Systemic treatment for advanced hepatocellular carcinoma: the search of new agents to join sorafenib in the effective therapeutic armamentarium

ABSTRACT

Introduction: Hepatocelullar carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite the implementation of screening programs for high-risk individuals, a significant proportion of patients present with advanced disease at the moment of diagnosis.

Areas covered: In this review we will focus in the current treatment of advanced HCC, the research that has been done in the past few years, the achievements and failures in this setting and future perspectives.

Expert opinion: Sorafenib was the first drug that has shown to increase survival in patients with advanced hepatocelullar carcinoma with an adequate safety profile. Recently, regorafenib was reported to improve survival in a second line randomised placebo controlled phase 3 clinical trial, which represents a major breakthrough in this field after many disappointing results coming from several clinical trials. However, still there is an unmet need for an effective and tolerable treatment for patients who progressed and/or have intolerance to sorafenib. The ultimate goal of the research is to provide drugs that improve survival with acceptable adverse events. Understanding of mechanisms of hepatocarcinogesis, individualizing therapy according to the profile of the population and finding reliable surrogate end-points for survival for early phase trials with new agents should improve the likelihood of achieving these objectives.

KEYWORDS:

• Clinical trial
• hepatocelullar carcinoma
• molecular therapy
• radiological progression
• sorafenib
• regorafenib

Article highlights

• Sorafenib is the only drug that has been shown to increase survival in patients with advanced HCC with a good safety profile in first line. Optimal candidates are those with preserved liver function and good performance status.

• Regorafenib has improved survival of patients progressing under sorafenib and might become the recommended treatment in second line for such patients.

• There is an unmet need for an effective and tolerable treatment for patients who may not be candidates for sorafenib or are intolerant to it.

• Studies strongly support the role of inflammation in the development and potentially in the cancer progression. Therefore, the reconstitution of immune surveillance might be a promising therapy for HCC.

• Improvement in the design of clinical trials will provide better tools for the assessment of new therapies. Proper definitions of tumor response reflecting drug activity and optimally being a surrogate for improved survival are needed.

This box summarizes key points contained in the article.

Declaration of interest

J Bruix has acted as a consultant for Daichi, Arqule, Bayer, Abbot, Biocompatibles, Bristol-Myers Squibb, GlaxoSmithKline, Kowa, Lilly, Novartis, Onxeo and Roche and been on the advisory boards for Bayer, Biocompatibles and Novartis. M Reig has acted as a consultant for Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

M Reig has received grant support from Instituto de Salud Carlos III (PI15/00145). J Bruix has received grant support from Instituto de Salud Carlos III (PI14/00962), AECC (PI044031), Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2014 SGR 605) and WCR (AICR) 16-0026. CIBERehd is funded by the Instituto de Salud Carlos III.