TACE combined with lenvatinib and PD-1 inhibitors: a promising strategy for unresectable huge HCC

Dear Editor, We read with great interest the multicenter retrospective cohort study by Liang et al[1], which demonstrated the superior efficacy of triple therapy (transarterial chemoembolization [TACE] + lenvatinib + PD-1 inhibitor) over TACE plus lenvatinib (TACE + Len) in patients with unresectable huge hepatocellular carcinoma (HCC; tumor diameter ≥10 cm), yielding significant improvements in progression-free survival (PFS) and overall survival (OS). This study addresses a high-risk patient subgroup that is frequently underrepresented in clinical trials and carries a particularly poor prognosis. While acknowledging the inherent limitations of its retrospective design, we believe this study provides valuable real-world evidence and raises important questions for future surgical and multidisciplinary management. This commentary is compliant with the TITAN Guidelines 2025[2]. The findings align with recent meta-analyses[3,4], which conclude that adding immune checkpoint inhibitors to TACE plus lenvatinib significantly improves objective response rate (ORR), disease control rate, PFS, and OS in intermediate or advanced HCC. These findings are now corroborated by the phase 3 LEAP-012 trial, in which the addition of lenvatinib plus pembrolizumab to TACE significantly improved PFS (HR 0.66, 95% CI 0.51–0.84; P = 0.0002) and achieved an ORR of 71% per mRECIST[5]. The observed efficacy is also consistent with mechanistic work[6] demonstrating that lenvatinib plus anti-PD-1 reinforces systemic anti-tumor immunity (e.g., increasing CD4+/CD8+ T cells and B cells) while weakening the immunosuppressive microenvironment (e.g., reducing myeloid-derived suppressor cells and co-inhibitory mediators like PD-L1 and LAG-3), which likely synergizes with the localized effect of TACE. Beyond survival gains, the most clinically significant surgical implication of this triple regimen is its potential to enable conversion surgery for initially unresectable huge HCC. The substantially higher ORR observed with triple therapy (51.4% vs. 21.1% at 6 months)[1] suggests that patients with extreme tumor burden may be successfully downstaged to meet criteria for curative resection. For hepatobiliary surgeons, key perioperative questions, including the optimal number of TACE sessions and systemic therapy cycles before surgery, remain unanswered. Notably, as a retrospective analysis, the study by Liang et al[1] remains susceptible to selection bias and residual confounding despite rigorous statistical adjustments. Moreover, the toxicity and substantial financial burden of these agents are worthy of consideration. To advance the current evidence and enhance the clinical utility of triple combination therapy for unresectable huge HCC, several key research directions should be prioritized. First, comprehensive biomarker discovery is essential. Future studies should incorporate multi-omics approaches to assess biomarkers such as PD-L1 expression, tumor mutational burden, immune cell infiltration, and circulating tumor DNA to identify reliable predictors of treatment response. Second, further mechanistic investigation through preclinical and translational research is warranted to clarify the immunological synergies underpinning this therapeutic regimen. Third, optimizing the combination strategy remains critical. Efforts should focus on determining the ideal sequencing, dosing, and treatment duration of the three modalities. In particular, the optimal number of TACE sessions in conjunction with systemic therapy requires systematic evaluation. Additionally, integrating other emerging strategies[7,8] – including CTLA-4 inhibitors, newer-generation tyrosine kinase inhibitors, bispecific antibodies, and chimeric antigen receptor T-cell therapy – into the backbone regimen may offer enhanced clinical benefits. In conclusion, the study by Liang et al[1] provides valuable real-world evidence suggesting that combining TACE with lenvatinib and a PD-1 inhibitor may represent an effective first-line approach for unresectable huge HCC. Large-scale prospective validation and systematic integration of broader real-world data are needed to refine and personalize this treatment strategy.