Background: TPST-1120 is a first-in-class, oral inhibitor of peroxisome proliferator-activated receptor (PPAR-α), a fatty-acid ligand-activated transcriptional factor that controls the expression of multiple genes involved in fatty acid oxidation (FAO), angiogenesis and inflammation. In a phase 1 open-label trial, TPST-1120 was administered as a single agent and in combination with nivolumab in multiple tumor types. Among the tumor types treated, 4 patients in the combination arm had Renal Cell Carcinoma (RCC). 2 of the patients experienced clinical and radiographic response confirmed by RECIST. On this study, we plan to further study the pharmacodynamic and radiographic changes in these patients with RCC to further understand signals to identify patients who may benefit from this treatment. Methods: Mutational analysis of ctDNA was assessed using the PredicineCARE assay (Predicine Inc.), and lipid analysis was performed by tandem mass spectrometry. Gene Expression changes were quantified using the nCounter PanCancer Iune Profiling Panel (Nanostring Inc.) supplemented with 30 PPAR-α target genes. The radiographic Analysis was performed with CT chest-abdomen-pelvis and response evaluated using RECIST criteria. Results: RCC patients with PR (2/4) confirmed by RECIST exhibit greater reductions in 6 PPAR-α regulated genes. They had an early increase in thrombospondin (TSP-1) level due to PPAR-α inhibition. An increase in long-chain fatty chain fatty acids was seen including circulating FFA, lysophosphorylcholine (LPC) or lysophosphorylethanolaine (LPE). They also had great reductions in 6 PPAR-α regulated genes including ACAD8, ACSL3, CPT2, FABP1, FABP3, HADHB. Conclusions: There is a paucity of treatment options for patients with stage IV RCC post anti-PD1 and anti-VEGF therapies. Novel therapies on this clinical scenario are needed. On this abstract we showed radiographic and pharmacodynamic data on patients with RCC who achieved a clinical partial response by RECIST on the phase I clinical trial TPST1120-001. The trial explored the se of a PPAR-α inhibitor in combination with Nivolumab. The pharmacodynamic data indicates that there is fatty acid oxidation perturbation and immune gene expression changes as potential biomarkers of clinical benefit. PI3K pathway or IDH mutations may indicating a signal that RCC patients may benefit from this combination therapy. Larger studies in the future may be designed to further explore the use of this combination in patients with RCC. Clinical trial information: NCT03829436.