TACITO: Fecal Microbiota Transplantation Improves Immunotherapy Response in Advanced Kidney Cancer

New evidence from the ​​phase 2a TACITO trial suggests fecal microbiota transplantation (FMT) improves the effectiveness of immunotherapy in patients with advanced metastatic renal cell carcinoma (mRCC) receiving pembrolizumab and axitinib.1

“Our working hypothesis was that transplanting a ‘favorable’ gut microbiota could enhance response to immunotherapy,” said principal study investigator Gianluca Ianiro, PhD, a tenure-track researcher in Digestive Diseases at Università Cattolica del Sacro Cuore and physician at the CEMAD of Fondazione Policlinico Gemelli IRCCS. “TACITO is the first randomized trial worldwide to compare immunotherapy outcomes following FMT from immunotherapy responders versus placebo.”2

Over the years, immunotherapy, specifically immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment across multiple disease denominations, including RCC. First-line therapy for this patient population is pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor monoclonal antibody combined with axitinib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor.1

In amalgamation, the 2 agents significantly improve survival, progression-free survival (PFS), and objective response rate (ORR) in patients with mRCC. However, these results are not sustained. Within 16 months, the majority of patients experience disease progression, with minimal second-line treatment options.1

Emerging support has posited a connection between gut microbiome composition and the efficacy of ICIs in epithelial tumors, including RCC. Patients with cancer who are receiving antibiotics, which are disruptive to the gut microbiome, have reported worse clinical response to ICIs. Additionally, certain microbial taxa and/or ecological communities have been associated with responses to ICIs in different epithelial cancers. Most compelling to TACITO study investigators, however, was evidence of the clinical benefit of FMI in ICI-refractory cancer mouse models.1

To expand clinical understanding, Ianiro and colleagues conducted a randomized, double-blind, placebo-controlled phase 2a TACITO study to evaluate whether FMT from complete ICI responders enhances clinical outcomes in treatment native patients with mRCC receiving pembrolizumab + axitinib.1

After conducting a baseline visit, investigators randomized patients in a 1 to 1 ratio to receive donor FMT (dFMT) or placebo 3 times in 6 months in the absence of disease progression. The median follow-up time was 32 months (interquartile range (IQR), 22–37 months).1

The primary endpoint was determined as the rate of patients free from disease progression at 12 months after randomization (12-month progression-free survival (PFS)). Secondary endpoints were median PFS and median overall survival, objective response rate (ORR), safety, and microbiome changes after randomization.1

The study included 45 patients with metastatic, histologically confirmed RCC who were eligible to receive pembrolizumab and axitinib as first-line therapy, and were divided between dFMT (n = 23) and placebo (n = 22).1

Upon analysis, 69% of patients (n = 33) experienced disease progression. Investigators observed PFS events in 61% of patients in the dFMT arm (n = 14) and 77% in the placebo group (n = 17). There was a significant improvement in median PFS in the dFMT arm (24.0 months) compared to placebo (9.0 months; 95% Confidence Interval [CI], 2.2–15.2 months; hazard ratio [HR], 0.50; 90% CI, 0.27–0.92; P = .035).1

There was an increased proportion of patients without disease progression or death 12 months post-randomization in the dFMT arm (16/23 patients; 70%) compared to placebo ( 9/22 patients; 41%; P = .053), which the authors pointed out supported their hypothesis for the primary efficacy outcome. After adjusting for established prognostic factors in mRCC, such as IMDC criteria and presence of liver metastases, investigators observed findings similar to those from the unadjusted analysis (HR, 0.48; 95% CI: 0.23–0.99; P = .048).1

By the data cutoff, 38% of patients (n = 17) died, 26% of the dFMT group, nad 50% of the placebo group. Median overall survival was increased in the dFMT group (41 months) compared to the placebo (28.3 months), but this was not significant (HR, 0.36; 95% CI, 0.13-0.99; P = .167).1

As for ORR, investigators reported a rate of 52% for dFMT (12/23 patients, 95% CI, 0.33–0.71) and 32% for placebo (7/22 patients; 95% CI, 0.14–0.55). They observed a complete response in 9% of the placebo group (n = 2), while there were no occurrences in those receiving dFMT.1

Upon safety analysis, which included 49 patients, experimental treatments were well tolerated. Only 1 patient in the p-FMT arm experienced a grade 3 treatment-related adverse event (TRAE), oral mucositis. Investigators reported no deaths related to experimental treatments or transmission of infectious agents after dFMT was observed.1

After treatments, investigators observed an increase in Shannon α-diversity versus baseline at week 1 (P = .05), week 4 (P < .001), week 12 (P = .02), and week 24 (P = .048) follow-ups, along with significantly increased species richness compared to baseline at week 4 follow-up (P = .001) in the dFMT group. Such a longitudinal increase in α-diversity was not observed in any of the follow-up timepoints of the placebo group, noted investigators.1

As both absolute α-diversity and β-diversity deviation from the baseline were increased in the dFMT arm compared with the placebo arm after treatments, investigators determined the preplanned microbiome-related secondary outcomes were achieved.1

“These results provide further evidence that the gut microbiota is a key modulator of immunotherapy response,” concluded Ianiro. “FMT from carefully selected donors may become an important complementary strategy to improve outcomes in metastatic renal cell carcinoma, likely by providing an immunological stimulus that enhances treatment response.”2

References

1. Fecal microbiota transplantation improves response to immunotherapy in advanced kidney cancer: TACITO study published in Nature Medicine. EurekAlert! Published January 28, 2026. Accessed February 2, 2026. https://www.eurekalert.org/news-releases/1114014

2. 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. Nature Medicine. Published online January 28, 2026. doi:https://doi.org/10.1038/s41591-025-04189-2

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