Early Data Shows Neoadjuvant Nivolumab Potentializes Electroporation in HCC


Neoadjuvant nivolumab shrank tumors in 29% of patients with hepatocellular carcinoma at high risk for recurrence, which may kickstart the ablation effect of electroporation.

Pierre Nahon, MD, PhD

Pierre Nahon, MD, PhD

Neoadjuvant nivolumab (Opdivo) shrank tumors in 29% of patients with hepatocellular carcinoma (HCC) at high risk for recurrence, which may kickstart the ablation effect of electroporation (EP), according to preliminary findings from the phase 2 NIVOLEP trial presented at the 2020 International Liver Cancer Association Virtual Meeting.1

Percutaneous ablation remains the only nonsurgical curative treatment for patients with HCC. During the past 20 years, advancements in the procedure has allowed physicians to offer the technique to more patients. However, many patients remain ineligible for thermal ablation techniques due to hazardous tumor location or severe comorbidities. The most recent development, irreversible EP, is a predominantly nonthermal ablative technology that induces apoptosis using high-voltage, low-energy DC current pulses, said Pierre Nahon, MD, PhD, during his presentation.2,3

Investigators of the NIVOLEP trial (NCT03630640) set out to optimize the efficacy of EP in patients with HCC using nivolumab as neoadjuvant therapy. The first 20 patients enrolled to the study were included in the preliminary neoadjuvant phase response data. Patients received 2 infusions of nivolumab and underwent radiological or pathological evaluations, or both, at baseline, following neoadjuvant treatment. Investigators identified a total of 37 HCC nodules; the mean size of largest nodule was 31.4 mm.1

Radiological reduction was observed in 11 (29%) nodules and 25 (68%) nodules were stable, defined as no change in size, following neoadjuvant treatment. Further, the results showed that all patients received neoadjuvant nivolumab without experiencing serious adverse events (AEs) and 19 patients went on to receive successful curative EP without delay.1

“The preliminary analysis of [data] from the neoadjuvant phase shows that there is active recruitment of CD8+ lymphocytes within the tumor and macroenvironment which may potentialize the ablation effect,” said Nahon, an associate professor in hepatology at University Paris 13, in France. “We also observed potential antitumor activity with reduction in size and/or HCC necrosis before ablation.”

In case analysis of 1 patient, Nahon explained that pathologic analysis following treatment with nivolumab showed near-complete necrosis of the tumor with major infiltration by polymorphonuclear, lymphocyte, and foam cells associated with extensive fibrosis. “These histological features suggest almost complete tumor regression,” Nahon added.

Seventeen nodules were assessed for both radiological and pathological modification. Of those, 3 (17%) demonstrated a tumor response pattern and 4 (23%) had an isolated increase of pertitumoral and intratumoral infiltrating lymphocytes. In total, 9 patients (53%) had either radiological or pathological modification following nivolumab infusion. One patient experienced progression.

“Induced radiological and pathological changes were reported in a substantial number of patients—nearly half of this small sample size. This suggests that neoadjuvant nivolumab may have antitumoral or immunomodulation effect in these patients, which will be correlated with their outcomes,” said Nahon.

Investigators initiated NIVOLEP to evaluate the combination of neoadjuvant or adjuvant biotherapy with EP in patients with Barcelona clinic liver cancer stage A HCC. The primary end point is recurrence-free survival (RFS) at 2 years. Target enrollment is 50 patients across 6 medical centers in France. Patients will receive 2 doses of neoadjuvant nivolumab followed by EP, then 12 monthly doses of adjuvant nivolumab for 1 year. Follow-up will occur every 3 months during the subsequent year.

Navigating Prior Efficacy Data

EP is particularly valuable for patients whose liver tumors are not accessible for surgery or who are contraindicated for surgery, and for patients with very early HCC or very small tumors.4

In 2017, Sutter et al, published results from a retrospective study of the safety and efficacy of EP in patients with HCC who were not candidates for surgery and were ineligible for thermal ablative techniques. In total 75 tumors, were completely ablated. Specifically, 58, 67, and 69 were completely ablated tumors were ablated following 1, 2, and 3 EP procedures, respectively. At a median follow-up of 9 months the 6- and 12-month overall local tumor PFS rates were 87% (95% CI, 77%-93%) and 70% (95% CI, 56%-81%), respectively.3

“What was observed was that 48 hours after the ablation, something happens in the nontumoral liver, it corresponds to systemic effects and immunogenity change, which are far more increased in electroporation compared with radiofrequency ablation with an influx of inflammatory,” Nahon said of the study results from Sutter et al. The hypothesis to combine immunotherapy with EP for these difficult to treat patients, grew from this observation, Nahon said of the NIVOLEP study design.

The technique also holds potential for patients who present with comorbidities. Unlike thermal procedures, the collagenic skeleton and the microvessels of surrounding nontumourous tissue are spared using EP.5 Findings from a 2016 study of 55 patients with Child-Pugh B HCC showed that, compared with microwave ablation, those who received EP had shorter hospital stays and a lower 90-day readmission rate. Furthermore, EP was better tolerated and the 6-month success rates were nearly identical at 97% and 100%, respectively, making it a more suitable option for fragile patients.6


  1. Nahon P, Seror O, Oberti F, et al. Radiological and pathological response to neoadjuvant nivolumab in patients with BCLC A HCC treated by curative percutaneous irreversible electroporation: preliminary report from the French Multicentre phase 2 NIVOLEP Trial. Presented at: the 2020 International Liver Cancer Association Virtual Conference, September 11-13, 2020; virtual. Abstract 0-25.
  2. Neoadjuvant and adjuvant nivolumab in HCC patients treated by electroporation (NIVOLEP). ClinicalTrials.gov. Updated July 9, 2020. Accessed September 16, 2020. https://clinicaltrials.gov/ct2/show/NCT03630640
  3. Sutter O, Calvo J, N’Kontchou G, et al. Safety and efficacy of irreversible electroporation for the treatment of hepatocellular carcinoma not amenable to thermal ablation techniques: a retrospective single-center case series. Radiology. 2017;284(3):877-886. doi:10.1148/radiol.2017161413
  4. Tameez-Ud-Din A, Chaudhary FMD, Chaudhary NA, Siddiqui KH. Irreversible electroporation for liver tumors: a review of literature. Cureus. 2019;11(6):e4994. doi:10.7759/cureus.4994
  5. Nahon P, Vibert E, Nault JC, Ganne-Carrié N, Ziol M, Seror O. Optimizing curative management of hepatocellular carcinoma. Liver Int. 2020;40(suppl 1):109-115. doi:10.1111/liv.14345
  6. Bhutiani N, Philips P, Scoggins CR, et al. Evaluation of tolerability and efficacy of irreversible electroporation (IRE) in treatment of Child-Pugh B (7/8) hepatocellular carcinoma (HCC). HPB (Oxford). 2016;18(7):593-599. doi:10.1016/j.hpb.2016.03.609
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