Efficacy and Safety of Systemic Therapies for Advanced Hepatocellular Carcinoma: A Network Meta-Analysis of Phase III Trials

Abstract

Aim/Background: After the introduction of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC), different studies tried to evaluate whether other systemic therapies can improve survival. To provide a comprehensive indirect treatment comparison of efficacy and safety of novel drugs, a network meta-analysis (NMA) of phase III randomized controlled trials was performed. Methods: After pertinent literature search up to November 1, 2016, 6 studies were eligible for the analysis including 4,812 individual patients with advanced HCC: 2,454 received sorafenib, 577 received brivanib, 530 received sunitinib, 514 received linifanib, 358 received sorafenib + erlotinib and 379 received placebo. Frequentist NMA was used to compare treatments within a single analytical framework. Results: NMA showed that sorafenib alone, regardless of combination with erlotinib, and linifanib provide a significant survival advantage over placebo (p < 0.05) but without any significant difference between each other. Conversely, all regimens significantly ameliorate progression-free survival versus placebo (p < 0.05). The rank order of efficacy was: sorafenib ± erlotinib, linifanib, brivanib, sunitinib, and placebo. Sorafenib ± erlotinib was the regimen with the fewest number of adverse events that required discontinuation of treatment, whereas linifanib and brivanib resulted in the most adverse events. The risk-benefit summary identified one cluster of therapies with a similar balance between efficacy and safety which included sorafenib alone or in combination with erlotinib, having, at the same time, the highest efficacy and safety. Conclusions: Sorafenib remains the best systemic treatment for advanced HCC; linifanib also resulted in survival advantages over placebo but with a lower safety profile.

Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition)

“…Sorafenib is the only molecular target drug approved at this time for the treatment of advanced liver cancer [113]. It is supported by two large-scale international multicenter phase III clinical trials demonstrating survival benefits for patients from different countries and regions and with different liver disease backgrounds [114] (evidence level 1).…”

Pembrolizumab for the Treatment of Hepatocellular Carcinoma

“…The exclusion criterion is tumor infiltration of the main portal vein (Vp4) or inferior vena cava [21]. Positive results of this phase III trial would lead to the worldwide approval of pembrolizumab as a promising treatment option in addition to conventional molecular-targeted agents [22, 23]. However, striking news released by Merck on February 19, 2017 indicate that this trial did not meet its primary endpoint of prolonging PFS or OS compared with placebo plus best supportive care [24].…”

A journey through the emergence of nanomedicines with poly(alkylcyanoacrylate) based nanoparticles

“…Search for sponsors to support clinical translation of the first nanomedicines was tedious for pioneers [Kreuter, 2007, Barrenholz, 2012 [Soma et al, 2012, Merle et al, 2017 [Later named Livatag®] and was proposed as a treatment of advanced HCC. This deadly drug resistant cancer of the liver remained without therapeutic option at the time of the start of the clinical trial in 2004 [EU/3/04/229 EUDRACT 2006-004088-77] [Keating and Santoro, 2009, Giglia et al, 2010, Cucchetti et al, 2017, Desai et al, 2017, Lu et al, 2018, Raoul et al, 2018. This choice was consistent with the established ability of dox-PIHCA nanoparticles to overcome multidrug resistance of cancers [Kattan et al, 1992, Colin de Verdière et al, 1997.…”