FMT combined with atezolizumab-bevacizumab in hepatocellular carcinoma refractory to immunotherapy: an open label, single-arm, phase II pilot study

Abstract Fecal microbiota transplantation (FMT) may help to overcome resistance to immunotherapy. In this single-center, single-arm phase II hypothesis-generating pilot study (FAB-HCC), we included 12 patients with advanced hepatocellular carcinoma (HCC) who progressed on atezolizumab plus bevacizumab. Patients received a single FMT via colonoscopy from a donor with HCC who responded to anti-PD-1 treatment or a healthy donor, combined with atezolizumab plus bevacizumab. The primary endpoint was safety as measured by incidence and severity of treatment-related adverse events (TRAEs). Secondary endpoints included radiological response and survival. Grade 3-4 TRAEs included arterial hypertension ( n = 5) and proteinuria ( n = 3), both related to bevacizumab, and diarrhea ( n = 1), related to FMT. No serious TRAEs were observed. Objective response rate was 33% ( n = 4/12) and median progression-free survival was 6.9 (95%CI, 3.0-10.8) months. Following FMT, recipient microbiome composition appeared more similar to that of the donor, and healthy donor FMT seemed to be associated with higher engraftment. FMT appeared to be associated with enrichment of response-associated and loss of deleterious gut bacteria. Circulating PD-1 + CD8 + T cells decreased and CD32b + CD14 high CD16 low monocytes increased following FMT plus immunotherapy. Phage-display immunoprecipitation sequencing revealed that antibody repertoire stability, rather than global diversity or composition, changed over time. Taken together, FMT combined with atezolizumab plus bevacizumab was safe and associated with a high response rate in patients with atezolizumab plus bevacizumab-refractory HCC. Given the limited sample size, these findings need cautious interpretation and confirmation in larger, adequately powered trials. ClinicalTrials.gov identifier: NCT05750030.