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Background Fecal microbiota transplantation (FMT) has shown promise in overcoming resistance to immune checkpoint inhibitors (ICIs) in early-phase cancer trials. We investigated the safety, feasibility and efficacy of FMT from ICI responders to patients with advanced cancers progressing on ICIs.Methods This was a single-arm phase IIa basket trial (MITRIC; NCT05286294) including patients with ICI-refractory cancer. Long-term ICI responders were used as FMT donors. Patients received FMTs in combination with ICIs; two FMT administrations (by colonoscopy) were scheduled before the first radiological evaluation after 6 weeks, and up to three later FMTs were allowed (by enema). Co-primary endpoints were the evaluation of FMT-related adverse events and objective response rate. Feasibility, clinical benefit rate, progression-free survival (PFS), overall survival (OS), implant engraftment, immune response and biomarkers were among the secondary objectives.Results The study enrolled 12 patients with melanoma (n=9), head and neck squamous cell carcinoma (HNSCC; n=1), renal cell carcinoma (n=1) or microsatellite instability-high pancreatic cancer (n=1). FMT was well tolerated, whereas immune-related toxicity occurred in 6/12 patients. All patients received the first FMT; 10/12 patients also underwent the second FMT. No objective responses were observed, while 5/12 patients recorded stable disease. Clinical benefit per-protocol (stable disease >6 months) was achieved in a patient with melanoma, who had regression of some lesions and remains alive after 33 months without further systemic treatment. Mixed responses with regression of some lesions were observed in another melanoma patient, and in a patient with HNSCC. The median PFS was 1.5 months, and median OS was 10.1 months. Sequencing of fecal samples indicated engraftment after the first FMT in most patients. Mass cytometry analysis of peripheral blood cells suggested that an activated and differentiated T-cell signature was associated with improved PFS and OS, while a naïve T-cell phenotype and a myeloid-dominant environment were unfavorable. CD14 + monocytes and serum interleukin-8 increased at group level over time.Conclusion FMT in combination with ICIs was safe and feasible in patients with advanced cancers, but with limited clinical activity. Further studies are required to clarify the potential benefit of FMT, identify the appropriate patient population and define criteria for donor selection.Trial registration number NCT05286294.