Early PIVKA-II Response Predicts Treatment Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Hepatocellular Carcinoma

Background and Aims: Early alpha-fetoprotein (AFP) response has been reported to predict the treatment efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced hepatocellular carcinoma (HCC). We evaluated the predictive value of another HCC tumor marker, protein induced by vitamin K absence/antagonists-II (PIVKA-II). Methods: We prospectively established a cohort of advanced HCC patients who received ICI treatment at two medical centers. Serum PIVKA-II levels were obtained before and within 4 weeks after treatment initiation. Any decline in serum PIVKA-II levels was defined as an early PIVKA-II response. Treatment response, overall survival (OS), and progression-free survival (PFS) were compared between patients with and without an early PIVKA-II response. Results: In total, 67 patients were included; liver reserve was Child–Pugh class A in all patients and albumin–bilirubin grade 1 in 67.2% of the patients. An early PIVKA-II response, which was observed in 19 (28.4%) patients, was associated with a higher objective response rate (50.0% vs 16.4%, p = 0.002). Patients with an early PIVKA-II response had superior OS (median 34.3 vs 13.7 months, p = 0.015) and PFS (median 8.4 vs 4.0 months, p = 0.049) compared with those without a response. In multivariate analysis, an early PIVKA-II response remained an independent predictor for longer OS (p = 0.012) and PFS (p = 0.044). An early PIVKA-II response can complement an early AFP response in predicting prognosis. Conclusion: An early PIVKA-II response is predictive of tumor response and superior survival outcomes in patients who received ICIs for advanced HCC. Plain Language Summary: PIVKA-II is an emerging tumor marker for HCC, widely used in diagnosis and prognostic stratification. Early PIVKA-II response, defined as any decline of serum PIVKA-II level within 4 weeks after initiation of ICIs treatment, may predict treatment efficacy for patients with advanced HCC.