTs that provided data for overall survival (OS) and progression-free survival (PFS) for sorafenib monotherapy as first-line systemic therapy for advanced HCC. We performed a pooled analysis using reconstructed individual participant data from published Kaplan-Meier curves to obtain robust estimates for OS and PFS. Of 1,599 articles identified, 29 studies (5,525 patients) met the inclusion criteria. Overall, the median OS was 10.4 (95% CI: 9.6-11.4) months. Median OS increased over time, from 9.8 (95% CI: 8.8-10.7) months in studies before 2015 to 13.4 (95% CI: 11.03-15.24) months in studies from 2015 onwards ( p < 0.001). OS did not differ by trial phase, geographical region, or study design. The overall median PFS was 4.4 (95% CI: 3.9-4.8) months, but PFS did not improve over time. Sensitivity analysis of studies from 2015 and onwards to account for the introduction of direct-acting antivirals determined that hepatitis C virus was associated with reduced mortality ( p < 0.001). There was minimal heterogeneity in the estimates for OS (all I ² ≤ 33).
Key Messages: Survival outcomes for sorafenib in advanced HCC have improved over time. These data have important implications for clinical trial design.
Competing Interests: AV reports personal fees from Roche, Bayer, Bristol Myers Squibb, Lilly, EISAI, AstraZeneca, Ipsen, Merck Sharp and Dohme, Sirtex, BTG, Servier, Terumo, and Imaging Equipment (Advanced Accelerator Applications). TY reports consulting fees from, honoraria from, and participation on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, EMD Serono, Exelixis, H3 Biomedicine, Ipsen, Merck Sharp and Dohme, New B Innovation, Novartis, OrigiMed, Pfizer, Sillajen, Sirtex, and Taiho Pharmaceutical. RL receives funding support from NIAAA (U01AA029019), NIEHS (5P42ES010337), NCATS (5UL1TR001442), NIDDK (U01DK130190, U01DK061734, R01DK106419, P30DK120515, R01DK121378, and R01DK124318), NHLBI (P01HL147835), and DOD PRCRP (W81XWH-18-2-0026). He also serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals, and Viking Therapeutics. His institutions have received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. He is co-founder of LipoNexus Inc. DH has served as an advisory board member for Eisai and receives funding support from Singapore Ministry of Health’s National Medical Research Council under its NMRC Research Training Fellowship (MOH-000595-01). All remaining authors have no conflicts of interest to declare.
(© 2023 The Author(s). Published by S. Karger AG, Basel.)