Early PIVKA-II Response Associated with Treatment Efficacy and Survival Outcomes for Patients with Advanced Hepatocellular Carcinoma Receiving Immune Checkpoint Inhibitors and Targeted Therapy

Zheng-Kang Fang,1,2 Yu-Ting Xiao,1 Xia Feng,1 Zhe-Jin Shi,1,3 Si-Yu Liu,4 Yang Yu,5 Li-Ming Jin,1 Dong-Sheng Huang,1 Cheng-Wu Zhang,1 Jun-Wei Liu,1 Lei Liang1 1Department of General Surgery, Cancer Center, Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Postgraduate Training Base Alliance, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of the second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 4Department of Laboratory Medicine, the Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Zhejiang University Lishui Hospital, Lishui, Zhejiang, People’s Republic of China; 5Department of Urology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Lei Liang, Department of General Surgery, Cancer Center, Hepatobiliary and Pancreatic Surgery and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People’s Republic of China, Email [email protected] Jun-Wei Liu, Email [email protected] & Aims: Prothrombin induced by vitamin K absence-II (PIVKA-II) levels have been reported to correlate with hepatocellular carcinoma (HCC) prognosis, but its utility for assessing early treatment response remains underexplored. This study evaluated early PIVKA-II changes for predicting response and survival in HCC patients undergoing immune checkpoint inhibitors (ICIs) and targeted therapy.Methods: Eighty-two HCC patients were enrolled. Serum PIVKA-II levels were measured at baseline and after the first treatment cycle. Patients were stratified based on early PIVKA-II dynamics into a biochemical response group (≥ 50% reduction, n=40) and a non-response group (< 50% reduction, n=42). Logistic regression and Cox proportional hazards models were used to identify predictors of objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results: Time-dependent ROC analysis established ≥ 50% PIVKA-II decline as the early response threshold. The PIVKA-II response group had a significantly higher proportion of patients with Child-Pugh A, a lower incidence of extrahepatic metastasis, and significantly higher ORR (82.5% vs 38.1%, P< 0.001). Median PFS and OS were not reached in the PIVKA-II responder group, compared to 8.9 months and 16.7 months, respectively, in the non-responder group (both P < 0.001). Multivariate analysis confirmed early PIVKA-II response as an independent predictor of PFS (HR=0.687, P< 0.001) and OS (HR=0.709, P< 0.001). Notably, in AFP-negative patients, an early PIVKA-II response was predictive of ORR and was associated with significantly longer PFS and OS.Conclusion: Early PIVKA-II response effectively predicts treatment response and prognosis in advanced HCC patients receiving ICI and targeted therapy, especially in AFP-negative patients.Keywords: hepatocellular carcinoma, PIVKA-II, target therapy, immune checkpoint inhibitors, objective response rate