Comparative efficacy and safety of anti-PD-1/L1 antibody plus anti-VEGF antibody and anti-PD-1/L1 antibody plus VEGFR-targeted tyrosine kinase inhibitor as first-line therapy for unresectable hepatocellular carcinoma (uHCC): a systematic review and network meta- analysis

Background: Anti-PD-1/L1 antibody + anti-VEGF antibody (A + A) and anti-PD-1/L1 antibody + VEGFR-targeted tyrosine kinase inhibitor (A + T) are both effective first-line therapies for uHCC. However, direct comparisons between them are not available. We conducted a network meta-analysis of them in terms of overall survival (OS), progression free survival (PFS), objective response rate (ORR) and incidence of treatment-related adverse events (TRAEs). Methods After a rigorous literature research, 6 phase III trials has been identified for the final analysis: IMbrave150, ORIENT-32, COSMIC-312, CARES-310, LEAP-002 and REFLECT. The experiments were classified into three groups: A + A, A + T and intermediate reference group. We derived hazard ratios (HR) with 95% confidence intervals (95%CI) for OS and PFS, odds ratio (OR) for ORR and relative risks (RR) for all grade and ≥ 3 TRAEs. With fixed effect models to estimate the indirect pooled HRs, ORs, RRs and 95%CI, a frequentist network meta-analysis was conducted using sorafenib as intermediate reference. Results With a P-score of 98%, A + A provided the greatest reduction in the risk of death, without significant difference from A + T (HR = 0.84, 95%CI: 0.66–1.06). Besides, A + T showed the greatest effect in prolonging PFS and improving ORR with 91% for P-score, but there are no statistical differences with A + A(HR = 1.06, 95%CI: 0.87–1.30, OR = 0.82, 95%CI: 0.47–1.46). A + A were significantly safer than A + T (RR = 0.91, 95%CI: 0.84–0.98) in all grade of TRAEs and ≥ 3 (RR = 0.91, 95%CI: 0.84–0.98). Conclusions A + A has the greatest probability of delivering the longest OS, while A + T is correlated with larger PFS benefit at the cost of a lower safety rate.