This study provides high-level evidence for surgical intervention following conversion therapy in hepatocellular carcinoma, clarifying the clinical value of dual inhibition of the PD-1/VEGFR pathways in expanding resectability, and offering direct guidance for the design of perioperative immunotherapy strategies.
Literature Overview
The article titled 'Sintilimab (PD-1 inhibitor) plus lenvatinib as conversion therapy followed by sequential surgery (SILENSES) for advanced unresectable hepatocellular carcinoma: a phase II, expansion trial,' published in Signal Transduction and Targeted Therapy, systematically investigates the efficacy and safety of sintilimab combined with lenvatinib as conversion therapy for unresectable hepatocellular carcinoma (HCC), and evaluates long-term survival outcomes in patients who undergo radical surgery after successful conversion. Through a prospective, single-arm, phase II trial design, the study provides the largest cohort data to date on long-term follow-up after conversion surgery, filling a critical gap in high-level evidence in this field.Background Knowledge
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, particularly prevalent in East Asia. Most patients are diagnosed at an advanced stage, rendering them ineligible for surgery, and systemic therapy becomes the primary treatment approach. Although PD-1/PD-L1 inhibitors combined with anti-angiogenic agents (such as VEGFR inhibitors) have become the standard first-line treatment for unresectable HCC—as demonstrated by the IMbrave150 trial, where atezolizumab plus bevacizumab significantly improved overall survival—the objective response rates (ORR) of these regimens typically range between 30% and 40%, making curative resection difficult. Therefore, converting unresectable tumors into resectable ones has become a key strategy to improve long-term outcomes. Conversion therapy aims to shrink tumors, eliminate vascular invasion, or eradicate metastatic lesions through multimodal treatments, thereby enabling surgical opportunities for previously unresectable HCC. However, standardized conversion protocols are currently lacking, and most evidence comes from retrospective studies, which are subject to selection bias and heterogeneity. Moreover, the response mechanisms of immune checkpoint inhibitors in HCC are complex, influenced by multiple factors such as the tumor microenvironment, T-cell infiltration, PD-L1 expression, and HBV infection status, making it challenging to accurately predict successful conversion. Based on preliminary exploratory data, this study employs sintilimab (a PD-1 inhibitor) combined with lenvatinib (a multi-kinase inhibitor targeting VEGFR, FGFR, etc.) as a fixed combination regimen, aiming to improve conversion rates, and reports 5-year long-term survival data for the first time, providing crucial evidence for precision conversion strategies in HCC.
Research Methods and Experiments
The study adopted a prospective, single-arm, phase II expansion trial design, enrolling 120 patients with radiologically confirmed unresectable HCC who received sintilimab (200 mg IV Q3W) combined with lenvatinib (weight-based oral dosing) as conversion therapy. Imaging assessments were performed every 6–8 weeks, with tumor response evaluated using mRECIST and RECIST v1.1 criteria. Conversion success was defined as ECOG PS ≤1, Child-Pugh class A/B, absence of distant metastases or presence of metastases amenable to R0 resection, preserved blood supply to the future liver remnant, and adequate future remnant liver volume (FRLV). After successful conversion, radical hepatectomy was performed based on multidisciplinary team (MDT) evaluation and patient preference. The primary endpoint was conversion rate; secondary endpoints included overall survival (OS), recurrence-free survival (RFS), objective response rate (ORR), and safety. All patients received at least one dose of treatment, with a median follow-up of 41.0 months. Survival analyses were conducted using Kaplan-Meier methods and Cox regression models, with IPTW adjustment to minimize bias. Pathological evaluation followed a standardized sampling protocol, defining pathological complete response (pCR), pathological partial response (pPR), and no pathological response (pNR).Key Conclusions and Perspectives
Research Significance and Prospects
This study provides a pivotal paradigm shift in the treatment of hepatocellular carcinoma, demonstrating the feasibility and survival benefit of systemic immunotherapy combined with targeted therapy as a conversion strategy. Its long-term follow-up data offer high-level evidence for clinical practice, supporting the integration of conversion therapy into comprehensive management pathways for unresectable HCC. Future studies should explore the use of baseline characteristics (such as AFP dynamics, radiomics, and liquid biopsy) to predict response to conversion, enabling personalized treatment. Furthermore, postoperative adjuvant strategies urgently need optimization; adjuvant PD-1 inhibitors or combination regimens based on pathological response stratification warrant investigation to further reduce recurrence risk.
Conclusion
This study establishes sintilimab combined with lenvatinib as a highly effective conversion regimen for unresectable hepatocellular carcinoma, with nearly 60% of patients achieving surgical conversion and over 70% 5-year survival post-surgery, significantly outperforming historical controls. These results not only validate the survival benefit of the 'conversion–resection' strategy in advanced HCC but also highlight the central role of multidisciplinary collaboration in precision hepatobiliary oncology. Mechanistically, dual inhibition of the PD-1 and VEGFR pathways may synergistically enhance anti-tumor immune responses by remodeling the immune microenvironment and suppressing angiogenesis, providing direction for future research. For laboratory researchers, this study suggests using HCC models to simulate the conversion therapy process to explore resistance mechanisms and biomarkers. From a clinical translational perspective, this regimen has the potential to become the new standard of care for selected stage III HCC patients, advancing HCC management from 'unresectable' toward 'potentially curable' and providing key evidence for global HCC care systems.
