First-Line Systemic Therapies for Advanced Hepatocellular Carcinoma: A Systematic Review and Patient-Level Network
Khi Yung Fong1, Joseph Jonathan Zhao1, Rehena Sultana2
1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Introduction:
Sorafenib was historically the standard of care for advanced hepatocellular carcinoma (aHCC) until it was superseded by the combination of atezolizumab and bevacizumab. Thereafter, several novel first-line combination therapies have demonstrated favorable outcomes. The efficacies of these treatments in relation to current and previous standards of care are unknown, necessitating an overarching evaluation.
Methods:
A systematic literature search was conducted on PubMed, EMBASE, Scopus, and the Cochrane Controlled Register of Trials for phase III randomized controlled trials investigating first-line systemic therapies for aHCC. Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) were graphically reconstructed to retrieve individual patient-level data. Derived hazard ratios (HRs) for each study were pooled in a random-effects network meta-analysis (NMA). NMAs were also conducted using study-level HRs for various subgroups, according to viral etiology, Barcelona Clinic Liver Cancer (BCLC) staging, alpha-fetoprotein (AFP) levels, macrovascular invasion, and extrahepatic spread. Treatment strategies were ranked using p scores.
Results:
Among 4,321 articles identified, 12 trials and 9,589 patients were included for analysis. Only two therapies showed OS benefit over sorafenib: combined anti-programmed-death and anti-VEGF pathway inhibitor monoclonal antibodies (Anti-PD-(L)1/VEGF Ab), including atezolizumab-bevacizumab and sintilimab-bevacizumab biosimilar (HR = 0.63, 95% CI = 0.53-0.76) and tremelimumab-durvalumab (HR = 0.78, 95% CI = 0.66-0.92). Anti-PD-(L)1/VEGF Ab showed OS benefit over all other therapies except tremelimumab-durvalumab. Low heterogeneity (I2 = 0%) and inconsistency (Cochran's Q = 0.52, p = 0.773) was observed. p scores for OS ranked Anti-PD-(L)1/VEGF Ab as the best treatment in all subgroups, except hepatitis B where atezolizumab-cabozantinib ranked highest for both OS and PFS, as well as nonviral HCC and AFP ≥400 μg/L where tremelimumab-durvalumab ranked highest for OS.
Conclusion:
This NMA supports Anti-PD-(L)1/VEGF Ab as the first-line therapy for aHCC and demonstrates a comparable benefit for tremelimumab-durvalumab which also extends to certain subgroups. Results of the subgroup analysis may guide treatment according to baseline characteristics, while pending further studies.
Insights
Combined anti-PD-(L)1/VEGF antibody therapies are the most effective first-line treatments for advanced hepatocellular carcinoma (aHCC), showing significant overall survival benefits. Tremelimumab-durvalumab also offers comparable benefits in certain patient subgroups.
Area of Science:
- Hepatocellular Carcinoma Research
- Oncology Therapeutics
- Systemic Therapy Evaluation
Background:
- Sorafenib was the standard first-line treatment for advanced hepatocellular carcinoma (aHCC).
- New combination therapies, including atezolizumab and bevacizumab, have emerged as superior options.
- The comparative efficacy of novel first-line therapies for aHCC remains unclear.
Purpose of the Study:
- To conduct an overarching evaluation of first-line systemic therapies for aHCC.
- To compare the efficacy of novel treatments against current and historical standards of care.
- To identify optimal treatment strategies based on patient subgroups.
Main Methods:
- Systematic literature search of phase III randomized controlled trials in PubMed, EMBASE, Scopus, and Cochrane.
- Graphical reconstruction of Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS).
- Random-effects network meta-analysis (NMA) of derived hazard ratios (HRs) and subgroup analyses.
Main Results:
- Twelve trials including 9,589 patients were analyzed.
- Combined anti-programmed-death (PD)-(L)1/VEGF pathway inhibitor monoclonal antibodies (Ab) and tremelimumab-durvalumab demonstrated OS benefit over sorafenib.
- Anti-PD-(L)1/VEGF Ab ranked highest for OS in most subgroups, with specific exceptions for hepatitis B, nonviral HCC, and high AFP levels.
Conclusions:
- Combined anti-PD-(L)1/VEGF Ab is supported as the optimal first-line therapy for aHCC.
- Tremelimumab-durvalumab offers comparable efficacy, particularly in specific patient subgroups.
- Subgroup analysis findings can guide personalized treatment selection for aHCC.
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