The randomized, double-blind, placebo-controlled phase 2a TACITO trial has shown that fecal microbiota transplantation (FMT) from complete immune checkpoint inhibitor (ICI) responders may improve outcomes in treatment-naïve patients with metastatic renal cell carcinoma (mRCC) receiving first-line pembrolizumab plus axitinib.
The investigator-initiated study enrolled patients with histologically confirmed metastatic RCC eligible for pembrolizumab + axitinib. Patients were randomized 1:1 to receive donor FMT (d-FMT) or placebo FMT (p-FMT) three times over six months (initial colonoscopy, followed by capsules at weeks 12 and 24). FMT donors were two patients with long-term complete response to ICI therapy.
The primary endpoint—proportion of patients progression-free at 12 months—was numerically higher with d-FMT (70%) than p-FMT (41%) but did not reach statistical significance (P = 0.053). However, median progression-free survival (PFS) was significantly longer in the d-FMT arm (24.0 months, 95% CI 8.0–40.0) compared to p-FMT (9.0 months, 95% CI 2.2–15.2; hazard ratio 0.50, P = 0.035). Median overall survival was numerically longer with d-FMT (41.0 months vs. 28.3 months; hazard ratio 0.36, P = 0.167). Objective response rate was 52% in the d-FMT arm versus 32% in the p-FMT arm.
Microbiome analysis (n = 246 patient samples, high-depth metagenomic sequencing) confirmed donor strain engraftment in the d-FMT group, with increased Shannon α-diversity and species richness at multiple timepoints (weeks 1, 4, 12, 24), larger β-diversity shifts from baseline, and higher acquisition of new species compared to p-FMT. While total engraftment was not linked to the primary endpoint, greater loss of baseline species early after FMT (weeks 1 and 4) showed a trend toward association with 12-month PFS in the d-FMT arm.
Safety was favorable: FMT-related adverse events were rare and mild (one grade 2 diarrhea after colonoscopy). No serious FMT-related adverse events, infections, or deaths occurred. Grade 3+ adverse events related to pembrolizumab/axitinib were comparable between arms.
The trial (ClinicalTrials.gov NCT04758507) supports the safety and potential efficacy of selected donor FMT to augment ICI-based therapy in mRCC. The findings warrant further investigation in larger studies.
The results were published open access in Nature Medicine on January 28, 2026 (doi:10.1038/s41591-025-03500-0). Lead authors include Serena Porcari, Chiara Ciccarese, and Gianluca Ianiro.
