Fecal Microbiota Transplantation Shows Feasibility in Metastatic RCC
A novel approach to treating metastatic renal cell carcinoma (RCC) – combining fecal microbiota transplantation (FMT) with standard immunotherapy – is showing promising results. The phase 2a TACITO trial (NCT04758507) investigated whether altering the gut microbiome could enhance the effectiveness of pembrolizumab (Keytruda) and axitinib (Inlyta), two commonly used cancer treatments.
Enhancing Immunotherapy with the Gut Microbiome
Researchers found that patients receiving donor FMT (d-FMT) experienced a significantly longer median progression-free survival (PFS) – 24.0 months – compared to those receiving a placebo FMT (p-FMT), who had a median PFS of 9.0 months. This difference was statistically significant (P = .035). While median overall survival (OS) also favored the d-FMT group (41.0 months vs 28.3 months), this difference was not statistically significant (P = .167).
The objective response rate (ORR) – the proportion of patients whose tumors shrank or disappeared – was also higher in the d-FMT group, at 52%, compared to 32% in the p-FMT group. Notably, while the p-FMT group saw two complete responses (CRs), the d-FMT group experienced no CRs, but a greater number of partial responses (PRs) – 12 versus 5.
Microbiome Changes Observed
Analysis of the patients’ gut microbiomes revealed notable changes following d-FMT. Researchers observed an increase in Shannon α-diversity – a measure of microbiome richness and evenness – at weeks 1, 4, and 24, as well as increased species richness by week 4. This suggests that d-FMT successfully altered the composition of the gut microbiome.
A post-hoc analysis revealed even more pronounced benefits of d-FMT among patients with intermediate- or poor-prognosis RCC, according to IMDC criteria. In this subgroup, median PFS was 18.8 months with d-FMT compared to 5.1 months with p-FMT (P = .033), and the ORR was 50% versus 8%, respectively.
Trial Details and Safety
The TACITO trial enrolled 45 patients with histologically confirmed metastatic RCC who were eligible for, or had recently started, immune checkpoint inhibitors. The median age of participants was approximately 62 years, with a majority being male (73-74%). Most patients had clear cell carcinoma (86-91%) and had undergone prior nephrectomy (56-59%).
The study’s primary endpoint was 12-month PFS, while secondary endpoints included median PFS, median OS, ORR, safety, and microbiome changes. The donor FMT material came from two individuals who had previously experienced a complete response to PD-1 inhibition with nivolumab (Opdivo) plus ipilimumab (Yervoy) or nivolumab alone.
The treatments were generally well-tolerated. Treatment-related adverse events (TRAEs) were infrequent, with one patient experiencing grade 2 diarrhea and another experiencing grade 3 oral mucositis in the p-FMT arm. Grade 3 or higher adverse events related to immune checkpoint inhibition occurred in 28% of the d-FMT group and 16% of the p-FMT group, leading to treatment interruption, dose reductions, or discontinuation in a small percentage of patients. No treatment-related deaths were reported.
Frequently Asked Questions
What is fecal microbiota transplantation (FMT)?
FMT involves transferring fecal matter, containing a community of microorganisms, from a healthy donor to a recipient. In this trial, the FMT was administered in capsule form.
What is progression-free survival (PFS)?
PFS is the length of time during a study that a patient lives with the disease not getting worse.
Who were the donors for the d-FMT?
The donors were two patients who had previously experienced a complete response to PD-1 inhibition with nivolumab (Opdivo) plus ipilimumab (Yervoy) or nivolumab alone.
Could further research into the gut microbiome and its interaction with immunotherapy lead to more personalized and effective cancer treatments?