Introduction
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several epithelial cancers, but can lead to significant immune-related adverse events (irAEs), often requiring interruption or permanent discontinuation of ICIs, with a consequent higher risk of disease progression and worse survival outcomes. GI toxicity is the second most common irAE, diarrhea and colitis being the predominant manifestations and high-dose corticosteroids and immunosuppressive biologic drugs being the main treatment. Thus, they may compromise the antitumor efficacy of ICIs and potentially accelerate disease progression, making the search for safer and more effective therapies an urgent and unmet clinical need.
Microbiome disruption can lead to excessive immune activation and mucosal inflammation during ICI therapy, and its restoration by fecal microbiota transplantation (FMT) may represent a novel approach to manage irAEs. FMT has been preliminarily explored in refractory ICI-induced colitis, with promising results deriving from small case series.
Here we present the first European cohort of patients with refractory ICI-induced colitis treated with FMT as salvage therapy.
Aims & Methods
This is a multi-centre retrospective observational cohort study, aimed to evaluate the efficacy of FMT in the treatment of ICI-colitis unresponsive to immunosuppressive drugs. Patients were enrolled in seven European FMT referral centers (Croatia, France, Italy, Spain, The Netherlands). Patients underwent single or multiple FMTs and were followed-up to until 24 weeks. Clinical, laboratoristic and endoscopic data were collected at baseline and at different post-FMT timepoints.
Results
30 patients were enrolled (Italy n=8; the Netherlands n=8; Spain n=6; Croatia n=5; France n=3), of whom 17 males (56%) with a median age of 60 years. Most patients had melanoma (43%), non-small-cell lung cancer (33%), and renal cell carcinoma (13%), with 27 patients having a metastatic disease. 20 patients received PD-1 inhibitors or PD-L1 inhibitors as monotherapy, while 10 were treated with a combination of PD-1 inhibitors with either CTLA-4 or LAG-3 inhibitors.
Most patients presented with a grade (G) 3 (n= 18, 60%) or G4 (n= 9, 30%) colitis, while only three (10%) experienced a G2 colitis. At baseline, median fecal calprotectin at baseline was 1800 mg/g, median C-reactive protein (CRP) was 27.5 mg/l, and median white blood cells count (WBC) was 9.1 cells/μl. All patients presented with an ulcerative colitis-like endoscopic picture at baseline, 67% of them having a severe endoscopic picture.
Over a 24-week follow-up, up to 81% of patients achieved a complete clinical response, and up to 87% experienced a clinical amelioration, with only mild AEs.
Nine patients died for cancer progression or opportunistic pneumonia, which might be both related to the sustained use of immunosuppressants.
Median fecal calprotectin after FMT, available for 30% of patients, was 440 mg/g at 4-week follow-up (p=0.0008) and 21 mg/g at 12-week follow-up (p<0.0001). Also, at 12-weeks post-FMT median CRP reduced to 4 mg/l (p= 0.0054) and WBC to 6 cells/μl (p= 0.016), respectively available for 27% and 23% of patients.
Moreover, baseline severe endoscopic picture was significantly associated with complete clinical response at 8 weeks (OR 0.07, 95% CI 0.003–0.69), while recent antibiotic exposure emerged as an independent predictor of FMT failure (OR 11.62, 95% CI 1.03–425.9).
Conclusion
Our findings support FMT as an effective option for refractory ICI-induced colitis and the investigation of its earlier use to avoid prolonged immunosuppression.
References
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- Porcari S, Ciccarese C, Heidrich V, et al. Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial. Nat Med. Published online January 28, 2026:1-9. doi:10.1038/s41591-025-04189-2.
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Disclosure
The Authors have no conflicts of interest to disclose.
