Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial

New insights into checkpoint inhibitor immunotherapy and its combined therapies in hepatocellular carcinoma: from mechanisms to clinical trials

“…Taken together, this treatment received accelerated approval in USA. Similar results were obtained in another study (ClinicalTrials.gov identifier NCT03222076) 152 . Researchers found that nivolumab plus ipilimumab could also be used during perioperative period for resectable HCC.…”

Neoadjuvant Immunotherapy for Hepatocellular Carcinoma

“…Also similar to the previous study, an enrichment in B cells and plasma cells was seen among responders, recapitulating findings from many studies in the advanced setting which have seen a correlation between the presence of B cells and response to checkpoint blockade. 15 …”

“…While the trial with cabozantinib was for patients who were deemed poor resection candidates at presentation, two window-of-opportunity trials for patients deemed resection candidates up-front were recently reported that showed promising pathologic and immunological response to more brief interventions. 14 , 15 One trial treated patients with two doses of the anti-PD-1 antibody cemiplimab, administered 3 weeks apart, followed by surgery as soon as 22 days following the initiation of immunotherapy; all patients underwent pre-treatment biopsies and regular blood collection, and following surgery patients received an additional 8 cycles of adjuvant therapy. 14 Notably this trial mandated that patients be up-front surgical candidates; though these were not small isolated lesions, 62% were BCLC-A while the remainder had multifocal disease or other high-risk features.…”

“…While this is a small cohort, these data suggest that PD-1 monotherapy may benefit only patients who have pre-existing immune infiltrate, while patients with “cold” tumors may stand to benefit from the more toxic combination with ipilimumab. 15 This is notable given the data supporting the potential of CTLA-4 blockade to induce de novo T cell clones. 19 Beyond PD-1 and CTLA-4 blockade, there are numerous trials looking at other combinations, including combination therapies often used in the metastatic setting, incorporating antibodies or TKIs targeting VEGF, and novel combinations of PD-1 and targets such as LAG-3 which have shown synergistic efficacy in melanoma ( Table 1 ).…”

Trial Designs for Integrating Novel Therapeutics into the Management of Intermediate-Stage Hepatocellular Carcinoma

“…Kaseb et al reported the first neoadjuvant ICI-based therapy for HCC ( Table 5 ). 122 Patients with resectable HCC were randomized to pre-operative nivolumab monotherapy (240 mg every 2 weeks for up to 3 doses) or the same dosage of nivolumab plus ipilimumab 1 mg/kg concurrent with the first dose of nivolumab. Subjects in the nivolumab monotherapy group received adjuvant nivolumab, 480 mg every 4 weeks for up to 2 years, and subjects in the nivolumab plus ipilimumab group received adjuvant nivolumab, 480 mg every 4 weeks for up to 2 years plus ipilimumab 1 mg/kg every 6 weeks for up to 4 doses.…”