A preferable signature of gut microbiota and bile acids predicted better outcomes of unresectable hepatocellular carcinoma to immune checkpoint inhibitors

early-stage HCC.The primary safety analysis assessed treatmentrelated adverse events (trAE) and delays to surgery.Secondary end point included overall response rates (ORR) by RECIST v1.1 and pathologic responses on resection specimens.Results: At data censoring on the 4th of November 2021, 12 patients were enrolled, of whom 83% (n = 10) were male, with a median age of 65 years (range 47-70).Liver cirrhosis was found in 75% (n = 9) of the patients, and the most frequent aetiology was viral hepatitis (50%, n = 4 with HCV and n = 2 with HBV infection).All patients were Child-Pugh A, with 58% classified as albumin-bilirubin (ALBI) grade 1. Median tumour diameter was 3.4 cm (interquartile range [IQR] 1.4, range 1.1-7.3),and the median number of liver nodules was 1 (IQR 1, range 1-3).Median baseline AFP was 6 mcg/L (IQR 115, range 2-11'777).Any-grade trAEs were reported by 75% of the patients (n = 9).Four patients (33%) reported grade 2 trAEs including hypothyroidism (n = 2), diarrhoea (n = 1), and fatigue (n = 1), and one (8%) grade 3 ALT/ ASTelevation.After a median follow-up of 9.1 months (IQR 19.1, range 2.5-24.9),no deaths had occurred, and one disease relapse was recorded 20.8 months after treatment commencement.Median time to LR from screening was 2.5 months (IQR 0.9, range 2.2-3.6).One patient had a surgery delay due to liver function worsening (ICPIunrelated) and remained progression-free by RECIST 9.6 months post-screening.In another patient LR was switched to radiofrequency ablation by the treating surgeon due to surgical risk independent of ICPI exposure.One patient was found to have cholangiocarcinoma (CCA) on LR specimen and was excluded from efficacy analyses.ORR was 18%, with two partial responses.Disease control rate was 91%, and one patient with mixed HCC/CCA histology showed primary progression.Of the nine pathologically evaluable patients, seven (78%) achieved a pathological response, including two (22%) complete responses.Conclusion: Neoadjuvant immunotherapy with nivolumab plus ipilimumab is tolerable and is characterised by evidence of antitumour efficacy in early-stage HCC.