The TACITO trial's preliminary results, presented at the 2024 European Society of Medical Oncology (ESMO) Annual Congress, suggest that fecal microbiota transplantation (FMT) can enhance the efficacy of immune checkpoint inhibitors (ICIs) in patients with metastatic renal cell carcinoma (mRCC). The randomized phase 2 study explored FMT versus placebo in patients receiving pembrolizumab plus axitinib.
Background and Rationale
Combinations of ICIs targeting PD-1/PD-L1 and VEGFR-TKIs have become standard first-line therapy for mRCC. The intestinal microbiota's composition influences response to ICIs in various cancers, including RCC. Gut dysbiosis, often caused by antibiotics, can impair ICI efficacy. Dietary interventions and FMT are strategies to modulate the gut microbiota. Prior studies, including one using CBM588 supplementation with nivolumab and cabozantinib, have shown preliminary signals of improved clinical activity with ICI-based combinations.
Study Design and Methods
The TACITO trial aimed to determine if FMT from a responder patient could increase the anti-tumor activity of axitinib plus pembrolizumab in treatment-naïve mRCC patients. The study enrolled 50 patients with RCC of any histology, eligible for axitinib + pembrolizumab, and with an ECOG PS of 0-1. Patients were randomized 1:1 to receive either FMT or placebo at three time points:
- Within 3 weeks from the start of axitinib + pembrolizumab
- 12 weeks after the first FMT/placebo
- 24 weeks after the first FMT/placebo
The primary endpoint was the rate of patients free of progression after 1 year from randomization.
The donor for the study was a 57-year-old male with clear cell renal carcinoma (ccRCC) who achieved a complete response to nivolumab and ipilimumab after radical nephrectomy and the development of numerous pulmonary metastases.
Key Findings
The primary endpoint was met, with FMT increasing the 1-year PFS rate to 66.7% compared to 35% in the placebo group. FMT also prolonged progression-free survival (PFS) and overall survival (OS), although longer follow-up is necessary. The median PFS was 14.2 months in the FMT group compared to 9.2 months in the placebo group.
The overall response rate was 52% in the FMT group compared to 28% in the placebo group. No complete responders have been identified in either group so far.
Safety and Tolerability
The study reported that FMT during treatment with pembrolizumab + axitinib was well tolerated, with no severe adverse events reported. 88% of eligible patients received FMT, and 89% received placebo in the third time-point of the study, demonstrating a high dose intensity of FMT/Pbo was achieved.
Implications and Future Directions
Dr. Chiara Ciccarese, the presenter of the study, concluded that the preliminary results suggest a role for FMT in increasing the activity of ICI + VEGFR-TKI therapies in mRCC patients. She noted that longer follow-up is necessary to assess the effect of FMT in prolonging median PFS and OS. Characterization of microbiota composition prior to and after FMT through microbiome analysis with shotgun sequencing techniques is ongoing. These data warrant further investigation in larger randomized clinical trials.
