Fecal microbiota transplantation extended median PFS with first-line pembrolizumab plus axitinib in metastatic RCC.
Selected donor fecal microbiota transplantation (FMT) from complete immune checkpoint inhibitor (ICI) responders enhanced progression-free survival (PFS) in patients with metastatic renal cell carcinoma (RCC) who received frontline pembrolizumab (Keytruda) plus axitinib (Inlyta) vs patients who received pembrolizumab plus axitinib without FMT, according to data from the phase 2a TACITO trial (NCT04758507) published in Nature Medicine.1
At a median follow-up of 32 months (IQR, 22-37), findings from TACITO demonstrated that patients who received donor FMT (n = 23) experienced a 12-month PFS rate of 70% compared with 41% among patients who received placebo FMT (n = 22); the study authors noted that the statistical difference between the 2 arms was only close to the preset significance threshold (P = .053). However, the median PFS values were 24.0 months (95% CI, 8.0-40.0) and 9.0 months (95% CI, 2.2-15.2), respectively (HR, 0.50; 90% CI, 0.27-0.92; P = .035).
“Although the primary end point [of 12-month PFS] was not met, the secondary end point of median PFS was significantly longer with donor FMT,” Serena Porcari of the Department of Translational Medicine and Surgery at Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia in Rome, Italy, and her coauthors wrote in the publication. “Our findings support the safety and potential efficacy of selected donor FMT to enhance ICI-based treatment in metastatic RCC, which deserves further investigations.”
TACITO was an Italian, double-blind, placebo-controlled, investigator-initiated trial that enrolled patients with metastatic, histologically confirmed RCC who were eligible to receive frontline pembrolizumab and axitinib.1,2 Patients were required to undergo radiological assessments within 8 weeks prior to enrollment and be eligible for ICI therapy for metastatic RCC or have started ICI treatment within 8 weeks.
Eligible patients were randomly assigned 1:1 to receive donor FMT or placebo FMT 3 times in 6 months unless disease progression occurred.1 Both arms underwent the first procedure by colonoscopy, followed by capsulized FMT after 12 weeks and 24 weeks, respectively. The study authors identified 5 patients with long-term complete responses (CRs) to ICI therapy as candidate donors; 2 of these individuals ultimately passed the screening process and were eligible to donate.
The primary end point was 12-month PFS rate per RECIST 1.1 criteria. Secondary end points included PFS, overall survival (OS), objective response rate (ORR), safety, and microbiome changes.
The baseline characteristics between the investigational and placebo arms were well balanced; the median ages were 62 years (range, 47-75) and 61 years (range, 41-79), respectively. Most patients in both arms were male (74% vs 73%), underwent prior nephrectomy (61% vs 59%), had clear cell histology (91% vs 86%), had an interval from nephrectomy of less than 1 year (56% vs 59%), and had lung metastases (74% vs 73%).
Additional findings from TACITO showed that the median OS in the investigational arm was 41.0 months compared with 28.3 months in the placebo arm (HR, 0.36; 95% CI, 0.13-0.99; P = .167). The respective ORRs were 52% (95% CI, 33%-71%) and 32% (95% CI, 14%-55%). Two patients in the placebo arm experienced a CR.
In the safety population, patients in the investigational (n = 25) and placebo (n = 24) arms experienced any-grade adverse effects (AEs) related to donor FMT and placebo FMT at rates of 0% and 8%. Patients in the placebo arm also experienced grade 3 or 4 AEs (4%) and AEs leading to treatment discontinuation (4%).
AEs related to pembrolizumab or axitinib occurred at rates of 28% and 16% in the investigational and placebo arms, respectively. Any-grade AEs of special interest consisted of diarrhea (52% vs 44%), colitis (12% vs 8%), nausea (12% vs 4%), and increased aspartate aminotransferase/alanine aminotransferase levels (20% vs 28%).
“To our knowledge, the TACITO trial is the first [randomized clinical trial] to investigate the effect of targeted FMT in patients with metastatic RCC undergoing first-line combination therapy with pembrolizumab plus axitinib as well as the first study to evaluate PFS and OS as clinical end points, with several intriguing findings,” Porcari and her coauthors wrote. “The investigation of further approaches to microbiome modulation, such as microbiome consortia/live biotherapeutic products, could overcome the issue of stool shortage and is also supported by the promising results coming from already available studies.”
