First-Line Systemic Therapies for Advanced Hepatocellular Carcinoma: A Systematic Review and Patient-Level Network Meta-Analysis

Abstract

Introduction: Sorafenib was historically the standard of care for advanced hepatocellular carcinoma (aHCC) until it was superseded by the combination of atezolizumab and bevacizumab.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≥400μg/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.

Atezolizumab in Combination with Bevacizumab for the Management of Patients with Hepatocellular Carcinoma in the First-Line Setting: Systematic Literature Review and Meta-Analysis

“…The results of the current NMA are broadly consistent in terms of direction of treatment effect with those from previously conducted NMAs in first-line HCC [ 20 – 23 , 38 ]. However, some differences can be observed in the methodology.…”

“…Table S7 [Supporting Information]). This is a consequence of the inclusion of data from ORIENT-32 [39] in the pooled atezolizumab-bevacizumab and sintilimab-bevacizumab data set, and thus the results are not directly comparable with the current analysis [38]. The results presented by Fulgenzi et al [23] are aligned with the current analysis in terms of point estimates and direction of treatment effect for both OS and PFS, although the analysis by Fulgenzi et al [23] does not include camrelizumab-rivoceranib, lenvatinib-pembrolizumab, and tislelizumab as comparators (online suppl.…”

“…Atezolizumab-Bevacizumab for First-Line HCC Liver Cancer 2023;12:510-520 DOI: 10.1159/000533166 517 [38], but neither analysis addressed this heterogeneity in their analyses. In comparison, the current NMA excludes patients with PVTT stage Vp4 from the IMbrave150 data set to align with the lower risk comparator study populations more closely, and a comprehensive exploration of multiple subgroup analyses was conducted for both outcomes.…”

Progression-Free and Overall Survival of First-Line Treatments for Advanced Renal Cell Carcinoma: Indirect Comparison of Six Combination Regimens

“…In recent years, the Shiny method has increasingly been used not only in oncology but also in other areas of of therapeutics, such as medical devices [ 20 ], surgery [ 21 , 22 ] and also in patients with COVID-19 [ 23 ]. However, oncology and oncohematology remain the two main areas of application, where the Shiny method represents a quite simple alternative to network meta-analysis [ 8 , 9 , 24 , 25 ].…”

Approved immune checkpoint inhibitors in hepatocellular carcinoma: a large-scale meta-analysis and systematic review

“…It is important to acknowledge that the impact of ICIs on HCC has been clearly demonstrated. Several meta-analyses have also been conducted to further elucidate the therapeutic effects of ICIs on HCC from various perspectives (Fong et al 2023 ; Kulkarni et al 2023 ). However, certain limitations exist within these meta-analyses.…”