Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial
Menés respectivement sur 21 et 27 patients atteints d'un carcinome hépatocellulaire résécable, ces deux essais de phase II évaluent l'efficacité, du point de vue du taux de nécrose tumorale et du taux de réponse, et la toxicité de deux stratégies de traitement néoadjuvant, l'une à base de cémiplimab (un anti-PD-1) et l'autre à base de nivolumab, dispensé en monothérapie ou en combinaison avec l'ipilimumab
Background : Hepatocellular carcinoma has high recurrence rates after surgery; however, there areno approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy hasbeen shown to improve survival in advanced hepatocellular carcinoma; we thereforeaimed to evaluate the safety and tolerability of perioperative immunotherapy in resectablehepatocellular carcinoma. Methods : In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumabintravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followedin the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years,or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery)plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperativedose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenouslyevery 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeksfor up to four cycles. Patients were randomly assigned to the treatment groups byuse of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. Findings : Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3–4 adverse eventswere higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumabalone (three [23%] of 13). The most common treatment-related adverse events of anygrade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartateaminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade3 or worse adverse events. Seven of 27 patients had surgical cancellations, but nonewas due to treatment-related adverse events. Estimated median progression-free survivalwas 9·4 months (95% CI 1·47–not estimable [NE]) with nivolumab and 19·53 months (2·33–NE)with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31–2·54); mediantime to progression was 9·4 months (95% CI 1·47–NE) in the nivolumab group and 19·53months (2·33–NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31–2·54).In an exploratory analysis, three (23%) of 13 patients had an overall response withnivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) ofnine patients had a major pathological response (ie, ≥70% necrosis in the resectedtumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumabplus ipilimumab. Interpretation : Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe andfeasible in patients with resectable hepatocellular carcinoma. Our findings supportfurther studies of immunotherapy in the perioperative setting in hepatocellular carcinoma.