Lenvatinib plus anti-PD-1 antibodies as conversion therapy for patients with unresectable intermediate-advanced hepatocellular carcinoma: a single-arm, phase II trial

Abstract

Background: Over 70% of the patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage and lose the opportunity for radical surgery. Combination therapy of tyrosine kinase inhibitors (TKIs) and anti-programmed cell death protein-1 (PD-1) antibodies has achieved a high tumor response rate in both the first-line and second-line treatment of advanced HCC. However, few studies have prospectively evaluated whether TKIs plus anti-PD-1 antibodies could convert unresectable intermediate-advanced HCC into resectable disease.

Methods: This single-arm, phase II study enrolled systemic therapy-naïve adult patients with unresectable Barcelona Clinic Liver Cancer stage B or C HCC. Patients received oral lenvatinib one time per day plus intravenous anti-PD-1 agents every 3 weeks (one cycle). Tumor response and resectability were evaluated before the fourth cycle, then every two cycles. The primary endpoint was conversion success rate by investigator assessment. Secondary endpoints included objective response rate (ORR) by independent imaging review (IIR) assessment per modified RECIST (mRECIST) and Response Evaluation Criteria in Solid Tumors, V.1.1 (RECIST 1.1), progression-free survival (PFS) and 12-month recurrence-free survival (RFS) rate by IIR per mRECIST, R0 resection rate, overall survival (OS), and safety. Biomarkers were assessed as exploratory objectives.

Results: Of the 56 eligible patients enrolled, 53 (94.6%) had macrovascular invasion, and 16 (28.6%) had extrahepatic metastasis. The median follow-up was 23.5 months. The primary endpoint showed a conversion success rate of 55.4% (31/56). ORR was 53.6% per mRECIST and 44.6% per RECIST 1.1. Median PFS was 8.9 months, and median OS was 23.9 months. Among the 31 successful conversion patients, 21 underwent surgery with an R0 resection rate of 85.7%, a pathological complete response rate of 38.1%, and a 12-month RFS rate of 47.6%. Grade ≥3 treatment-related adverse events were observed in 42.9% of patients. Tumor immune microenvironment analysis of pretreatment samples displayed significant enrichment of CD8⁺ T cells (p=0.03) in responders versus non-responders.

Conclusion: Lenvatinib plus anti-PD-1 antibodies demonstrate promising efficacy and tolerable safety as conversion therapy in unresectable HCC. Pre-existing CD8⁺ cells are identified as a promising biomarker for response to this regimen.

Trial registration number: Chinese Clinical Trial Registry, ChiCTR1900023914.

Keywords: Drug Therapy, Combination; Immune Checkpoint Inhibitors; Immunotherapy; Liver Neoplasms.

Figure 1

CONSORT (Consolidated Standards of Reporting Trials) diagram and study design. AE, adverse event; BCLC, Barcelona Clinic Liver Cancer; CBC, complete blood count; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; NE, not estimable; ORR, objective response rate; OS, overall survival; pCR, pathological complete response (no viable tumor cells in the resection specimens, including completely resected primary tumors, tumor thrombosis, and lymph nodes); PD-1, programmed cell death protein-1; PFS, progression-free survival; PS, performance status; pNR, pathological non-response (> 50% viable tumor cells in the primary tumor or appearance of new lesions); pPR, pathological partial response (≤50% viable tumor cells in the primary tumor).

Figure 2

Response of 56 patients with HCC to conversion therapy with lenvatinib and anti-PD-1 antibodies (A and B) Waterfall plot of the best percentage change in target-lesion size from baseline by IIR assessment according to mRECIST (A) and RECIST 1.1 (B). (C) Swimmer plot of overall survival in 56 patients with HCC receiving lenvatinib plus PD-1 inhibitors. BCLC, Barcelona Clinic Liver Cancer; CNLC, China Liver Cancer; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HVTT, hepatic vein tumor thrombosis; IIR, independent imaging review; mRECIST, modified RECIST; NE, not estimable; PD, progressive disease; PD-1, programmed cell death protein-1; PR: partial response; PVTT: portal vein tumor thrombus; RECIST 1.1, Response Evaluation Criteria in Solid Tumors V.1.1.

Figure 3

Kaplan-Meier analysis of PFS (A) and OS (B) in the overall (n=56), conversion success (n=31), and conversion failure population (n=25). PFS was assessed by IIR according to mRECIST. IIR, independent imaging review; mRECIST, modified Response Evaluation Criteria in Solid Tumors. OS, overall survival; PFS, progression-free survival.

Figure 4

Association between immune cell infiltration and response to lenvatinib plus PD-1 inhibitors in 20 patients with HCC. Response was assessed by IIR per mRECIST. (A) The differences between the response and non-response groups for CD8⁺ T cells, M1 macrophages, M2 macrophages, CD56^dim NK cells, and CD56^bright NK cells. (B) The representative images of immunohistochemical staining of tumor-infiltrating immune cells. Cells with only CD68 expression were considered M2 macrophages, and dual-labeled cells for CD68 and HLA-DR were considered M1 macrophages. HCC, hepatocellular carcinoma; IIR, independent imaging review; mRECIST, modified Response Evaluation Criteria in Solid Tumors; NK, natural killer; NR, non-response; PD, progressive disease; PD-1, programmed cell death protein-1; PR, partial response; R, response; SD, stable disease; HLA-DR, human leukocyte antigen DR.