Alpha-Fetoprotein and Des-Gamma-Carboxy Prothrombin-Based Tumor Marker Score for First-Line Immunotherapy Selection in Hepatocellular Carcinoma.

Background: Atezolizumab plus bevacizumab (Atez/Bev) and durvalumab plus tremelimumab (Dur/Tre) are standard first-line therapies for unresectable hepatocellular carcinoma (HCC). However, predictive biomarkers to guide treatment selection remain undefined. In this study, we aimed to evaluate the prognostic utility of a modified tumor marker (mTM) score, incorporating alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), for selecting between Atez/Bev and Dur/Tre and in stratifying treatment outcomes of unresectable HCC. Methods: We conducted a multicenter retrospective study of 1,313 patients with unresectable HCC treated with either Atez/Bev (n = 1,157) or Dur/Tre (n = 156). The mTM score was defined based on baseline AFP (≥100 ng/mL) and DCP (≥100 mAU/mL), assigning one point to each elevated marker. Patients were categorized as mTM low (score 0) or mTM high (score 1-2). Survival outcomes were analyzed using Kaplan-Meier curves and Cox proportional hazards models, with inverse probability of treatment weighting applied for confounder adjustment. Results: Among the mTM low patients, Atez/Bev was associated with significantly longer progression-free survival (PFS) (11.5 vs. 4.4 months, p < 0.001) and overall survival (30.6 vs. 17.0 months, p = 0.023) than Dur/Tre. In contrast, in mTM high patients, PFS was comparable between Atez/Bev and Dur/Tre (6.6 vs. 6.5 months, p = 0.873). However, in patients with DCP >400 mAU/mL, Dur/Tre was associated with improved PFS. Conclusion: The mTM score is a clinically relevant biomarker for treatment stratification in unresectable HCC. Atez/Bev may be preferable in mTM low patients, whereas Dur/Tre may provide greater benefit in those with elevated DCP levels. Prospective validation is warranted to refine the optimal cutoff values for clinical implementation.