Early on-treatment alpha-fetoprotein and des-gamma-carboxy prothrombin responses are associated with outcomes in unresectable hepatocellular carcinoma receiving transarterial chemoembolization, tyrosine kinase inhibitors and programmed cell death protein-1 inhibitors.
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BACKGROUND: Transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and programmed cell death protein-1 (PD-1) inhibitors is increasingly used for unresectable hepatocellular carcinoma (uHCC). This study evaluated whether the depth of early alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) response was associated with treatment outcomes in this setting. METHODS: This single-center retrospective cohort study included consecutive patients with uHCC receiving TACE combined with TKIs and PD-1 inhibitors. Patients with baseline AFP ≥100 μg/L or DCP ≥100 mAU/mL were included in the corresponding biomarker-evaluable cohorts; patients with elevation of both markers contributed to both analyses. Week-8 biomarker response was categorized as deep (>80% decrease), intermediate (20-80% decrease), or limited (<20% decrease or increase). Associations with week-8 modified Response Evaluation Criteria in Solid Tumors (mRECIST)-based objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: Among 98 patients, 64 were included in the AFP-evaluable cohort and 87 in the DCP-evaluable cohort, with 53 included in both. ORR increased with response depth in both cohorts (AFP: 85.7%, 53.3% and 21.4%; DCP: 84.1%, 52.4% and 4.5% for deep, intermediate, and limited responses, respectively; both P<0.001). Median PFS was 17.5, 10.3 and 5.7 months across the AFP response groups and 13.1, 8.5 and 6.2 months across the DCP response groups (both P<0.001). Median OS was 26.4 months, not reached, and 10.4 months in the deep, intermediate, and limited AFP response groups, respectively, and 28.9, 16.7 and 13.0 months in the corresponding DCP groups (both P<0.001). In multivariable Cox models including biomarker response category, week-8 mRECIST-based ORR, Barcelona Clinic Liver Cancer (BCLC) stage, and Child-Pugh class, deep AFP response remained independently associated with longer PFS [hazard ratio (HR) 0.155, 95% confidence interval (CI): 0.061-0.397] and OS (HR 0.157, 95% CI: 0.036-0.684), as did deep DCP response for PFS (HR 0.245, 95% CI: 0.111-0.544) and OS (HR 0.299, 95% CI: 0.104-0.862). CONCLUSIONS: Week-8 AFP and DCP response depth was associated with radiological response and survival in biomarker-evaluable patients with uHCC receiving TACE, TKIs and PD-1 inhibitors. These biomarkers may provide complementary on-treatment information alongside imaging, pending prospective validation.