New chemical treatment options in second-line hepatocellular carcinoma: what to do when sorafenib fails?

ABSTRACT

Introduction: There have been no therapies available for patients who experience disease progression after sorafenib treatment. Regorafenib inhibits multiple kinases involved in tumor proliferation and neoangiogenesis, which has produced a survival benefit in hepatocellular carcinoma (HCC) after sorafenib failure. Other active candidate agents are c-Met inhibitors and immune checkpoint inhibitors.

Areas covered: This paper presents an updated summary of the preclinical and clinical experience with regorafenib, c-Met inhibitors (tivantinib, cabozantinib and tepotinib), and a checkpoint inhibitor (nivolumab, pembrolizumab) in HCC. The reported data were obtained from abstracts of international conferences and journal articles published up to August 2016 and found in a PubMed search.

Expert opinion: Based on favorable data from preclinical and clinical trials, regorafenib, c-Met inhibitor, and checkpoint inhibitors are promising agents for HCC after sorafenib failure. However, further efforts to maximize the survival benefit and minimize adverse events of these drugs in the treatment of HCC are still necessary. Additionally, searching for predictors of good responders could allow these new drugs to be applied in personalized treatments of HCC.

KEYWORDS:

• Cabozantinib
• c-Met inhibitor
• hepatocellular carcinoma
• immune checkpoint inhibitor
• nivolumab
• pembrolizumab
• regorafenib
• sorafenib
• tepotinib
• tivantinib

Article highlights

• Regorafenib (BAY 73-4506), a novel bi-aryl urea targeting multiple kinases involved in both tumor cell proliferation/survival and tumor vasculature, have been shown to play important roles in HCC and improve survival compare to placebo in recent phase III trial for patient with HCC progressing on sorafenib.

• Tivantinib, a c-Met inhibitor, demonstrated anti-HCC activity in a second-line phase II trial, with the improvements in both TTP and OS being more pronounced in subjects with c-Met-positive tumors.

• Cabozantinib, a c-Met/VEGFR-2 inhibitor, exhibits potent inhibitory activity against several receptor tyrosine kinases that are known to influence the growth, metastasis, and angiogenesis of tumors and demonstrated anti-HCC activity in a second-line phase II trial.

• Nivolumab, PD-1 checkpoint inhibitor, has produced OS benefits in multiple phase III trials including in lung cancer, melanoma, and RCC and produced promising preliminary efficacy and safety data in a phase I/II HCC trial.

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Declaration of interest

The authors have no 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; this includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A2A2A01004489) and by clinical research grant from Pusan National University Hospital in 2015.