Fecal Microbiota Transplantation Boosts Response to Pembrolizumab Plus Axitinib in mRCC

Fecal microbiota transplantation (FMT) increased the activity of pembrolizumab (Keytruda) plus axitinib (Inlyta) in patients with metastatic renal cell carcinoma (RCC), according to data from the phase 1/2 TACITO trial (NCT04758507) presented during the 2024 ESMO Congress.¹

Preliminary findings from TACITO demonstrated that at a minimum follow-up of 12 months, patients who received FMT with pembrolizumab and axitinib (n = 24) achieved a 1-year progression-free survival (PFS) rate of 66.7% (95% CI, 33.7%-90.8%) vs 35.0% (95% CI, 8.6%-70.7%) among those who received placebo in place of FMT (n = 20; P = .036), meeting the primary end point of the study. At a median follow-up of 28.2 months for PFS, the median PFS was 14.2 months (95% CI, 0.9-27.6) vs 9.2 months (95% CI, 3.0-15.4), respectively.

“The composition of intestinal microbiota is a key regulator [in terms of] influencing the response to immunotherapy in several cancer types, including RCC,” Chiara Ciccarese, MD, PhD, a medical oncologist at Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy, said during the presentation. “Early-phase trials have recently demonstrated the possibility of modulating the gut microbiota composition through dietary interventions with preliminary signals of improved immunotherapy activity. FMT has emerged as a potential tool to overcome the development of immune resistance, and our trial sought to investigate if this might be the case [in RCC].”

Enrollment Criteria and Patient Characteristics in TACITO

TACITO was an Italian study that enrolled patients 18 to 80 years of age with metastatic RCC of any histology who were eligible to receive pembrolizumab and axitinib. Additional inclusion criteria included having an ECOG performance status of 0 or 1 and patients must have undergone radiological assessment within 8 weeks prior to enrollment. Patients were excluded if they had any major comorbidities; had concomitant gastrointestinal or autoimmune disorders or HIV, HBV, HCV infection; were receiving continuative corticosteroid therapy; underwent prior treatment with systemic immune-suppressants or immune-modulatory drugs; or received antibiotic therapy within 4 weeks preceding enrollment.^1,2

Eligible patients were randomly assigned 1:1 to receive FMT (n = 25) or placebo (n = 25), both in combination with pembrolizumab and axitinib per standard-of-care dosing. Within 8 weeks of the start of pembrolizumab and axitinib, patients in the investigational arm received FMT via colonoscopy, then received FMT via frozen oral capsules at weeks 12 and 24 after the initial FMT administration. Placebo was given in place of FMT at the same time points in the control arm.¹

The primary end point of the study was 1-year PFS rate. Secondary end points included median PFS, median overall survival (OS), overall response rate (ORR), safety, and microbiota characterization.

The baseline characteristics were generally well balanced between the FMT and placebo arms; the median age was 61 years (range, 47-78) vs 61 years (range, 42-80), respectively. Most patients in both arms were male (76.0% vs 76.0%), underwent a prior nephrectomy (56.0% vs 64.0%), and had clear cell histology (92.0% vs 84.0%). Metastatic sites in the FMT arm vs placebo arm included the lungs (76.0% vs 64.0%), lymph nodes (36.0% vs 60.0%), bones (28.0% vs 24.0%), pancreas (24.0% vs 8.0%), and liver (12.0% vs 24.0%). IMDC prognostic classes for risk consisted of favorable (28.0% vs 32.0%), intermediate (56.0% vs 48.0%), and poor (16.0% vs 20.0%), respectively.

Further Findings Show Benefit With Addition of FMT

Additional findings from TACITO showed that, at a median follow-up of 18.9 months for OS, the median OS in the FMT arm was not yet reached (NR; 95% CI, NR-NR) compared with 25.3 months (95% CI, 17.1-33.6) in the placebo arm. The ORRs per RECIST 1.1 criteria were 52.0% vs 28.0%, respectively; no patients in either arm achieved a complete response. Additionally, patients experienced stable disease at a rate of 38.0% in the FMT arm vs 44.0% in the placebo arm.

“Although premature, the [OS] curves are nicely diverged,” Ciccarese noted. “Furthermore, even taking into account the technical difficulties related to the transplantation procedure, up to 90% of eligible patients received all 3 transplantations with a high dose intensity.”

In terms of safety, patients in the placebo arm experienced any-grade adverse effects (AEs) related to placebo at a rate of 8%, including 1 patient with a grade 3 or 4 AE and 1 patient with an AE leading to treatment discontinuation; no patients in the FMT arm experienced such AEs related to FMT. Thirty-two percent of patients in both arms experienced grade 3 or 4 AEs related to pembrolizumab and/or axitinib.

Any-grade AEs of interest in the investigational and placebo arms included diarrhea (52% vs 44%), colitis (12% vs 8%), nausea (12% vs 4%), and increased aspartate aminotransferase or alanine aminotransferase levels (20% vs 28%). These AEs occurred at grade 3 or 4 at rates of 12% vs 4%, 0% vs 4%, 4% vs 0%, and 12% vs 8%, respectively.

“In conclusion, the TACITO trial [results] suggest the role of FMT in increasing the activity of VEGFR-[directed] TKI plus anti–PD-1 treatments in patients with metastatic RCC,” Ciccarese said. “This is the first randomized [trial to] demonstrate the possibility to transfer the immune response from 1 patient to another through FMT. FMT was feasible, with a high dose intensity achieved, safe, and deserves further investigation.”

Disclosures: Dr Ciccareseis on the advisory board of Leopharma and MSD. She is also a consultant for Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, EISAI, Ipsen, Johnson & Johnson, Merck, MSD, Novartis, and Pfizer.

References

1. Ciccarese C, Porcari S, Buti S, et al. Fecal microbiota transplantation (FMT) versus placebo in patients receiving pembrolizumab plus axitinib for metastatic renal cell carcinoma: Preliminary results of the randomized phase II TACITO trial. Ann Oncol. 2024;35(suppl 2):1-72. doi:10.1016/annonc/annonc1623
2. Fecal microbiota transplantation to improve efficacy of immune checkpoint inhibitors in renal cell carcinoma (TACITO). ClinicalTrials.gov. Updated September 5, 2024. Accessed September 26, 2024. https://clinicaltrials.gov/study/NCT04758507