Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma

Abstract

Diarrhoea is one of the most burdensome and common adverse events of chemotherapeutics, and has no standardised therapy to date. Increasing evidence suggests that the gut microbiome can influence the development of chemotherapy-induced diarrhoea. Here we report findings from a randomised clinical trial of faecal microbiota transplantation (FMT) to treat diarrhoea induced by tyrosine kinase inhibitors (TKI) in patients with metastatic renal cell carcinoma (ClinicalTrials.gov number: NCT04040712). The primary outcome is the resolution of diarrhoea four weeks after the end of treatments. Twenty patients are randomised to receive FMT from healthy donors or placebo FMT (vehicle only). Donor FMT is more effective than placebo FMT in treating TKI-induced diarrhoea, and a successful engraftment is observed in subjects receiving donor faeces. No serious adverse events are observed in both treatment arms. The trial meets pre-specified endpoints. Our findings suggest that the therapeutic manipulation of gut microbiota may become a promising treatment option to manage TKI-dependent diarrhoea.

Conflict of interest statement

A.G. reports personal fees for consultancy for Eisai S.r.l., 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, Sinergie S.r.l. Board MRGE and Sanofi S.p.A, personal fees for acting as a speaker for Takeda S.p.A, AbbVie and Sandoz S.p.A and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. G.I. has received personal fees for acting as speaker for Biocodex, Danone, Metagenics, and for acting as consultant/advisor for Ferring Therapeutics, Giuliani, Metagenics. None of the other authors has any competing interest to disclose.

Figures

Fig. 1. Study design and summary of clinical results.

a Study design: after baseline clinical and microbiome assessments, patients were randomised to receive either donor faecal microbiota transplantation (D-FMT) or placebo FMT (P-FMT). Then, all patients were followed up to 8 weeks (follow-up visits at 1, 2, 4 and 8 weeks after treatments). b Summary of clinical results: D-FMT was significantly more effective than P-FMT in achieving the complete resolution of TKI-induced diarrhoea at 1 week (n = 10 vs n = 3, 100% vs 30%, p = 0.02), 2 weeks (n = 9 vs n = 0, 90% vs 0%, p = 0.0007), 4 weeks (primary outcome, n = 7 vs n = 0, 70% vs 0%, p = 0.003), but not at 8 weeks of follow-up (n = 3 vs n = 0, 30% vs 0%, p = 1), consistently with the single FMT infusion approach of the study. Nonetheless, the benefit of D-FMT over P-FMT in decreasing diarrhoea up to G1 grade or lower remained significant for the whole follow-up period, including 1 week (n = 10 vs n = 3, 100% vs 30%, p = 0.02), 2 weeks (n = 10 vs n = 2, 100% vs 20%, p = 0.005), 4 weeks (n = 10 vs n = 2, 100% vs 20%, p = 0.005) and 8 weeks (n = 8 vs n = 1, 80% vs 10%, p = 0.04) after the end of treatments. Differences in cure percentages were determined with Fisher’s exact test (with two-tailed p values). The Bonferroni adjustment was applied for multiple secondary outcomes.

Fig. 2. Long-term donor microbial strain engraftment in mRCC patients receiving D-FMT.

We evaluated the effect of D-FMT in patients by assessing how much the overall microbiome got closer to that of the donor after FMT using a pairwise Bray-Curtis distances calculated on species-level abundances (p values from left to right: p = 0.74, p = 0.17, p = 0.06, p = 0.004, p = 0.177, p = 0.74 and p = 0.013), b the fraction of shared species (p values from left to right: p = 0.724, p = 0.381, p = 0.007, p = 0.018, p = 0.047, p = 0.889 and p = 0.04), and c strains between pairs of samples (see Methods) (p values from left to right: p = 0.18, p = 0.262, p = 1.5 × 10−10, p = 0.007, p = 2.8 × 10−11, p = 0.723 and p = 5.36 × 10−14). All p values were calculated using a two-sided Wilcoxon rank-sum test. While all patients had a microbiome as distinct from the donors as control patients, after D-FMT the donor-recipient microbiome distance was reduced with significantly more species and strains shared. The donor’s strains remained in the recipient for up to 30 days, highlighting the high engraftment potential of a single D-FMT treatment in the patients. Box-plots report median (central lines), 25th and 75th percentiles (box limits), and the upper and lower whiskers extend from the hinges to the largest (or smallest) value no further than ×1.5 interquartile range from the hinge, defined as the distance between the 25th and 75th percentiles. d Species with the highest number of D-FMT patients showing evidence of acquisition of the donor’s strain and of e maintenance of pre-FMT strains. f Representative phylogenetic tree of Alistipes putredinis showing strain transmission and replacement events for this species between D-FMT patients and their respective donors.