Highlights
The NIVOLEP trial represents a significant advancement in the multimodal treatment of hepatocellular carcinoma. Neoadjuvant and adjuvant nivolumab combined with irreversible electroporation achieved a one-year local recurrence-free survival rate of 70.6% in patients with BCLC A HCC at high risk of recurrence. Pathological response rates reached 26.3% following neoadjuvant immunotherapy, with RNA sequencing confirming robust immune activation within the tumor microenvironment. The combination approach demonstrates acceptable safety with grade 3-4 adverse events occurring in only 2 patients, though one treatment-related mortality was observed. These findings suggest that perioperative immunotherapy may enhance the efficacy of ablation-based treatment strategies in liver cancer.
Background
Hepatocellular carcinoma represents the sixth most common malignancy worldwide and the third leading cause of cancer-related mortality. Among patients with early-stage disease classified as BCLC A, those with high-risk features—such as large tumor size, multifocal lesions, or unfavorable anatomical locations—face substantially elevated rates of local recurrence following curative-intent treatments. Irreversible electroporation has emerged as a valuable non-thermal ablation technique particularly suited for treating hepatocellular carcinoma in challenging locations where thermal ablation poses risks to adjacent critical structures. Despite technical success with IRE, one-year local recurrence rates exceeding 50% have been documented in high-risk populations, highlighting a significant unmet clinical need.
The rationale for combining immunotherapy with ablation therapy stems from the observation that tumor destruction can release tumor-associated antigens and damage-associated molecular patterns, potentially creating an in-situ vaccine effect. Nivolumab, a fully human monoclonal antibody targeting programmed cell death protein 1, has demonstrated efficacy in advanced hepatocellular carcinoma. However, its role in the perioperative setting for early-stage disease, particularly in combination with local ablative therapies, remained unexplored. The NIVOLEP trial was designed to test the hypothesis that peri-procedural immunotherapy could synergize with IRE to reduce local recurrence through enhanced antitumor immune responses.
Study Design
NIVOLEP is a multicenter phase 2 clinical trial conducted across multiple French hepatology centers. The study enrolled patients with BCLC A hepatocellular carcinoma deemed appropriate for curative-intent irreversible electroporation. The treatment protocol consisted of a perioperative immunotherapy schedule: two neoadjuvant nivolumab infusions administered before ablation, followed by curative IRE, and subsequently twelve monthly adjuvant nivolumab infusions. Tumor biopsies were systematically obtained at baseline and during the IRE procedure to enable correlative science studies examining tumor biology and immune responses.
The primary endpoint was one-year local recurrence-free survival, defined as the interval from IRE to the first documented local recurrence or death from any cause. Secondary endpoints included pathological and radiological response rates following neoadjuvant therapy, overall survival, safety profile, and biomarker analyses. The intention-to-treat population included all enrolled patients, while a per-protocol analysis was performed for those completing the planned treatment course. RNA sequencing of tumor tissue and circulating protein analyses were conducted to identify molecular correlates of treatment response.
Study Population
The trial enrolled 43 patients (mean age: 71 years, 88% male) harboring 62 hepatocellular carcinoma nodules with a mean size of 30.0 millimeters. The majority of patients (81%) had underlying cirrhosis, reflecting the typical epidemiology of HCC in Western populations. All enrolled patients received at least one dose of neoadjuvant nivolumab. Among the cohort, 35 patients underwent curative IRE; the remaining eight patients did not receive ablation due to IRE procedural failures (4 patients), hepatocellular carcinoma progression (3 patients), or death prior to procedure (1 patient).
Results
Primary Endpoint: Local Recurrence-Free Survival
The NIVOLEP trial met its primary endpoint with a one-year local recurrence-free survival rate of 70.6% (95% confidence interval: 55.3% to 85.9%). This represents a meaningful improvement compared to historical controls receiving IRE monotherapy, where one-year recurrence rates typically exceed 50% in similar high-risk populations. The two-year overall survival rate reached 74.2% in the intention-to-treat analysis, suggesting that the combined approach provides durable disease control in a substantial proportion of patients.
Response Rates Following Neoadjuvant Immunotherapy
An important finding was the observed activity of neoadjuvant nivolumab administered alone, prior to ablation. Radiological response assessment after neoadjuvant immunotherapy demonstrated objective responses in 24.2% of nodules. More notably, pathological examination of tumors resected or biopsied at the time of IRE revealed a pathological response rate of 26.3%. This finding indicates that immunotherapy can induce tumor cell death even in the absence of direct tumor ablation, supporting the concept of systemic immune-mediated antitumor effects.
Immune Correlates and Biomarker Analysis
RNA sequencing performed on tumor tissue obtained after neoadjuvant nivolumab revealed significant transcriptional changes consistent with immune activation. Enriched pathways included leukocyte migration, T cell activation, and infiltration of CD8+ T lymphocytes and B cells. These immune signatures were specifically associated with pathological response, suggesting that tumors demonstrating pre-treatment immune susceptibility may be most likely to benefit from the combined approach. Circulating protein variations during treatment were also associated with both response and local recurrence outcomes, providing potential biomarkers for patient stratification.
Safety Profile
The combination of perioperative nivolumab with IRE demonstrated an acceptable safety profile. Grade 3 or 4 adverse events attributed to nivolumab occurred in 2 patients. Importantly, one patient death was considered related to nivolumab therapy, highlighting the need for careful patient selection and monitoring when implementing perioperative immunotherapy approaches. Overall, the treatment protocol was generally well-tolerated, with most adverse events manageable using standard protocols.
Expert Commentary
The NIVOLEP trial represents a pioneering effort to integrate immunotherapy into the curative treatment paradigm for hepatocellular carcinoma. The observed pathological response rate exceeding 25% following neoadjuvant nivolumab is particularly noteworthy, as it demonstrates that immune checkpoint inhibition can induce meaningful tumor regression in a substantial subset of patients with early-stage disease. This finding aligns with emerging data from neoadjuvant immunotherapy trials in other solid tumors, suggesting that the liver tumor microenvironment, despite its immunosuppressive nature, can be successfully activated to mount effective antitumor responses.
The correlative science findings provide mechanistic insights into treatment efficacy. The enrichment of T cell activation pathways and CD8+ lymphocyte infiltration in responding tumors suggests that neoadjuvant nivolumab primes the tumor microenvironment for enhanced immune surveillance. When combined with IRE, which may further amplify antigen release and immune activation, this multimodal approach creates multiple complementary mechanisms of tumor control.
Several limitations warrant consideration when interpreting these results. The single-arm design without a control group limits direct comparison with standard therapy, though historical data provides context. The sample size of 43 patients, while appropriate for a phase 2 study, precludes definitive conclusions about subgroup effects. The treatment-related mortality observed underscores the importance of careful patient counseling regarding risks. Additionally, the population was predominantly male and elderly, potentially limiting generalizability to broader demographics.
The integration of perioperative immunotherapy into hepatocellular carcinoma treatment algorithms represents a paradigm shift that requires careful implementation. Future studies should examine optimal sequencing and duration of adjuvant therapy, identify biomarkers for patient selection, and evaluate combination approaches incorporating additional immunomodulatory agents or locoregional therapies.
Conclusion
The NIVOLEP phase 2 trial demonstrates that perioperative nivolumab combined with irreversible electroporation achieves promising local control rates in BCLC A hepatocellular carcinoma patients with high-risk features. The one-year local recurrence-free survival of 70.6% and pathological response rate of 26.3% suggest meaningful clinical activity. Immune correlates indicate that neoadjuvant immunotherapy primes the tumor microenvironment, creating a biological rationale for the multimodal approach. While the treatment appears generally tolerable, the observed mortality underscores the need for careful patient monitoring. These findings warrant further investigation in larger randomized trials to definitively establish the role of perioperative immunotherapy in hepatocellular carcinoma management.
Funding
This work was supported by Bristol-Myers Squibb. The study was conducted as an investigator-initiated trial with academic coordination.
ClinicalTrials.gov Identifier
NCT03630640
References
Nahon P, Ziol M, Pan L, Portal JJ, Oberti F, Aube C, Blanc JF, Trillaud H, Merle P, Rode A, Assenat E, Guiu B, Lequoy M, Cornelis F, Bouattour M, Talib Z, Tibi A, Zeng Q, Bouda Y, Ganne-Carrié N, Sutter O, Sutton A, Guyot E, Barget N, Zucman-Rossi J, Campani C, Bamba-Funck J, Calderaro J, Nault JC, Vicaut E, Seror O. Neoadjuvant and adjuvant nivolumab associated with irreversible electroporation in patients with BCLC a hepatocellular carcinoma and high risk of recurrence (NIVOLEP trial). Hepatology (Baltimore, Md.). 2026-04-08. PMID: 41950497.