Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma

Abstract

Molecular targeted therapy for advanced hepatocellular carcinoma (HCC) has changed markedly. Although sorafenib was used in clinical practice as the first molecular targeted agent in 2007, the SHARPE and Asian-Pacific trials demonstrated that sorafenib only improved overall survival (OS) by approximately 3 months in patients with advanced HCC compared with placebo. Molecular targeted agents were developed during the 10-year period from 2007 to 2016, but every test of these agents from phase II or phase III clinical trial failed due to a low response rate and high toxicity. In the 2 years after, 2017 through 2018, four successful novel drugs emerged from clinical trials for clinical use. As recommended by updated Barcelona Clinical Liver cancer (BCLC) treatment algorithms, lenvatinib is now feasible as an alternative to sorafenib as a first-line treatment for advanced HCC. Regorafenib, cabozantinib, and ramucirumab are appropriate supplements for sorafenib as second-line treatment for patients with advanced HCC who are resistant, show progression or do not tolerate sorafenib. In addition, with promising outcomes in phase II trials, immune PD-1/PD-L1 checkpoint inhibitors nivolumab and pembrolizumab have been applied for HCC treatment. Despite phase III trials for nivolumab and pembrolizumab, the primary endpoints of improved OS were not statistically significant, immune PD-1/PD-L1 checkpoint therapy remains to be further investigated. This review summarizes the development and progression of molecular targeted and immune-based checkpoint therapies in HCC.

Identification and validation of an immune-related prognostic signature for hepatocellular carcinoma

“…HCC is one of the most prevalent and life-threatening cancers around the world, with rapid progression and di culty in treatment [16]. Although radiotherapy, molecular targeted therapy, and other treatment regimens can modestly prolong the survival time of HCC patients, the clinical outcomes of these patients are still unsatisfactory [1,17,18]. It has been reported that the immune system is involved in tumor development and progression.…”

“…It has been reported that the immune system is involved in tumor development and progression. However, immune PD-1/PD-L1 checkpoint therapy, such as nivolumab and pembrolizumab, remains to be further investigated due to the unsatisfactory OS [5,18].…”

Establishment of a Patient‐Derived Xenograft Tumor From Hepatitis C–Associated Liver Cancer and Evaluation of Imatinib Treatment Efficacy

“…Lidocaine was infiltrated at the wound edges to control postoperative pain. When tumor volume reached >600 mm 3 , the mouse was humanely sacrificed (CO 2 asphyxiation), and the tumors were cryopreserved or explanted for passage in another NSG mouse using the same protocol.…”

“…A recent phase 2 clinical trial reported that nivolumab produced a response rate of ~14% and a 13.8-month survival rate of 74%. (3) Surgical resection and orthotropic liver transplantation are potentially curative options for treating hepatocellular carcinoma (HCC), although the use of these approaches is limited to one-third of patients, and donor organ availability is low. Moreover, the 5-year recurrence of HCC after surgical resection approaches ~70%.…”

Integrative analysis of the characteristic of lipid metabolism-related genes for the prognostic prediction of hepatocellular carcinoma

“…Most patients with HCC are diagnosed at the advanced stage, at this stage they cannot benefit from surgery or chemoradiotherapy [2]. In recent years, therapies based on biological targets have been proposed for patients with HCC [3]. However, the clinical benefit of available biomarker for early diagnosis and prognostic assessment was still limited.…”