Second line systemic therapies for hepatocellular carcinoma: Reasons for the failure

Abstract

Hepatocellular carcinoma (HCC) is the main cause of death in patients with cirrhosis, with an increasing incidence worldwide. Sorafenib is the choice therapy for advanced HCC. Over time several randomized phase III trials have been performed testing sunitinib, brivanib, linifanib and other molecules in head-to-head comparison with Sorafenib as first-line treatment for advanced-stage HCC, but none of these has so far been registered in this setting. Moreover, another feared vacuum arises from the absence of molecules registered as second-line therapy for patients who have failed Sorafenib, representing an urgent unmet medical need. To date all molecules tested as second-line therapies for advanced hepatocellular carcinoma, failed to demonstrate an increased survival compared to placebo. What are the possible reasons for the failure? What we should expect in the near future?

The albumin–bilirubin grade improves hepatic reserve estimation post‐sorafenib failure: implications for drug development

“…Due to limited evidence‐based treatment options in patients who fail sorafenib, the enhanced discriminative power of the ALBI in advanced HCC is particularly important for optimal patient stratification, especially in suitable candidates for clinical trials . The accurate definition of patient subpopulations with prolonged stability in liver functional reserve might enhance efficacy testing in phase II–III trials by reducing the heterogeneity stemming from concomitant liver failure . This is particularly important in trial design, where inaccurate assumptions over predicted survival times in placebo group as well as the choice of pre‐planned stratification factors has been a problematic issue in the development of molecularly targeted therapies in the second‐line setting …”

“…In the clinic, neoplastic disease progression, deteriorating PS, hepatic decompensation or unacceptable treatment‐related toxicity are the leading causes of permanent sorafenib discontinuation . At treatment cessation, the majority of patients will only qualify for best supportive care, whereas a smaller proportion might be suitable for second‐line therapies, an area that is currently at the focus of intense clinical research efforts …”

Molecular and proteomic insight into Notch1 characterization in hepatocellular carcinoma

“…Sorafenib (Nexavar) remains the only systemic therapy recognized to improve overall survival in patients with advanced HCC [2]. However, for patients who are intolerant of or progress on sorafenib no other drug has been approved as second line option [3]. Thus, the development of new agents to block HCC progression is the primary research objective.…”

Sorafenib for Hepatocellular Carcinoma: From Randomized Controlled Trials to Clinical Practice

“…In this line, it is very important a correct identification of the reasons for sorafenib discontinuation (liver decompensation, tumor progression, or adverse effects), in order to: (1) obtaining an optimal management of HCC patients, (2) calculating the sample size and stratifying subjects in phase 2 and 3 RCTs, and (3) assessing treatment effect size to formulate therapeutic strategies [32,33]. …”