Hepatocellular carcinoma (HCC) is highly aggressive and ranks among the leading causes of cancer-related deaths worldwide. The evaluation of treatment options and outcomes for patients with advanced HCC remains a major focus in both clinical practice and research. Significant progress has been made in the treatment of advanced HCC with the introduction of various systemic therapies, including lenvatinib and regimens based on immune checkpoint inhibitors. However, a critical question remains: How to compare the relative effectiveness of immunotherapy versus multi-target tyrosine kinase inhibitors in real-world populations, thereby providing evidence for personalized first-line treatment decisions across different etiologies and patient subgroups.
A study by Ahn et al.1 applied a target trial emulation framework to compare first-line immunotherapy and lenvatinib in a large, multiethnic U.S. cohort of patients with advanced HCC. The authors reported a significant overall survival benefit associated with immunotherapy (median OS: 545 days vs. 425 days; HR: 0.86). Notably, subgroup analyses indicated particularly marked survival advantages in patients with viral hepatitis and alcohol-related liver disease, as well as among African American and Asian patients. These findings provide valuable real-world evidence to support more personalized treatment strategies.
The study mentioned that sex-stratified analysis showed a significant survival benefit for male patients receiving immunotherapy, but no significant difference was observed in female patients. This finding is consistent with several existing studies. However, some research suggests that the protective effects of estrogen, including enhanced T-cell activation and improved immune surveillance, contribute to better treatment responses in females, while the immunosuppressive effects of testosterone lead to poorer prognosis in males.2,3 In this study, the median patient ages were 67.2 and 65.6 years, respectively. Females in this age group are mostly postmenopausal, which might overlook the impact of estrogen on immunotherapy, potentially explaining the lack of significant difference in females. Future stratification of female patients by age or menopausal status could help further guide treatment. Second, the study showed that immunotherapy provided significant benefit in patients with viral hepatitis and alcoholic liver disease, but no significant difference was observed in MASLD/MASH-related patients. The metabolic characteristics of MASLD/MASH patients (such as obesity, diabetes, etc.) vary considerably, which may lead to high variability in efficacy, skewing the overall results.4 Therefore, stratifying by metabolic characteristics and conducting subgroup analyses for MASLD/MASH patients is clinically meaningful. For instance, factors like obesity, diabetes, and fatty liver may significantly impact survival outcomes.5
In summary, the study by Ahn et al.1 provides valuable preliminary evidence comparing immunotherapy with lenvatinib in a real-world setting, particularly offering important reference value for multi-ethnic American populations. However, given the inherent limitations of observational studies, especially unmeasured confounding and insufficient statistical power in subgroup testing, the results should be interpreted as hypothesis-generating rather than conclusive evidence for establishing causal treatment effects. We encourage further validation of these findings in more detailed real-world data or prospective studies to provide a more robust evidence base for personalized first-line treatment selection in advanced HCC.
CRediT authorship contribution statement
Tingfeng Huang: Writing – original draft, Conceptualization. Jiahao Law: Writing – original draft. Ningqi Pang: Writing – original draft. Shichuan Tang: Writing – review & editing, Writing – original draft.
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Declaration of generative AI and AI-assisted technologies in the writing process
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Funding
This study was supported by the National Natural Science Foundation of China (Grant number: 82503833).
Declaration of competing interest
The authors and funder have no conflicts of interest to declare.
Acknowledgments
None.
References
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