The benefit and risk of adding PD-1/PD-L1 inhibitors plus anti-VEGF drugs to transarterial chemoembolisation for unresectable, non-metastatic hepatocellular carcinoma: a pooled analysis of four RCTs

Background Transarterial chemoembolisation (TACE) is the standard treatment for unresectable, non-metastatic hepatocellular carcinoma (UR/NM HCC). The addition of PD-1/PD-L1 inhibitors (PIs) plus anti-VEGF drugs (AVDs) after TACE (TPA group) has been proposed as a strategy to enhance antitumor efficacy; however, evidence regarding its survival benefit is still uncertain. To address this issue, we performed a pooled analysis of randomized controlled trials (RCTs) to determine whether this combination strategy confers additional clinical benefit over TACE alone. Methods Six databases were systematically searched to identify eligible RCTs comparing TPA with TACE alone among individuals diagnosed with UR/NM HCC. Key endpoints consisted of overall survival (OS) and progression-free survival (PFS), whereas additional endpoints covered tumor responses, adverse events (AEs), and patient status at the data cutoff. PFS and tumor responses were assessed according to both RECIST version 1.1 and mRECIST criteria. Results A total of 4 RCTs (CARES-005, EMERALD-1, LEAP-012, and TALENTACE) involving 1,431 patients were included. Compared with TACE alone, TPA significantly improved PFS (HR: 0.62 [0.47, 0.81], p = 0.0006) and objective response rate (ORR, RR: 1.44 [1.25, 1.66], p < 0.00001), whereas no statistically significant improvement in OS was observed (HR: 0.87 [0.71, 1.07], p = 0.20). Subgroup analyses demonstrated that the PFS benefit of the TPA group was consistent across nearly all predefined subgroups. However, TPA also showed an increased occurrence of grade 3–4/serious treatment-emergent AEs (TEAEs), grade 3–4/serious treatment-related AEs (TRAEs), and total/grade 3–4 immune-related AEs (irAEs). At the cutoff, more patients in the TPA group discontinued treatment due to AEs, whereas fewer discontinued due to disease progression. Conclusion In patients with UR/NM HCC, TPA significantly improves PFS and ORR but does not yet demonstrate a significant OS benefit, and it is associated with increased grade 3–4 AEs. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420261290301 , CRD420261290301.