1475 Combination of LND101, a healthy donor microbiome transplantation product, to doublet immunotherapy or immunotherapy combined with targeted therapy in metastatic renal cell carcinoma patients

<h3>Background</h3> Metastatic renal cell carcinoma (mRCC) is treated with dual immune checkpoint inhibitors (ICI) or ICI with a VEGF-TKI. Despite improved outcomes, some patients do not benefit from the treatment due to disease resistance or serious adverse events. We hypothesized that re-establishing a healthy microbiome in mRCC patients before and during treatment with ICI based combination therapy via healthy microbiome transplantation does not increase toxicity and improves clinical response. The PERFORM trial (NCT04163289) is a single-arm phase I study evaluating the safety of multiple microbiome transplantation procedures before and during ICI based therapy in the first-line setting (1L) for patients with mRCC. <h3>Methods</h3> In this single-centre study, 20 patients with untreated mRCC received one full dose of LND101(a full consortia healthy donor microbiome product) followed by two-half doses of LND101 before the first 3 cycles of doublet ICI or ICI combined with VEGF-TKI. The primary endpoint is the feasibility and safety of combining LND101 with standard of care. Secondary endpoints include the incidence of irAEs , objective response rate (ORR) , and finally changes in patient‘s microbiome, immune profile, and metabolome. We include a preliminary analysis of all 20 patients for the clinical outcomes. <h3>Results</h3> 16 patients received LND101 plus ipilimumab/nivolumab, 3 patients received LND101 plus pembrolizumab/axitinib, and one patient received pembrolizumab/lenvatinib. The median age was 60 years old, and 90% were male. All patients had intermediate or poor-risk disease. No dose-limiting toxicities due to LND101 were observed. Median follow-up was 22.87 months. Nine patients (45%) discontinued treatment due to irAEs to include colitis (n=3), arthritis (n=1), nephritis (n=1), diarrhea (n=1), pneumonitis (n=1), and bullous pemphigoid (n=1). Grade 3 AEs were experienced by 11 patients (55%). 18 patients had measurable disease according to RECIST 1.1 criteria and a response was confirmed in 8/18 patients (ORR 44%), including one complete response. Clinical benefit was confirmed in 13/18 patients (72%). Targeted plasma metabolomics revealed 67 metabolites elevated in patients with Grade 3 toxicity at an FDR of &lt;0.05 relative to patients with no toxicity. <h3>Conclusions</h3> Our results suggest that microbiome modification with LND101 added to ICI-based combination therapy as 1L in patients with mRCC was safe. Furthermore, the addition of LND101 may prevent or reduce the occurrence of irAEs. For those who developed grade 3 irAEs, we observed important alterations in the gut microbiota. Finally, our results suggest that LND101 added to ICI-based combination therapy as 1L in mRCC may improve clinical outcomes. <h3>Acknowledgements</h3> Funding: Medical Oncology Research Funding, Academic Medical Organization of Southwestern Ontario Opportunities Grant, London Regional Cancer Centre Catalyst Keith Samitt Translational Cancer Research Grant and London Health Sciences Foundation. <h3>Trial Registration</h3> NCT04163289. <h3>Ethics Approval</h3> Ethics number: 114962.