Signal Transduction and Targeted Therapy | Lenvatinib combined with TACE and PD-1 inhibitors for conversion therapy in unresectable hepatocellular carcinoma

This study is the first to prospectively demonstrate in a phase II trial that the LEN-TAP triplet regimen significantly improves surgical conversion rates and long-term survival in patients with unresectable hepatocellular carcinoma, and that levels of peripheral blood HLA-DR+CD38+CD8+ T cells may serve as a potential biomarker for predicting treatment response.

 

Literature Overview

This article, titled 'Lenvatinib plus transarterial chemoembolization and PD-1 inhibitors as conversion therapies for unresectable intermediate-advanced hepatocellular carcinoma: a phase 2 trial and exploratory biomolecular study,' published in Signal Transduction and Targeted Therapy, reviews and summarizes the results of a prospective multicenter phase II clinical trial evaluating the LEN-TAP triplet regimen (lenvatinib, TACE, and PD-1 inhibitors) as conversion therapy for unresectable intermediate-to-advanced hepatocellular carcinoma (uHCC). The study compares the triplet regimen with TACE monotherapy in terms of resection conversion rate, objective response rate, survival outcomes, and safety, while also exploring potential immune biomarkers through single-cell sequencing and flow cytometry. The results show that LEN-TAP significantly improves resection rates and antitumor efficacy, with treatment response correlating with the expansion of peripheral HLA-DR+CD38+CD8+ T cells. This study provides high-quality prospective evidence for uHCC conversion therapy and holds significant clinical implications.

Background Knowledge

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and most patients are diagnosed at intermediate or advanced unresectable stages, missing the opportunity for curative surgery. Although TACE is the standard treatment for intermediate-stage HCC, its efficacy as conversion therapy is limited, with conversion rates of only about 10%. In recent years, advances in systemic therapy, particularly the use of multikinase inhibitors (e.g., lenvatinib) and immune checkpoint inhibitors (e.g., PD-1 inhibitors), have brought new treatment options for advanced HCC. Preclinical studies suggest that TACE can induce immunogenic cell death and release tumor antigens, lenvatinib can inhibit the VEGF/FGF pathway to normalize tumor vasculature and modulate the immune microenvironment, and PD-1 inhibitors can restore T-cell antitumor activity, providing a theoretical basis for synergistic effects with the triplet combination. However, prospective data supporting its use in conversion therapy remain lacking. Moreover, reliable biomarkers to identify patients who may benefit from this strategy are still missing. Therefore, conducting high-quality prospective studies to evaluate the efficacy and safety of the triplet regimen and to explore predictive biomarkers has become a key direction in current HCC research.

 

 

Research Methods and Experiments

This study was a multicenter, prospective, open-label phase II clinical trial (NCT04997850), which enrolled 142 patients with unresectable intermediate-to-advanced HCC, randomly assigned in a 1:1 ratio to either the LEN-TAP group (n=71) or the TACE monotherapy group (n=71). The LEN-TAP group received oral lenvatinib (weight-based dosing) combined with TACE and PD-1 inhibitors (sintilimab or camrelizumab), while the TACE group received TACE alone. The primary endpoint was salvage liver resection (SLR) rate. Secondary endpoints included objective response rate (ORR), overall survival (OS), event-free survival (EFS), recurrence-free survival (RFS), and safety. Exploratory analyses used single-cell RNA sequencing and flow cytometry to examine dynamic changes in immune cell subsets in peripheral blood and tumor tissues to identify potential predictive biomarkers.

Key Conclusions and Perspectives

• The SLR rate in the LEN-TAP group was 59.2%, significantly higher than the 18.3% in the TACE group (P < 0.001)
• According to mRECIST criteria, the ORR in the LEN-TAP group was 78.9%, far exceeding the 16.9% in the TACE group (P < 0.001)
• The median OS in the LEN-TAP group was not reached, compared to 23.0 months in the TACE group (HR=0.48, P < 0.001); median EFS was 20.03 months vs. 6.52 months (P < 0.001); median RFS was 36.6 months vs. 19.0 months (P=0.048)
• The rate of grade 3 treatment-related adverse events was 60.6% in the LEN-TAP group, higher than the 21.1% in the TACE group (P < 0.001), but no grade 4 or higher toxicities were observed, indicating manageable safety
• Single-cell sequencing and flow cytometry revealed a significant increase in the proportion of HLA-DR+CD38+CD8+ T cells in peripheral blood after treatment, which strongly correlated with treatment response
• Mechanistic studies showed that this T-cell subset exerts antitumor activity through the CXCR6–PI3K–AKT signaling axis, with CXCR6 interaction with CXCL16 secreted by tumor cells being key to its function

Research Significance and Prospects

This study provides the first prospective phase II evidence that the LEN-TAP triplet regimen has significant potential as conversion therapy in patients with unresectable HCC, effectively improving resection rates and prolonging long-term survival. The efficacy advantage may stem from the synergistic effects of TACE for local control, lenvatinib for anti-angiogenesis and immune modulation, and PD-1 inhibitors for T-cell activation.

More importantly, the study identifies peripheral blood HLA-DR+CD38+CD8+ T cells as a potential predictive biomarker for treatment response, offering new insights for developing personalized treatment strategies. This finding suggests that monitoring dynamic changes in this T-cell subset may help identify responders early and optimize treatment decisions.

Although this study brings new hope for uHCC conversion therapy, limitations remain, such as the relatively small sample size and the lack of a systemic therapy control group (e.g., lenvatinib monotherapy). Larger phase III randomized controlled trials are needed to further validate the superiority of this triplet regimen and explore its broader applicability.

 

 

Conclusion

This study systematically evaluated the efficacy and safety of Lenvatinib combined with TACE and PD-1 inhibitors (LEN-TAP) as conversion therapy for unresectable intermediate-to-advanced hepatocellular carcinoma through a prospective multicenter phase II clinical trial. The results show that, compared to TACE monotherapy, the LEN-TAP regimen significantly improves the salvage liver resection rate (59.2% vs. 18.3%), objective response rate, and long-term survival outcomes, with manageable safety. Mechanistic exploration revealed that the expansion of HLA-DR+CD38+CD8+ T cells in peripheral blood after treatment is closely associated with treatment response, and this subset exerts antitumor effects via the CXCR6–PI3K–AKT signaling axis, suggesting its potential as a predictive biomarker. This study not only provides a new conversion therapy strategy for patients with unresectable HCC but also offers important clues for the development of biomarkers in personalized immunotherapy, demonstrating significant clinical translational value. Future studies with larger sample sizes are needed to further validate the clinical benefits of this regimen and promote its real-world application.

 

Xiaoyun Zhang, Haozheng Cai, Wei Peng, Shuqun Cheng, and Tianfu Wen. Lenvatinib plus transarterial chemoembolization and PD-1 inhibitors as conversion therapies for unresectable intermediate-advanced hepatocellular carcinoma: a phase 2 trial and exploratory biomolecular study. Signal Transduction and Targeted Therapy.