ESMO 2024: Fecal Microbiota Transplantation vs Placebo in Patients Receiving Pembrolizumab plus Axitinib for Metastatic Renal Cell Carcinoma. Preliminary Results of the Randomized Phase 2 TACITO Trial.

(UroToday.com) The 2024 European Society of Medical Oncology (ESMO) Annual Congress held in Barcelona, Spain between September 13^th and 17^th was host to the session Mini oral session: GU tumours, non-prostate. Dr. Chiara Ciccarese presented the preliminary results of the randomized phase 2 TACITO trial, exploring fecal microbiota transplantation (FMT) versus placebo in patients receiving pembrolizumab plus axitinib for metastatic renal cell carcinoma (mRCC).

Dr. Ciccarese began her presentation by saying that combinations of immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 plus VEGFR-TKIs have become the standard first-line therapy for patients with metastatic renal cell carcinoma (mRCC). It has been previously demonstrated that the composition of the intestinal microbiota plays an important role in influencing the response to ICIs in various cancer types, including RCC. Therefore, treatment with antibiotics can lead to gut dysbiosis and potentially impair ICI efficacy.¹

One strategy to modulate the gut microbiota through dietary interventions has been studied in early-phase trials. A Study using supplementation with CBM588, a bifidogenic live bacterial product in patients with RCC receiving Nivolumab + Cabozantinib has shown preliminary signals of improved clinical activity of ICI-based combinations.² Another alternative is fecal microbiota transplantation (FMT), which is currently used to regulate microbiota-related diseases and potentially could become a tool to overcome resistance to ICIs in different diseases.

The TACITO study aimed to explore whether 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 who were eligible for axitinib + pembrolizumab and had an ECOG PS of 0-1. Patients were randomized 1:1 to receive either FMT or placebo at three different 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 study design is shown below:

Dr. Ciccarese briefly introduced the donor for the study: a 57-year-old gentleman with clear cell renal carcinoma (ccRCC) who had undergone a radical nephrectomy (pT3a pN1 M0). Follow-up CT scans revealed over 60 bilateral pulmonary metastases. The patient was treated with Nivolumab and Ipilimumab, achieving a complete response with no evidence of disease.

The TACITO trial screened 54 patients for eligibility. Of these, 50 were included and randomized: 25 received the first FMT and 25 received a placebo. In the second round, only 20 patients received FMT and 18 received placebo. In the third round, 14 patients received FMT and 16 received placebo. Patient characteristics were well balanced and are reported below:

The primary endpoint of the study was met, FMT increased the 1-year PFS rate 31.7% compared to placebo. The 1-year PFS in the FMT was 66.7 % vs. 35% in the placebo group.

FMT 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.

Dr. Ciccarese highlighted the difficulty in completing all the proposed FMT/placebo transplants. However, 88% of eligible patients received FMT, and 89% received placebo in the third time-point of the study. Despite FMT procedure-related difficulties, a high dose intensity of FMT/Pbo was achieved;

To conclude her presentation Dr Ciccarese left the floor with the following key points:

The preliminary results of the TACITO trial suggest the role of FMT in increasing the activity of ICI + VEGFR-TKI therapies in mRCC patients
FMT versus placebo significantly increased the 1-y PFS rate of pembrolizumab + axitinib and met the primary endpoint of the study
FMT during treatment with pembrolizumab + axitinib was well tolerated, with no severe adverse events reported
Longer follow-up is necessary to assess the effect of FMT in prolonging median PFS and OS
Characterization of microbiota composition prior and after FMT through microbiome analysis with shotgun sequencing techniques is currently ongoing
This data warrants further investigation in larger randomized clinical trials

Presented by: Chiara Ciccarese, MD, Medical Oncologist at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome, Italy.

Related content: Fecal Microbiota Transplant Boosts Immunotherapy in Metastatic Renal Cell Carcinoma in TACITO-II Trial - Chiara Ciccarese

Written by: Julian Chavarriaga, MD –Urologic Oncologist at Cancer Treatment and Research Center (CTIC) Luis Carlos Sarmiento Angulo Foundation via Society of Urologic Oncology (SUO) Fellow at The University of Toronto. @chavarriagaj on Twitter during the 2024 European Society of Medical Oncology (ESMO) Annual Meeting, Barcelona, Spain, Fri, Sept 13 – Tues, Sept 17, 2024.

Related content: Fecal Microbiota Transplant Boosts Immunotherapy in Metastatic Renal Cell Carcinoma in TACITO-II Trial - Chiara Ciccarese

References:

Login