Chemotherapy for hepatocellular carcinoma: current status and future perspectives

Abstract

Chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). On the basis of the results of two pivotal Phase III placebo-controlled studies, sorafenib is currently acknowledged worldwide as the standard therapeutic agent for advanced HCC. Following the introduction of sorafenib for the treatment of HCC, Phase III trials of numerous other agents as first-line or second-line chemotherapy have been conducted to determine if any of these agents might offer superior survival benefit to sorafenib. In 2016, a clear survival benefit of regorafenib over placebo was demonstrated in HCC patients showing disease progression after sorafenib treatment. A year later, in 2017, lenvatinib has been shown to be non-inferior to sorafenib, in terms of the overall survival, in chemo-naïve patients with advanced HCC. More recently, promising outcomes have also been reported with new agents, such as nivolumab and cabozantinib. At present, various novel combination regimens including these agents are currently under development. Hepatic arterial infusion chemotherapy (HAIC) is frequently adopted for the treatment of locally advanced HCC in Japan, based on reports of high response rates and favorable long-term outcomes. Although some randomized controlled trials of HAIC plus sorafenib vs. sorafenib alone as first-line therapy have been conducted in patients with advanced HCC, no firm evidence of the superiority of one over the other has been established yet. In the future, demonstration of the survival advantage of HAIC and the recognition of HAIC as one of the standard treatments for patients with advanced HCC are expected.

Clinical characteristics and outcomes of candidates for second‐line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma after sorafenib treatment

“…In the near future, several other promising second‐line agents, such as cabozantinib, ramucirumab, nivolumab, and pembrolizumab, will become available in the clinical setting for patients refractory or intolerant to sorafenib. The post‐progression survival (PPS) of patients who are refractory or intolerant to sorafenib is expected to improve by switching from sorafenib to second‐line therapy …”

Novel approaches for molecular targeted therapy against hepatocellular carcinoma

“…In October 2017, cabozantinib, an oral multikinase inhibitor targeting MET, RET, AXL, and VEGFR1–3, was announced to improve median OS compared with placebo in patients with advanced HCC who have previously received sorafenib in the global phase III CELESTIAL trial (NCT01908426) . Cabozantinib was approved in 2012 for the treatment of progressive metastatic medullary thyroid cancer following a successful phase III trial .…”

“…In addition, tumors stopped growing (stable disease) for at least 6 months in 40% of the patients. Furthermore, remarkable prolongation of the median survival (sorafenib‐naïve patients, 28.6 months vs. sorafenib‐experienced patients, 15.6 months) was reported from an updated analysis of the CheckMate‐040 trial . A randomized phase III trial of nivolumab versus sorafenib as first‐line treatment with advanced‐stage HCC is ongoing (NCT02576509) .…”

“…Furthermore, remarkable prolongation of the median survival (sorafenib‐naïve patients, 28.6 months vs. sorafenib‐experienced patients, 15.6 months) was reported from an updated analysis of the CheckMate‐040 trial . A randomized phase III trial of nivolumab versus sorafenib as first‐line treatment with advanced‐stage HCC is ongoing (NCT02576509) . In addition, a phase III trial of pembrolizumab, another anti‐PD‐1 antibody as compared to placebo is also ongoing (KEYNOTE‐240, NCT02702401) …”

“…A randomized phase III trial of nivolumab versus sorafenib as first‐line treatment with advanced‐stage HCC is ongoing (NCT02576509) . In addition, a phase III trial of pembrolizumab, another anti‐PD‐1 antibody as compared to placebo is also ongoing (KEYNOTE‐240, NCT02702401) …”