AbstractBackgroundAlthough the appearance of portal vein tumor thrombus (PVTT) is significantly associated with unfavorable prognosis, there is insufficient evidence to confirm the efficacy and safety of the triple combination of transarterial chemoembolization (TACE), lenvatinib, and programmed cell death‐1 (PD‐1) inhibitor for patients with hepatocellular carcinoma (HCC) and PVTT. Furthermore, it remains unclear which patient type can obtain the best survival benefit from this combination therapy.MethodsThe data of 160 patients with HCC and PVTT treated with TACE combined with lenvatinib plus PD‐1 inhibitor (TACE+LEN + PD‐1 group) or TACE combined with lenvatinib (TACE+LEN group) were retrospectively collected and analyzed. To estimate the efficacy and safety of combination therapy for patients with advanced HCC, tumor response, progression‐free survival (PFS), overall survival (OS), biochemical indices, and adverse events (AEs) were assessed in this study. More importantly, tumor immune‐related cytokines were used to identify biomarkers predicting the therapeutic response of combination therapy.ResultsTACE+LEN + PD‐1 was superior to TACE+LEN in OS (23.5 vs. 18.3 months,p= 0.0002) and PFS (7.5 vs. 4.3 months,p< 0.0001). Moreover, TACE+LEN + PD‐1 achieved more preferable benefits with respect to disease control rate (80.00% vs. 56.67%) and objective response rate (38.57% vs. 24.45%) compared with TACE+LEN in patients with HCC and PVTT (p= 0.025). Multivariate analysis showed that Child–Pugh grade, PVTT classification, treatment option, and interleukin (IL)‐6, IL‐17, interferon (IFN)‐α, and vascular endothelial growth factor (VEGF) levels were independent factors related to OS, whereas PVTT classification, treatment option, and IL‐6 and IFN‐α levels were independent factors related to PFS. Furthermore, the subgroup analysis illustrated that the inflammatory cytokines VEGF, IL‐6, IL‐17, and IFN‐α might be novel biomarkers for predicting the survival prognosis of patients with advanced HCC and PVTT treated with TACE+LEN + PD‐1. The safety in the combination group was acceptable.ConclusionsCompared with TACE+LEN, the triple combination treatment of TACE+LEN + PD‐1 has more promising clinical outcomes and acceptable safety in patients with HCC and PVTT. Child–Pugh grade, PVTT classification, and IL‐6, IL‐17, IFN‐α, and VEGF levels are independent prognostic factors for survival time.