Phase 1 Trial Explores FMT–ICI Combination in mRCC

A phase 1 clinical trial has reported that fecal microbiota transplantation (FMT) from healthy donors, when administered alongside immune checkpoint inhibitors (ICIs), was safe and potentially associated with favorable clinical outcomes in patients with previously untreated metastatic renal cell carcinoma (mRCC). The findings were published in Nature Medicine as part of the PERFORM trial (NCT04163289).

The trial enrolled 20 treatment-naive patients with intermediate- or poor-risk mRCC. Participants received oral encapsulated FMT (LND101) from one of seven rigorously screened healthy donors, followed by one of three standard ICI-based therapies: ipilimumab plus nivolumab (n=16), pembrolizumab plus axitinib (n=3), or pembrolizumab plus lenvatinib (n=1). The primary endpoint was safety, measured by the incidence and severity of immune-related adverse events (irAEs). Secondary endpoints included clinical response, microbiome and immune correlates, and patient-reported quality of life.

No grade 4 or 5 irAEs were observed. Grade 3 irAEs occurred in 50% of patients, and 85% experienced irAEs of any grade. One patient experienced a mild (grade 1) gastrointestinal event considered related to FMT. No serious adverse events were attributed to the FMT product. Most irAEs occurred within the first three months of initiating ICI therapy.

Among 18 patients evaluable for efficacy, the objective response rate was 50% (9 of 18), including two complete responses. Twelve patients achieved clinical benefit, defined as complete response, partial response, or stable disease lasting six months or more. Notably, only one of the nine responders experienced a grade 3 irAE. In contrast, eight of the nine non-responders experienced grade 3 toxicity, including six cases of colitis. This association between response and toxicity reached statistical significance (χ² = 8.00, P = 0.005).

Microbiome analyses revealed that patients who did not develop grade 3 irAEs demonstrated greater alpha diversity in their gut microbiota by week 10 following FMT and had more durable engraftment of donor microbial strains and functions. Taxonomic and functional convergence toward donor microbiomes was observed more consistently in patients without severe toxicity and in those who responded to treatment.

By contrast, patients who developed grade 3 irAEs exhibited enrichment of the bacterial species Segatella copri following FMT, particularly when treated with ipilimumab plus nivolumab. Elevated S. copri levels—regardless of donor or recipient origin—were associated with a higher incidence of severe irAEs. At a threshold abundance greater than 10 counts per million at week 10, S. copri presence was also associated with lack of treatment response in patients receiving ipilimumab-containing regimens.

Targeted metabolomics indicated that patients without grade 3 irAEs maintained higher plasma levels of metabolites such as cortisol, stearoylcarnitine, L-histidine, and inosine triphosphate, which have been previously associated with immune regulation. In contrast, patients with grade 3 irAEs showed reductions in these metabolites over time. Similar patterns were observed among responders compared to non-responders.

Immune profiling further demonstrated differences in T cell, monocyte, and natural killer (NK) cell populations between patients with and without severe irAEs. Patients without grade 3 toxicity showed sustained levels of regulatory immune cell subsets and increased markers associated with tissue repair, while patients with grade 3 irAEs exhibited higher levels of activated memory T cells and reduced regulatory NK cells.

The study was not powered to assess clinical efficacy. Its primary objective—evaluating the safety and feasibility of combining healthy donor FMT with ICI-based therapy—was met. The results support further investigation of microbiome-directed strategies in the context of immunotherapy for mRCC. The authors note that larger, randomized trials will be needed to validate these findings and determine optimal donor selection criteria.