In patients with resectable hepatocellular carcinoma, perioperative nivolumab alone and nivolumab plus ipilimumab appear to be safe and effective, according to a single-center, open-label, phase 2 study (ClinicalTrials.gov Identifier: NCT03222076) published in The Lancet Gastroenterology & Hepatology.
While immune checkpoint therapy with blockade of the PD-1–PD-L1 and CTLA-4 pathways has shown improvement in clinical outcomes in advanced hepatocellular carcinoma, it has not been studied in early-stage hepatocellular carcinoma. Studies in other cancer types have shown that a major pathological response with immune checkpoint therapy improves survival outcomes in the postoperative period.
Researchers investigated the safety and efficacy of immunotherapy with anti-PD1 antibody nivolumab both alone or in combination with anti-CTLA-4 antibody ipilimumab in 27 patients with resectable hepatocellular carcinoma. Secondary outcomes included rates of overall response, progression-free survival, and time to progression.
Overall, 13 patients were included in the nivolumab alone group and 14 patients in the nivolumab plus ipilimumab group. Median participant age in both groups was 64 years; most patients were men. Roughly 50% of patients had a history of viral hepatitis.
Investigators found that both nivolumab monotherapy and nivolumab plus ipilimumab combination therapy were safe and well tolerated, and that immune checkpoint blockade induced a major pathological response in 30% of patients who underwent resection. Although no recurrences were noted among these patients after a median follow-up of 2 years, recurrence was noted in 50% of patients who did not have a major pathological response.
The researchers noted a greater percentage of T cells and B cells and an increased CD8+ T-cell/regulatory T-cell cell ratio in the tumor microenvironment of patients who had a major pathological response compared with those who did not.
Adverse events (AEs) of grades 3 or 4 occurred more frequently in the nivolumab plus ipilimumab group (6/14 patients; 43%) compared with the nivolumab alone group (3/13 patients; 23%). The most commonly occurring AEs included increased levels of both alanine aminotransferase and aspartate aminotransferase (23% of patients in the nivolumab alone group vs 50% of patients in the nivolumab plus ipilimumab group for both AEs, respectively).
Investigators acknowledge this study was limited by its single-center design and small sample size. Both selection and measurement bias may have been present due to lack of compliance and loss to follow-up.
“Our results suggest that combination therapy with nivolumab with or without ipilimumab in the perioperative setting was safe for patients with resectable hepatocellular carcinoma and induced a pathological response,” researchers concluded. “These findings have important implications for the design of future clinical trials and could improve outcomes for patients with resectable hepatocellular carcinoma.”
Disclosure: This research was supported by Bristol Myers Squibb and the US National Institutes of Health. Please see the original reference for a full list of disclosures.
Kaseb AO, Hasanov E, Tran Cao HS, et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2022;7(3):208-218. doi: 10.1016/S2468-1253(21)00427-1