Targeted and immune therapies for hepatocellular carcinoma: Predictions for 2019 and beyond
1Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka 589-8511, Japan. m-kudo@med.kindai.ac.jp.
Abstract:
Systemic therapy for hepatocellular carcinoma (HCC) has markedly advanced since the survival benefit of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacific trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However, development of a more potent first-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction. Many agents in the 1st line and 2nd line setting were attempted to develop between 2007 and 2016, but all of these clinical trials failed. On the other hand, clinical trials of 4 agents (regorafenib, lenvatinib, cabozantinib, and ramucirumab) succeeded in succession in 2017 and 2018, and their use in clinical practice is possible (regorafenib and lenvatinib) or underway (cabozantinib and ramucirumab). Furthermore, all of 5 clinical trials of combination therapy with transcatheter chemoembolization (TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and sorafenib (TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early, intermediate and advanced stage, is expected to be changed drastically in the very near future.
Insights
Systemic therapy for hepatocellular carcinoma (HCC) has advanced with new targeted agents like sorafenib. Recent breakthroughs in 2017-2018 offer improved options for advanced HCC, with ongoing trials exploring novel combinations and immunotherapies.
Area of Science:
- Hepatocellular Carcinoma (HCC) Research
- Molecular Targeted Therapy
- Cancer Treatment Advancements
Background:
- Sorafenib, a molecular targeted agent, demonstrated survival benefits for advanced HCC in 2007, improving long-term survival possibilities.
- Despite sorafenib's benefits, limitations include lack of tumor-shrinking effects and severe adverse events, necessitating more potent first- and second-line agents.
- Numerous clinical trials between 2007-2016 failed to develop superior alternatives to sorafenib.
Purpose of the Study:
- To review the evolution of systemic therapy for hepatocellular carcinoma (HCC).
- To highlight recent successes in molecular targeted agents and combination therapies for advanced HCC.
- To discuss the future treatment paradigm shift driven by ongoing clinical trials.
Main Methods:
- Review of clinical trial outcomes for systemic agents in HCC.
- Analysis of advancements in molecular targeted therapy and combination treatments.
- Examination of ongoing Phase 3 trials for immune checkpoint inhibitors and combination therapies.
Main Results:
- Four agents (regorafenib, lenvatinib, cabozantinib, ramucirumab) showed success in 2017-2018, expanding treatment options.
- The combination of transcatheter chemoembolization (TCE) and sorafenib (TACTICS trials) demonstrated success.
- Ongoing trials of immune checkpoint inhibitors and combination therapies indicate a significant future treatment paradigm shift.
Conclusions:
- The landscape of HCC treatment is rapidly evolving with new molecular targeted agents and combination therapies.
- Recent clinical trial successes offer improved options for patients with advanced HCC.
- Future treatment strategies for HCC, across all stages, are expected to be revolutionized by ongoing research.
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