Neoadjuvant and adjuvant nivolumab associated with irreversible electroporation in patients with BCLC a hepatocellular carcinoma and high risk of recurrence (NIVOLEP trial)

Background: Irreversible electroporation (IRE) is a non-thermal ablation technique suited for difficult-to-treat hepatocellular carcinoma (HCC) with one-year local recurrence (LR) rates above 50% Objective: We hypothesized that peri-procedural immunotherapy could synergize with IRE to decrease local recurrence. Design: NIVOLEP is a multicenter phase 2 trial evaluating nivolumab combined with IRE in patients with BCLC A HCC. Patients received two neoadjuvant nivolumab infusions, IRE with curative intent, and 12 monthly adjuvant nivolumab infusions. Tumor biopsies were performed at baseline and during IRE. Primary endpoint was 1-year local recurrence-free survival (LRFS). Results: 62 HCC nodules (mean size: 30.0 mm) from 43 patients (mean age: 71 y, 88% male, 81% cirrhosis) were considered. All patients received neoadjuvant nivolumab, 35 underwent curative IRE (8 others: 4 IRE failures, 3 HCC progressions, 1 death). After neoadjuvant nivolumab, radiological or pathological response were observed in 24.2% and 26.3% nodules respectively. One-year LRFS was 70.6% (95% CI: 55.3 – 85.9), two-year overall survival was 74.2% in intention-to-treat analysis. Grade 3 or 4 adverse events related to nivolumab occurred in 2 patients, 1 patient died due to nivolumab. RNA sequencing analysis of tumor after neoadjuvant nivolumab showed an enrichment of pathways associated with leukocyte migration, T cell activation or CD8+ T and B cell infiltration associated with pathological response. Circulating protein variations were associated with pathological or radiological responses and local recurrence. Conclusion: Neoadjuvant and adjuvant nivolumab in BCLC A HCC patients eligible for IRE lead to pathological response related to immune activation and show anti-tumoral effect. ClinicalTrials.gov Identifier: NCT03630640