Oncology · Medical Literature
Safety and efficacy of fecal microbiota transplantation in solid cancers resistant to immune checkpoint inhibitors: results of the MITRIC trial.
Abstract
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. 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. 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. 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. NCT05286294.
Clinical relevance
In patients with advanced solid cancers that have progressed on immune checkpoint inhibitors (ICIs), is fecal microbiota transplantation (FMT) from long-term ICI responders — administered in combination with continued ICI therapy — safe, feasible, and associated with meaningful clinical activity? __SNAPSHOT__ {"studyDesign":"Single-arm phase IIa basket trial (MITRIC; NCT05286294)","setting":"Not reported (multi-institutional presumed given basket design; country not specified in abstract)","sampleSize":"n=12 (single arm; no comparator)","population":"Patients with ICI-refractory advanced solid cancers: melanoma (n=9), head and neck squamous cell carcinoma (HNSCC; n=1), renal cell carcinoma (n=1), and microsatellite instability-high (MSI-H) pancreatic cancer (n=1)","intervention":"FMT derived from long-term ICI responders, delivered by colonoscopy (two administrations before first radiological evaluation at 6 weeks) plus up to three additional FMTs by enema; administered in combination with continued ICI therapy","comparator":"Not applicable (single-arm study)","primaryOutcome":"Co-primary endpoints: (1) FMT-related adverse events (safety); (2) objective response rate (ORR)","followUp":"Minimum radiological evaluation at 6 weeks; one patient reported alive at 33 months; overall follow-up duration not formally reported","fundingSource":"Not reported; competing interests disclosed include prior research support from Bristol Myers Squibb, F. Hoffmann-La Roche, NanoString, NEC OncoImmunity, Biogen, Amgen, Roche, and Novartis among named investigators"}
Key findings
Among 12 enrolled patients with ICI-refractory solid cancers, no objective responses (partial or complete) were observed, yielding an ORR of 0% (0/12). Stable disease was recorded in 5/12 patients (42%; calculated). Formal clinical benefit per protocol — defined as stable disease exceeding 6 months — was achieved in 1/12 patients (8%; calculated), a melanoma patient who also demonstrated regression of some lesions and remains alive at 33 months without further systemic therapy. Mixed responses (regression of some but not all lesions) were observed in two additional patients: one melanoma patient and the HNSCC patient. Median progression-free survival (PFS) was 1.5 months; median overall survival (OS) was 10.1 months. No absolute effect sizes, hazard ratios, confidence intervals, or p-values are reported in the abstract. FMT was well tolerated from a procedure-related standpoint; however, immune-related adverse events (irAEs) occurred in 6/12 patients (50%; calculated). All 12 patients received the first FMT; 10/12 (83%; calculated) completed the second colonoscopic FMT. Fecal sequencing demonstrated donor microbiome engraftment after the first FMT in most patients. NNT and NNH are not calculable given the absence of a comparator arm.
Practice implications
The MITRIC trial establishes that colonoscopic FMT from ICI responders is procedurally safe and feasible in patients with ICI-refractory advanced solid cancers, with all enrolled patients able to receive at least one FMT and 83% completing the scheduled second colonoscopic administration. However, the study did not demonstrate meaningful tumor-level clinical activity: the ORR was 0%, and the median PFS of 1.5 months is consistent with progressive disease and natural history of ICI-refractory malignancy rather than a treatment benefit. The one patient with durable clinical benefit (alive at 33 months) and two patients with mixed responses are intriguing but must be interpreted with extreme caution given the very small, heterogeneous, non-randomized cohort. The 50% rate of irAEs, although not clearly attributed solely to FMT in the abstract, warrants close monitoring in future studies. Engraftment was confirmed in most patients, indicating that biological delivery was achieved even when clinical response was not. The study is heavily enriched for melanoma (75% of patients), limiting generalizability to other cancer types. Patients with MSI-H pancreatic cancer (n=1), HNSCC (n=1), and RCC (n=1) are too few to draw any tumor-type-specific conclusions. This summary is based on the published abstract only; the full manuscript may contain additional outcome data, confidence intervals, toxicity grading, and biomarker analyses not available here. __LIMITATIONS__ Critically small sample size (n=12) with no statistical power to evaluate efficacy; the study is hypothesis-generating only.,Single-arm design with no concurrent comparator; it is impossible to distinguish treatment effect from natural disease course or spontaneous fluctuation.,Marked tumor-type heterogeneity (basket design) prevents tumor-specific efficacy conclusions.,Melanoma overrepresentation (9/12 patients) limits generalizability to other solid tumors.,Absence of reported confidence intervals, hazard ratios, or p-values for any efficacy endpoint in the abstract.,ICI continuation alongside FMT confounds attribution of any clinical signal to FMT specifically.,Donor selection criteria (long-term ICI responders) are not standardized and may introduce variability in microbiome composition between FMT preparations.,Short median PFS (1.5 months) suggests most patients progressed rapidly; formal follow-up duration is not reported.,Feasibility of engraftment does not establish therapeutic relevance; mechanistic biomarker data not fully reported in abstract.,Potential conflicts of interest from investigator ties to multiple pharmaceutical companies, though funding source is not formally disclosed.,Only the abstract is available for this review; full-text data may substantially alter interpretation. __BOTTOM_LINE_CATEGORY__ not_ready_for_clinical_application __BOTTOM_LINE__ The MITRIC trial demonstrates that FMT from ICI responders is procedurally safe and can achieve donor microbiome engraftment in ICI-refractory solid cancer patients, but yielded no objective tumor responses and a median PFS of only 1.5 months, indicating no meaningful efficacy signal in this setting. Immune-related adverse events occurred in half of patients, underscoring the need for careful safety monitoring. FMT for ICI-refractory solid cancers should not be adopted into clinical practice outside of clinical trials; larger randomized studies with refined patient selection and donor criteria are needed before any efficacy conclusions can be drawn.