Fecal microbiota transplantation plus immunotherapy in metastatic renal cell carcinoma: the phase 1 PERFORM trial.

Immune checkpoint inhibitors (ICIs) improve outcomes in metastatic renal cell carcinoma (mRCC) but are hindered by immune-related adverse events (irAEs). Modulation of the gut microbiome may enhance efficacy and mitigate toxicity, yet the safety and mechanisms of healthy donor fecal microbiota transplantation (FMT) in mRCC remain unexplored. In this phase 1 trial, 20 treatment-naive patients with mRCC received encapsulated healthy donor FMT (LND101) combined with ipilimumab/nivolumab (n = 16), pembrolizumab/axitinib (n = 3) or pembrolizumab/lenvatinib (n = 1). The primary endpoint was safety, defined by the incidence and severity of irAEs. Secondary endpoints included clinical response (Response Evaluation Criteria in Solid Tumors version 1.1), gut microbiome and immune correlates and patient-reported quality of life. The safety endpoint was met with 50% (10/20) of patients experiencing grade 3 irAEs and no serious FMT-related toxicities or grade 4 or 5 irAEs. Among evaluable patients, the objective response rate was 50% (9/18), including two complete responses (11%, 2/18). Notably, most treatment responders did not develop any grade 3 or higher irAEs. Alpha (α) diversity improvement and durable engraftment of taxa and metabolic functions associated with anti-inflammatory properties correlated with reduced toxicity and improved response. Conversely, patients experiencing grade 3 irAEs exhibited expansion of Segatella copri, particularly with ipilimumab/nivolumab, and elevated levels of donor-derived microbial enzymes previously linked to pro-inflammatory activity. Resilience to toxicity correlated with the maintenance of protective metabolites and increased levels of immune regulatory cells, whereas the presence of grade 3 irAEs and S. copri enrichment was associated with high immune dysregulation. These findings demonstrate the safety and potential for functional microbiome engraftment to optimize response and minimize toxicity in ICI-treated mRCC. ClinicalTrials.gov identifier: NCT04163289 .