Sintilimab–Lenvatinib Enables Conversion Surgery in Advanced HCC : Signal Transduct Target Ther | May 2026

Introduction

Most patients with Hepatocellular Carcinoma present with advanced unresectable disease, limiting curative-intent treatment opportunities. Although systemic therapy remains the standard for advanced-stage HCC, modern immunotherapy-based combinations have raised the possibility of “conversion therapy,” where effective tumor regression permits subsequent surgical resection. The SILENSES phase II expansion trial evaluated whether combined PD-1 inhibition with sintilimab and multikinase inhibition with lenvatinib could convert initially unresectable HCC into surgically treatable disease.

Problem Statement

Advanced HCC with macrovascular invasion or extrahepatic disease has historically carried poor long-term survival, with systemic therapy rarely leading to durable remission. Whether modern immunotherapy-targeted therapy combinations can reliably create a surgical window and improve long-term survival remains uncertain.

Summary

This prospective single-arm phase II trial enrolled 120 treatment-naïve patients with radiologically confirmed unresectable HCC, the majority of whom had very advanced disease features including BCLC stage C disease, macrovascular invasion and extrahepatic metastases. Patients received sintilimab plus lenvatinib, with multidisciplinary reassessment of resectability every 6–8 weeks. Successful conversion was achieved in 56% of patients, and 60 individuals ultimately underwent curative-intent hepatectomy. Most surgical candidates achieved resectability within approximately 3 months of systemic therapy initiation.

Radiologic responses were substantial, with objective response rates approaching 58% by mRECIST and 46% by RECIST v1.1. Importantly, pathological tumor regression was also profound among resected patients. Pathological complete response occurred in 35% of surgical patients, while an additional 42% achieved pathological partial response, supporting the ability of combined immunotherapy and targeted therapy to induce major biological tumor regression beyond radiographic shrinkage alone.

Long-term survival outcomes were particularly notable. Across the entire cohort, median overall survival reached 36 months. However, patients who successfully underwent surgery demonstrated markedly superior outcomes, with estimated 5-year overall survival approaching 74%, compared with poor survival among nonsurgical patients. Landmark analyses designed to reduce immortal time bias continued to demonstrate major survival advantages associated with sequential surgery following successful conversion therapy. Recurrence-free survival after curative-intent resection reached a median of 40 months, although recurrence remained common, occurring in nearly half of resected patients. Depth of pathological response emerged as a major prognostic determinant for both recurrence-free and overall survival.

Treatment-related toxicity was frequent but generally manageable. Nearly all patients experienced adverse events, while grade 3–5 toxicities occurred in approximately one-third of cases. Serious immune-related and hemorrhagic complications were uncommon but clinically important, including several treatment-related deaths. Surgical morbidity was acceptable despite the complexity of operations following systemic conversion therapy.

Overall, the SILENSES study provides important proof-of-concept evidence that effective immunotherapy-targeted therapy combinations can create meaningful surgical opportunities in selected patients with advanced unresectable HCC. The findings support routine multidisciplinary reassessment of resectability during systemic therapy and reinforce the evolving paradigm of biology-guided conversion surgery in advanced liver cancer. However, randomized multicenter validation studies remain necessary before widespread adoption of this strategy.