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.

Abstract

e16148 Background: Anti-PD-1/L1 antibody combined with anti-VEGF antibody and anti-PD-1/L1 antibody combined with VEGFR-targeted tyrosine kinase inhibitor are both effective first-line therapies for uHCC in clinical practice widely. However, direct comparisons across the two regimens 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 literature research performed in PubMed, MEDLINE, Embase, the Cochrane library and several major scientific societies from January 1 2007 to November 6 2022, 3,279 records were obtained. 6 phase III trials has been identified for the final analysis: REFLECT, IMbrave150, ORIENT-32, COSMIC-312, Qin 2022 and LEAP-002. The experiments were broadly classified into three groups: anti-PD-1/L1 antibody + anti-VEGF antibody (IMbrave150 and ORIENT-32), anti-PD-1/L1 antibody + VEGFR-targeted tyrosine kinase inhibitor (COSMIC-312, Qin 2022 and LEAP-002) and intermediate reference group (lenvatinib vs sorafenib, REFLECT). 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 grade ≥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: 4,012 patients were included in the analysis overall, among them, 1815 patients were treated with anti-PD-1/L1 antibody+VEGF-antibody (A+A), 1,099 patients were treated with anti-PD-1/L1 antibody+VEGFR-TKI (A+T), 877 patients were treated with lenvatinib (LEN) and 1,320 patients were treated with sorafenib (SOR). With a p-score of 98%, the combination of A+A provided the greatest reduction in the risk of death, was not significantly different from A+T (HR=0.84, 95%CI: 0.66-1.06). Besides, A+T were associated with 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). Considering the risk of TRAEs, A+A were significantly safer than A+T (RR=0.91, 95%CI: 0.84-0.98) in all grade of TRAEs and ≥3 grade (RR=0.91, 95%CI: 0.84-0.98). Conclusions: The combination of anti-PD-1/L1 antibody and anti-VEGF antibodies has the greatest probability of delivering the longest OS, while anti-PD-1/L1 antibody plus VEGFR-targeted tyrosine kinase inhibitor is correlated with larger PFS benefit at the cost of a lower safety rate.