Impact of PD ‐1 Inhibitor Timing Relative to Locoregional Therapy on Outcomes in uHCC Treated With Lenvatinib‐Based Triple Therapy

BACKGROUND AND AIMS: The optimal sequencing of programmed cell death protein 1 (PD-1) inhibitors relative to locoregional therapy (LRT) in unresectable hepatocellular carcinoma (uHCC) remains undefined. This study evaluated the impact of PD-1 inhibitor timing on outcomes in patients receiving hepatic arterial infusion chemotherapy (HAIC) or transarterial chemoembolisation (TACE) plus lenvatinib and PD-1 inhibitors. METHODS: Patients with initially uHCC who received LRT in combination with lenvatinib and PD-1 inhibitors across six academic centres were stratified by LRT modality (HAIC vs. TACE) and categorised into two groups based on PD-1 inhibitor timing (Pre-LRT PD-1 and Post-LRT PD-1 group). Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method; propensity score matching (PSM) and landmark analyses were applied to mitigate potential biases. RESULTS: A total of 350 patients were included, with 185 in the HAIC cohort and 165 in the TACE cohort. Pre-LRT PD-1 group was associated with significantly improved OS in the overall population, driven primarily by the HAIC cohort rather than the TACE cohort (34.03 m vs. 30.6 m, p = 0.032); these findings remained consistent after PSM and landmark analyses. Subgroup analyses further supported the survival benefit of Pre-LRT PD-1 initiation. After PSM, Pre-LRT PD-1 was also associated with significantly prolonged PFS in the HAIC cohort. According to RECIST 1.1 criteria, the Pre-LRT PD-1 group showed a higher objective response rate (ORR) (p = 0.002). CONCLUSIONS: In patients with uHCC receiving HAIC combined with lenvatinib and PD-1 inhibitors, initiation of PD-1 inhibitors prior to HAIC is associated with superior survival outcomes.