Second-Line TKI after First-Line Immunotherapy-based Treatment in Advanced HCC: Reconstructed IPD Meta-analysis

BACKGROUND: The efficacy of second-line tyrosine-kinase inhibitors (TKIs) after first-line immunotherapy-based (IO) treatment in advanced hepatocellular carcinoma (HCC) is not well-established. METHODS: A systematic search was conducted to include studies presenting a TKI in the second line after progression with first-line IO-based treatment. Studies presenting/combining data of the third line and beyond were excluded. Individual patient survival data were reconstructed from Kaplan-Meier curves. Overall survival (OS) (primary endpoint) and progression-free survival (PFS) were analyzed by restricted mean survival time (RMST), and random-effects univariable and adjusted meta-regression analyses were performed. Proportion and inverse generic methods were used for baseline characteristics. RESULTS: 1663 patients (16 studies) were included Sorafenib (n=769), Lenvatinib (n=691), Regorafenib (n=105), Cabozantinib (n=98). Most patients received atezolizumab-bevacizumab in the first line. Cabozantinib was excluded from primary analyses as 83.7% of the data were derived from a single study, and baseline characteristics data were limited. The regorafenib group had significantly more Child-Pugh-A and less macrovascular invasion. Median OS of all patients was 9.8 months (95% Confidence Interval (CI): 9.4-10.2). 12-month OS was significantly longer with lenvatinib or regorafenib compared to sorafenib ΔRMST, 1.49 months (95%CI:1.10-1.88), p<0.001 and 1.16 months (95%CI:0.41-1.96), p=0.002. The median PFS for all patients was 3.2 months (95% CI: 3.0-3.4). The 6-month PFS with lenvatinib or regorafenib was significantly longer than with sorafenib ΔRMST, 1.28 months (95%CI:1.08-1.49), p<0.001, and 0.73 months (95%CI:0.38-1.09), p<0.001. Meta-regression analyses suggested similar results. CONCLUSIONS: In this reconstructed-IPD meta-analysis of predominantly retrospective studies, survival outcomes with second-line TKIs after IO-based therapy were heterogeneous. Lenvatinib and regorafenib showed consistent survival compared with sorafenib; however, findings are exploratory, limited by the observational nature of the data and residual confounding. Prospective studies are needed to define optimal post-immunotherapy sequencing strategies. PROSPERO ID: CRD420251133124 IMPACT AND IMPLICATIONS: This study addresses a critical evidence gap in advanced hepatocellular carcinoma by synthesizing available real-world data on second-line tyrosine kinase inhibitors (TKI) after immunotherapy-based first-line treatment, using reconstructed individual patient data and restricted mean survival time to accommodate non-proportional hazards and heterogeneous follow-up.The findings should not be interpreted as a recommendation for any specific TKI. Instead, they describe current survival patterns across heterogeneous retrospective cohorts and underscore the absence of robust comparative evidence in the post-immunotherapy setting.The results are relevant for clinicians and multidisciplinary teams caring for patients who progress after immunotherapy, as they may help contextualize expectations, support shared decision-making with patients and caregivers, and highlight areas of doubt in routine practice.This work highlights the unmet need for prospective randomized trials and high-quality real-world registries to define optimal treatment sequencing, inform regulatory decisions, and ensure equitable access to evidence-based therapies.