Healthy donor fecal microbiota transplantation combined with immunotherapy in metastatic renal cell carcinoma: Results from the phase I PERFORM trial.

559 Background: Despite advances with immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF)–targeted tyrosine kinase inhibitors, outcomes in metastatic renal cell carcinoma (mRCC) remain variable, with primary resistance and treatment-limiting toxicities The gut microbiome influences both ICI response and immune-related toxicity. The PERFORM trial (NCT04163289) is a single-arm, phase I study evaluating the safety of healthy-donor fecal microbiota transplantation (FMT) given before and during first-line ICI-based therapy in patients with mRCC. Methods: In this trial, 20 untreated mRCC patients received encapsulated healthy-donor FMT (LND101) prior to standard ICI-based regimens (ipilimumab–nivolumab, pembrolizumab–axitinib, or pembrolizumab–lenvatinib). The primary endpoint was safety. Secondary clinical endpoints included objective response (ORR), clinical benefit (complete or partial response or stable disease lasting six months or longer), progression-free survival (PFS), overall survival (OS), and quality of life (QoL). Results: FMT was well-tolerated with no FMT-related serious toxicity. Median follow-up was 21.9 months (range, 5.6–53.3). One patient (5%) experienced grade 1 gastrointestinal event attributed to FMT. Any-grade irAEs occurred in 95%; grade ≥3 in 50%, consistent with historical ICI rates. No grade 4–5 toxicities related to FMT or systemic therapy were observed. Among 18 evaluable patients, the ORR was 44% (n = 8) including two complete responses (11%). Primary progressive disease occurred in five patients (28 %). Clinical benefit was achieved in 72% (n = 13). Only 1 of 8 responders (12.5%) developed grade ≥3 irAEs vs 8 of 10 non-responders (80%) (p = 0.018). Median PFS and OS were 11.15 and 36 months, respectively. QoL remained stable over the first four treatment cycles without evidence of decline attributable to FMT. Conclusions: Encapsulated healthy-donor FMT administered before ICI-based therapy was safe and feasible in patients with previously untreated mRCC. Clinical activity was consistent with contemporary regimens, and severe immune-related toxicity was uncommon among responders. These data support further evaluation of FMT with ICI therapy in larger, multi-center trials to validate safety and clinical benefit. Clinical trial information: NCT04163289 .