Fecal Microbiota Transplantation plus Anti–PD-1 Is Safe in a First-line Setting

Nearly half of patients with melanoma who were treated with single-agent anti–PD-1 therapy will develop resistance. The gut microbiome can affect immune checkpoint inhibitor (ICI) response, and fecal microbiota transplantation (FMT) has been indicated as a potential strategy to overcome ICI resistance. However, the use of FMT in a first-line treatment setting has not been evaluated; therefore, Routy, Lenehan, and colleagues conducted a phase I clinical trial in which 20 patients with previously untreated, advanced melanoma underwent FMT from healthy donors and received the PD-1 inhibitor nivolumab or pembrolizumab. The primary endpoint of the study was safety, with secondary endpoints being objective response rate, gut microbiome composition, and immune profile alterations. Survival analysis was also included as an exploratory endpoint. Evaluation of safety indicated that eight patients (40%) experienced grade 1–2 FMT-related toxicities, with no grade 3 adverse events reported with FMT alone. Five patients (25%) who received combination treatment reported grade 3 immune-related adverse events. An objective response was observed in 13 patients (65%), with four patients (20%) achieving a complete response and nine patients (45%) having a partial response. The median follow-up was 20.7 months, at which point the median progression-free survival was still not reached. Analysis of changes in the composition of the gut microbiome after FMT revealed that responders had an increasing similarity toward their donor microbiome, which was retained over time, as well as enrichment in Ruminococcaceae SGB15234 and SGB14909, Alistipes communis, and Blautia SGB4831 as compared to nonresponders. Moreover, an increase in ICOS⁺ CD8⁺ T cells was observed after FMT in responders, while nonresponders demonstrated an abundance of monocytic myeloid-derived suppressor cells. Furthermore, the therapeutic potential of FMT was confirmed in avatar mice that were recolonized with healthy donor stool. In summary, the results of this trial show that FMT from healthy donors combined with anti–PD-1 therapy is safe in the first-line setting and suggest that further clinical testing of this combination in this setting should be explored.

Routy B, Lenehan JG, Miller WH Jr, Jamal R, Messaoudene M, Daisley BA, et al. Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial. Nat Med2023;29:2121–32.

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