9528 Background: Gut microbiome composition has been implicated as a potential biomarker of response to ICIs in melanoma pts, but it is unclear whether baseline gut microbiome composition may predict emergence of specific ICI resistance subtypes (primary vs. acquired resistance) or immune-related adverse events (irAEs). We sought to define clinical characteristics and baseline gut microbiome features that correlate with ICI resistance subtypes and irAEs in melanoma pts. Methods: We identified 90 pts from our institution’s fecal biorepository of advanced melanoma pts who received ICIs and who had ≥ 1 pre- or on-treatment fecal sample available for 16S rRNA amplicon sequencing. Pts were categorized into 3 responder subgroups: responder (R, no progression on ICI), primary resistance (pR, progression < 6 months from ICI start), or acquired resistance (aR, progression ≥ 6 months from ICI start). Associations between clinical covariates and survival were analyzed using Kaplan-Meier and Cox proportional hazards models. Microbial features were compared using alpha and beta diversity metrics and pairwise comparisons at each taxonomic level using Wilcoxon rank-sum tests. Results: Baseline demographic and clinical characteristics were similar between subgroups (R, n = 35; pR, n = 32; aR, n = 23). IrAE occurrence rates significantly differed between responder subgroups (p = 0.048). Pts who developed irAEs had significantly longer progression-free survival (PFS) than those without irAEs (median PFS 1412 vs. 106 days, p = 0.026). Later treatment line and receipt of prior ICI were associated with significantly higher hazard ratios (HRs) for death and progression, while resectable disease and development of any-grade irAE were associated with lower HRs for death and progression. There was no significant difference in baseline alpha diversity between responder subgroups or irAE groups. A trend toward differences in baseline beta diversity between responder subgroups was observed (p = 0.084). Abundance of Faecalibacterium prausnitzii , a known butyrate producer, was significantly higher in R than pR (p < 0.001, p adj = 0.029), aR than pR (p < 0.001, p adj = 0.071), and in pts who did not develop irAEs (p = 0.02). Other operational taxonomic units more abundant in responders (aR vs. pR, R vs. aR/pR) and pts who did not develop irAEs include the short-chain fatty acid (SCFA) producers Coprococcus comes , Dorea longicatena , and Blautia glucerasea (p < 0.001, p adj = 0.071). Conclusions: Although no significant differences in baseline alpha diversity were observed between responder subgroups or irAE groups, responders and those without irAEs had significantly higher levels of SCFA-producing taxa at baseline, suggesting a potential immunomodulatory role for SCFAs such as butyrate in mediating ICI response and protection from irAEs.
Ferreira et al. (Thu,) studied this question.