Background: Previous studies have associated specific stool bacterial species with response to both targeted therapy and immunotherapy (Routy et al Science 2018; Dizman et al Cancer Med 2020). Abundant fungal elements also constitute the human microbiome (the so-called “mycobiome”); we explore whether these could be related to clinical benefit (CB) from TT. Methods: Pts from 2 simultaneously conducted studies were included in the analysis. Both studies enrolled patients with histologically confirmed RCC with metastatic disease; in one study, pts received standard of care (SOC) TT, while in the other pts received SOC IO. In both studies, stool was collected at baseline and at multiple timepoints thereafter. Whole metagenome sequencing was performed for fungal microbiome composition (TGen North, AZ). Linear discriminant analysis (LDA) effect size (LEfSe) was used for comparison of the gut mycobiome in patients who obtained clinical benefit (CB; complete response, partial response or stable disease > 6mos) versus no clinical benefit (NCB; progressive disease or stable disease ≤6mos) from TT or IO. Results: A total of 50 samples from 24 pts (19:5 M:F) were included in the analysis. The majority of pts (19; 79%) had clear cell histology. 15 pts received TT while 9 pts received IO. The fungal genera demonstrating the highest abundance was Saccharomyces with a median relative abundance of 86.9% (range, 11%-99%). LEfSe performed in different taxonomic levels revealed Malassezia globosa (LDA = 4.93; P = 0.038) and Alternaria infectoria (LDA 4.94; P = 0.018) as gut mycobiome components associated with NCB, and order Russulales associated with CB from TT (LDA = 4.93; P = 0.018). In contrast, no association was identified between mycobiome profile and CB in the IO-treated group. The presence of several pathogenic fungi such as Candida albicans and Aspergillus fumigatus was noted in a minority of pts and did not have any bearing on clinical outcome. In pts with serial samples, a trend towards decreasing Saccharomyces spp. (the most abundant species) and increasing fungal diversity was noted. Conclusions: Our study is the first to highlight potential associations between the mycobiome and CB with TT. Our finding of Malassezia spp resulting in lack of CB with TT bolsters findings from Aykut et al (Nature 2019), implicating the same genera in progression of pancreatic cancer. Confirmation of these findings in larger series is underway.