The METAL Score for Early Stratification of Radiological Response and Survival in Hepatocellular Carcinoma Treated with TACE and Immunotherapy Combinations.

[RATIONALE AND OBJECTIVES] To develop and validate a prognostic stratification tool for patients with unresectable hepatocellular carcinoma (uHCC) receiving transarterial chemoembolization (TACE) combined with targeted and immunotherapy (triple therapy).

[MATERIALS AND METHODS] This multicenter retrospective study included uHCC patients treated with first-line triple therapy at 13 tertiary hospitals from December 2018 to August 2023. A prognostic score was developed (n=378) based on multivariate Cox regression and validated in an external cohort (n=148). Radiological response and overall survival (OS) were assessed across different risk strata. Score performance was compared to existing prognostic models and further evaluated in a separate cohort receiving systemic therapy without TACE (n=232).

[RESULTS] A three-variable score (METAL) integrating metastatic burden, alpha-fetoprotein, and albumin-bilirubin grade was developed. Median OS for low-, intermediate-, and high-risk groups was 30.8, 25.2, and 11.6 months in the derivation cohort, and 34.6, 23.0, and 14.8 months in the external validation cohort, respectively (all p<0.001). In both cohorts, confirmed objective response rates (ORR) also declined progressively across risk strata (all p<0.001). The current score was superior to existing TACE- or immunotherapy-related models, with higher discrimination and lower prediction error (C-index, 0.70 and 0.70; integrated Brier score, 0.140 and 0.122 in the derivation and validation cohorts, respectively). The METAL-low score successfully identified a subgroup achieving significantly longer OS (32.6 vs. 23.8 months; p=0.034) and higher ORR (77.2% vs. 48.1%; p<0.001) with triple therapy compared to systemic therapy alone.

[CONCLUSION] The proposed METAL score enables early identification of ideal uHCC candidates most likely to benefit from triple therapy.