Is PD-1/PD-L1 inhibitor plus bevacizumab superior to sorafenib as first-line treatment for advanced hepatocellular carcinoma? A pooled analysis of four phase 3 RCTs

Abstract Background Sorafenib has served as standard treatment for advanced hepatocellular carcinoma (HCC). Recently, several randomized controlled trials (RCTs) have explored the use of programmed cell death protein 1/programmed death-ligand 1 inhibitor plus bevacizumab (PIB) in alternative first-line regimens; however, the magnitude and consistency of their clinical benefits remain to be systematically quantified. We therefore conducted a meta-analysis aimed at evaluating PIB versus sorafenib regarding efficacy and safety among treatment-naïve individuals with advanced HCC. Methods Comprehensive search through 6 data sources was performed to identify phase 3 trials assessing PIB versus sorafenib in the target population. The main endpoints for assessing effectiveness included progression-free survival (PFS) and overall survival (OS). Additional outcomes assessed tumor responses, adverse events (AEs), and patient condition at the time of data cutoff. Results Four phase 3 RCTs (HEPATORCH, IMbrave150, ORIENT-32, and SCT-I10A-C301) encompassing 1,744 patients were included. Compared with sorafenib, PIB significantly improved the OS (HR: 0.65 [0.57, 0.74], P < 0.00001) and PFS (HR: 0.60 [0.53, 0.67], P < 0.00001). Subgroup analyses showed that the treatment benefits of the PIB group in both PFS and OS were consistent across nearly all subgroups. In addition, the combination regimen achieved significantly higher objective response rate (ORR) and disease control rate (DCR) based on RECIST version 1.1 and mRECIST criteria. However, the PIB group also led to higher rates of serious treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs). The top three grade 3–4 TRAEs reported for PIB patients included hypertension (121/1108, 10.92%), platelet count decreased (58/946, 6.13%), and proteinuria (50/1108, 4.51%). Conclusions PIB demonstrates superior survival and tumor response benefits over sorafenib as initial treatment in patients with advanced HCC, with an acceptable and manageable safety profile. PROSPERO ID CRD 420261294641.