Fecal Microbiota Transplantation Shows Feasibility in Metastatic RCC

Selected donor fecal microbiota transplantation (FMT) may safely enhance the efficacy of immune checkpoint inhibition with pembrolizumab (Keytruda) and axitinib (Inlyta) for the treatment of patients with metastatic renal cell carcinoma (RCC), according to findings from the phase 2a TACITO trial (NCT04758507) published in Nature Medicine.¹

Efficacy data from the trial revealed that among patients treated with donor FMT (d-FMT; n = 23) vs placebo FMT (P-FMT; n = 22), the median progression-free survival (PFS) was 24.0 months (95% CI, 8.0-40.0) vs 9.0 months (95% CI, 2.2-15.2), respectively (HR, 0.50; 90% CI, 0.27-0.92; P = .035). Additionally, the median overall survival (OS) in the respective arms was 41.0 months vs 28.3 months, but the difference was not statistically significant (HR, 0.36; 95% CI, 0.13-0.99; P = .167).

The objective response rates (ORRs) in the d-FMT and p-FMT arms were 52% (95% CI, 33%-71%) vs 32% (95% CI, 0.14-0.55), respectively. Two (9%) complete responses (CRs) were observed in the p-FMT arm, as well as 5 (23%) partial responses (PRs); no CRs were observed with d-FMT, and 12 (52%) patients experienced a PR.

Following treatment, an increase in Shannon α-diversity was observed at weeks 1 (P = .05), 4 (P <.001), 12 (P = .02), and 24 (P = .048) in the d-FMT group, as well as in species richness by week 4 follow-up (P = .001). A higher number of species was also acquired after treatment in the d-FMT group (P < .006).

A post hoc analysis showed a more profound difference in median PFS between the d-FMT and p-FMT arms among those with intermediate- and poor-prognoses at 18.8 months vs 5.1 months (P = .033). Additionally, the ORR in the respective arms was 50% (95% CI, 28%-72%) vs 8% (95% CI, 0%-35%).

“[D]onor FMT was superior to placebo in significantly improving the median PFS, with a considerable difference in its duration… However, when evaluating the 12-month PFS (the primary outcome), the statistical difference between arms was only close to the pre-set significance threshold (70% vs 41% for d-FMT vs p-FMT, respectively, P = 0.053),” Serena Porcari, of the Department of Translational Medicine and Surgery at Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia in Rome, Italy, wrote in the publication with study coinvestigators. “The post hoc analysis of patients with intermediate or poor prognosis based on IMDC criteria showed stronger results of d-FMT compared with p-FMT.”

The investigator-initiated trial phase 2a clinical trial enrolled patients with histologically confirmed metastatic RCC and those eligible for immune checkpoint inhibitors or those who have started these agents within 8 weeks of study treatment. Patients were treated with capsulized FMT at approximately 12 and 24 weeks following initial treatment.

The median age in the d-FMT and p-FMT groups was 62 years (range, 47-75) vs 61 years (range, 41-79). Additionally, 74% vs 73% of each group were male, and 61% vs 59% received prior nephrectomy. The most common histology was clear cell carcinoma (91% vs 86%), most patients had an interval from nephrectomy to therapy of less than 1 year (56% vs 59%), and the most common site of metastasis was lung (74% vs 73%). Furthermore, 61% vs 45% of the respective groups had intermediate-prognosis disease.

The primary end point of the trial was 12-month PFS. Secondary end points included median PFS, median OS, and ORR in the full analysis set, in addition to safety and microbiome changes post-treatment. Two patients who experienced a CR to PD-1 inhibition with nivolumab (Opdivo) plus ipilimumab (Yervoy) or nivolumab alone were the donors of the study.

Of 49 patients included in the safety analysis, experimental treatments were generally well tolerated. Treatment-related adverse effects (TRAEs) were observed relatively infrequently. One patient experienced grade 2 diarrhea after colonoscopic p-FMT, but the event was self-limited and resolved in a few days. Additionally, 1 patient in the p-FMT arm experienced a grade 3 treatment-related oral mucositis event.

Grade 3 or higher AEs related to immune checkpoint inhibition occurred in 28% of patients in the d-FMT group vs 16% of the p-FMT group. Moreover, they led to treatment interruption in 8% and 6%, dose reductions in 12% and 12%, and dose discontinuation in 8% and 0% of the respective arms. No deaths related to treatment were observed on the trial.

References

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. doi:10.1038/s41591-025-04189-2