Adjuvant immune checkpoint inhibitor therapy after curative-intent resection or ablation for high-risk hepatocellular carcinoma: A systematic review and meta-analysis of randomized controlled trials.

Abstract

e16289 Background: The risk of recurrence of hepatocellular carcinoma (HCC) remains high after curative-intent resection or local ablation. We evaluated the efficacy and safety of adjuvant immune checkpoint inhibitor (ICI) based therapy. Methods: PubMed, Embase, Cochrane Library and ClinicalTrials.gov were searched for RCTs comparing adjuvant ICI-based therapy versus placebo/active surveillance after resection/ablation in patients with high-risk HCC. High-risk HCC was defined using trial-specific criteria for elevated recurrence risk after curative-intent therapy, based on tumor burden/pathologic features like tumor size and number, microvascular invasion, portal vein invasion, poor differentiation, or protocol-specified recurrence-risk stratification. Included regimens were atezolizumab + bevacizumab, pembrolizumab, and sintilimab. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival (OS) and grade ≥3 adverse events (AEs). Hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for binary outcomes were pooled using inverse-variance random-effects models. Heterogeneity was assessed with I². Results: Three RCTs were included: IMbrave050 (atezolizumab+bevacizumab vs surveillance), Wang et al (sintilimab vs surveillance), and KEYNOTE-937 (pembrolizumab vs placebo; total N = 1,825). All trials enrolled Child-Pugh A and ECOG 0-1 patients. Across trials reporting baseline demographics (IMbrave050 and Wang et al; n = 866), 143/866 (16.5%) were female, median age ranged from 53–60 years, and HBV was the predominant etiology (561/866, 64.8%), followed by HCV (77/866, 8.9%). High-risk features were common: in IMbrave050, 52–60% had tumors > 5 cm, 60–61% had microvascular invasion and 6–8% had Vp1/Vp2 invasion (segmental portal vein invasion), in Wang et al, 52–59% had tumors > 5 cm and 35–40% had preoperative AFP > 400 ng/mL. KEYNOTE-937 stratified randomization by using AFP level at diagnosis and a protocol-defined recurrence-risk stratification, but the interim report did not specify the exact recurrence risk criteria. Adjuvant ICI-based therapy did not significantly improve RFS HR 0.76 (95% CI 0.51-1.14; I² = 82.8%) or OS HR 0.97 (95% CI 0.60-1.56; I² = 63.1%). Grade ≥3 AEs were more frequent with adjuvant therapy (308/907 vs 159/912) RR 2.12 (95% CI 1.20-3.77; I² = 87.3%). Conclusions: Adjuvant ICI-based therapy after curative-intent therapy for trial-defined high-risk HCC showed no significant overall RFS or OS benefit, with increased grade ≥3 adverse events. Results were heterogeneous, suggesting that any benefit may vary by regimen and patient risk profile; longer follow-up is needed to identify which patients are most likely to benefit, ongoing phase 3 trials will further clarify the role of adjuvant ICI.