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The emerging therapies are reshaping the first-line treatment for advanced hepatocellular carcinoma: a systematic
Wei Peng1,2, Yangxun Pan1,2, Lan Xie1,3
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China.
Background:
Given the superior performance of various therapies over sorafenib in advanced hepatocellular carcinoma (HCC) and the absence of direct comparisons, it is crucial to explore the efficacy of these treatments in phase III randomized clinical trials.
Objectives:
The goal is to identify which patients are most likely to benefit significantly from these emerging therapies, contributing to more personalized and informed clinical decision-making.
Design:
Systematic review and network meta-analysis.
Data Sources And Methods:
PubMed, Embase, ClinicalTrials.gov, and international conference databases have been searched from 1 January 2010 to 1 December 2023.
Results:
After screening, 17 phase III trials encompassing 18 treatments were included. In the whole-population network meta-analysis, the newly first-line tremelimumab plus durvalumab (Tre + Du) was found to be comparable with atezolizumab plus bevacizumab (Atezo + Beva) in providing the best overall survival (OS) benefit [hazard ratio (HR) 1.35, 95% confidence interval (CI): 0.93-1.92]. Concerning OS benefits, sintilimab plus bevacizumab biosimilar (Sint + Beva), camrelizumab plus rivoceranib (Camre + Rivo), and lenvatinib plus pembrolizumab (Lenva + Pemb) appear to exhibit similar effects to Tre + Du and Atezo + Beva. In the context of progression-free survival, Atezo + Beva seemed to outperform Tre + Du (HR: 0.66 CI: 0.49-0.87), while the effects are comparable to Sint + Beva, Camre + Rivo, and Lenva + Pemb. Upon comparison between Asia-Pacific and non-Asia-Pacific cohorts, as well as between hepatitis B virus (HBV)-infected and non-HBV-infected populations, immune checkpoint inhibitor (ICI)-based treatments seemed to exhibit heightened efficacy in the Asia-Pacific group and among individuals with HBV infection. However, combined ICI-based therapies did not show more effectiveness than molecular-targeted drugs in patients without macrovascular invasion and/or extrahepatic spread. As for grades 3-5 adverse events, combined therapies showed comparable safety to sorafenib and lenvatinib.
Conclusion:
Compared with sorafenib and lenvatinib, combination therapies based on ICIs significantly improved the prognosis of advanced HCC and demonstrated similar safety. At the same time, the optimal treatment approach should be tailored to individual patient characteristics, such as etiology, tumor staging, and serum alpha-fetoprotein levels. With lower incidence rates of treatment-related adverse events and non-inferior efficacy compared to sorafenib, ICI monotherapies should be prioritized as a first-line treatment approach for patients who are not suitable candidates for ICI-combined therapies.
Trial Registration:
PROSPERO, CRD42022288172.
Insights
New combination therapies for advanced hepatocellular carcinoma (HCC) show improved survival and comparable safety to sorafenib. Immune checkpoint inhibitor (ICI)-based treatments are effective, especially in specific patient groups.
Area of Science:
- Hepatocellular Carcinoma (HCC) Research
- Oncology Drug Efficacy
- Clinical Trial Analysis
Background:
- Advanced hepatocellular carcinoma (HCC) treatments show varied efficacy, necessitating direct comparisons.
- Sorafenib was a previous standard, but newer therapies offer improved outcomes.
- Phase III trials are crucial for evaluating these advanced HCC treatments.
Purpose of the Study:
- Identify patients most likely to benefit from emerging HCC therapies.
- Personalize clinical decision-making for advanced HCC.
- Compare the efficacy of novel treatments against existing standards.
Main Methods:
- Systematic review and network meta-analysis of phase III randomized clinical trials.
- Searched PubMed, Embase, ClinicalTrials.gov, and conference databases (2010-2023).
- Included 17 trials with 18 treatments for advanced HCC.
Main Results:
- Tremelimumab plus durvalumab (Tre+Du) and atezolizumab plus bevacizumab (Atezo+Beva) showed comparable overall survival (OS) benefits.
- Other combinations (Sint+Beva, Camre+Rivo, Lenva+Pemb) demonstrated similar OS effects.
- Atezo+Beva showed better progression-free survival than Tre+Du; ICI-based therapies were more effective in Asia-Pacific and HBV-infected populations.
Conclusions:
- ICI-based combination therapies significantly improve advanced HCC prognosis with similar safety to sorafenib and lenvatinib.
- Treatment selection should be individualized based on patient characteristics (etiology, stage, AFP).
- ICI monotherapies are recommended first-line for patients unsuitable for combination therapies due to lower adverse event rates.
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