Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma
Ziyu Liu1, Yan Lin2, Jinyan Zhang2
1School of Oncology, Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China.
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.
Insights
Molecular targeted therapies for advanced hepatocellular carcinoma (HCC) have evolved, with new drugs like lenvatinib offering first-line options. Newer agents provide second-line choices for sorafenib-resistant cases, while immunotherapy requires further investigation.
Area of Science:
- Hepatobiliary Oncology
- Medical Oncology
- Pharmacological Research
Background:
- Sorafenib, the first molecular targeted agent for advanced hepatocellular carcinoma (HCC), offered limited survival benefits (approx. 3 months OS).
- Numerous targeted agents developed between 2007-2016 failed in clinical trials due to low response rates and high toxicity.
- Recent advancements (2017-2018) introduced novel drugs and updated treatment guidelines for advanced HCC.
Purpose of the Study:
- To review the development and progression of molecular targeted therapies for advanced HCC.
- To summarize the emergence and application of immune checkpoint inhibitors in HCC treatment.
- To provide an overview of current and investigational therapeutic strategies for advanced HCC.
Main Methods:
- Literature review of clinical trials and treatment guidelines for advanced HCC.
- Analysis of the efficacy and safety data of molecular targeted agents.
- Evaluation of the current status of immune-based checkpoint therapies in HCC.
Main Results:
- Lenvatinib is now a first-line alternative to sorafenib for advanced HCC.
- Regorafenib, cabozantinib, and ramucirumab serve as second-line options for sorafenib-resistant/intolerant patients.
- Immune PD-1/PD-L1 checkpoint inhibitors show promise but require further investigation due to non-significant OS improvements in phase III trials.
Conclusions:
- The therapeutic landscape for advanced HCC has significantly improved with new targeted agents.
- Second-line targeted therapies offer valuable options for patients progressing on or intolerant to sorafenib.
- While promising, immune checkpoint inhibitors need further research to establish their role in advanced HCC treatment.
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