Efficacy and safety of frontline systemic therapy for advanced hepatocellular carcinoma (aHCC): A network meta-analysis of landmark phase III trials.
Authors: Fulgenzi Claudia A.M. , Korolewicz James , D'Alessio Antonio , Scheiner Bernhard , Stikas Charalampos-Vlasios , Gennari Alessandra , Cortellini Alessio , Scotti Lorenza , Pinato David J. James 
Published: January 2023

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Background: First line systemic therapy for advanced aHCC is rapidly expanding with new treatment options. However, direct comparisons across regimens are not available. We performed a network meta-analysis of phase III of trials to compare first line systemic treatments for aHCC in terms of overall survival (OS), progression free survival (PFS) and incidence of grade >3 adverse events (AEs). Methods: After performing a literature review from January 2008 to September 2022, we identified 6329 studies for screening, 3009 for revision, leading to identification of 15 phase III trials for the analysis: SHARP, Asia Pacific, Cheng 2013, Johnson 2013, Cainap 2015, REFLECT, CheckMate459, IMbrave150, ORIENT-32, HIMALAYA, COSMIC-312 and Qin 2021, Qin 2022, LEAP-002 and RATIONALE-301. These tested respectively: sorafenib (S) vs placebo (SHARP and Asia Pacific), sunitinib (Sun) vs S, brivanib (Bri) vs S, linifanib (Lin) vs S, lenvatinib (L) vs S, nivolumab (Nivo) vs S, atezolizumab+bevacizumab (A+B) vs S, sintilimab+IBI-305 vs S, durvalumab+tremelimumab (D+T) vs S, atezolizumab+cabozantinib (A+C) vs S, donafenib vs S, camrelizumab plus rivoceranib (C+R) vs S, pembrolizumab plus lenvatinib (P+L) vs L, and tislelizumab (TS) vs S as first line treatments for aHCC. Relative risks (RR) for grade >3 adverse events (AEs), and hazard ratios (HR) with 95% confidence intervals (95%CI) for overall (OS) and progression free survival (PFS) were extracted for each study. A frequentist network meta-analysis, with fixed effect multivariable meta-regression models to estimate the indirect pooled HRs, RRs and corresponding 95%CI, was performed considering S as reference. Results: In total, 10820 patients were included in the analysis, among them, 10444 received active treatment and 376 placebo. Sintilimab plus IBI-350 and A+B provided the greatest reduction in the risk of death compared to S, with a HR of 0.57 (95%CI:0.43-0.75), and 0.58 (95%CI:0.42-0.82), respectively; followed by C+R (HR:0.62; 95%CI:0.49-0-79), P+L (HR:0.77; 95%CI:0.62-0.97) and D+T (HR:0.78; 95%CI:0.66-0.93). Considering PFS, C+R and P+L were associated with the greatest reduction in the risk of PFS events compared to S, with HR of 0.52 (95%CI:0.41-0.65; 0.35-0.77, respectively). When looking at the risk of AEs, the combination of A+C (RR: 1.55;95%CI:0.80-3.02), C+R (RR:1.54;95%CI:0.95-2.50) and P+L (RR:1.23;95%CI:0.72-2.11) were associated with the highest risk of grade >3 AEs; whereas immune-checkpoint inhibitors (ICI) monotherapy (Nivo and TS) had the lowest risk (RR:0.46; 95%CI:0.20-1.05 and RR: 0.74; 95%CI:0.45-1.21). Conclusions: Combination of ICI + anti-VEGF antibodies leads to the greatest OS benefit compared to sorafenib, whereas ICI + kinase inhibitor regimens are associated with greater PFS benefit at the cost of higher toxicity rates.