e16192 Background: Immune checkpoint inhibitors (ICIs) are integral to the treatment of advanced hepatocellular carcinoma (HCC); however, most patients eventually experience disease progression. The clinical efficacy and safety of ICI rechallenge following prior ICI failure remain poorly defined. We conducted a systematic review and meta-analysis to evaluate outcomes of ICI rechallenge in advanced HCC. Methods: A systematic search of PubMed, Embase, and the Cochrane Library was performed through January 2026 to identify studies evaluating ICI rechallenge in adults with advanced or unresectable HCC previously treated with ICIs. Eligible studies included rechallenge with PD-1, PD-L1, CTLA-4 inhibitors, or their combinations. Primary outcomes were objective response rate (ORR) and disease control rate (DCR). Secondary outcomes included progression-free survival (PFS), overall survival (OS), treatment-related adverse events (TRAEs), grade ≥3 adverse events, immune-related adverse events (irAEs), and treatment discontinuation. Pooled proportions were calculated using a random-effects model to account for interstudy heterogeneity. Results: Four retrospective cohort studies comprising 201 patients were included in the quantitative synthesis, with one case report included qualitatively. The pooled ORR with ICI rechallenge was 20.1% (95% CI: 15.2–25.6; I² = 47%), and the pooled DCR was 57.4% (95% CI: 49.1–65.4; I² = 42%). Median PFS across studies ranged from 4.0 to 6.0 months, and median OS ranged from 9.2 to 12.1 months. Dual immune checkpoint blockade with CTLA-4 and PD-1 inhibitors yielded higher response rates compared with PD-1/PD-L1 monotherapy rechallenge. The pooled incidence of grade ≥3 adverse events was 21.8% (95% CI: 16.4–27.8). Immune-related adverse events were generally manageable, and treatment discontinuation due to toxicity occurred in less than 10% of patients. Conclusions: Immune checkpoint inhibitor rechallenge in advanced HCC following prior ICI failure is associated with meaningful antitumor activity and an acceptable safety profile, particularly with combination immunotherapy strategies. These findings support ICI rechallenge as a therapeutic option in carefully selected patients and highlight the need for prospective studies to optimize patient selection and rechallenge strategies.
Deeksha et al. (Thu,) studied this question.