Microbiome intervention with SER-401 prior to nivolumab for unresectable or metastatic melanoma: a randomized placebo-controlled, biomarker-stratified multicenter phase 1b trial

Gut microbiota modulation shows promise in improving immune checkpoint blockade response (ICB); however, precision biomarker-driven trials using rationally-designed consortia are lacking. To address this, we performed a multi-center, randomized placebo-controlled, biomarker-stratified phase 1 trial in patients with ICB-naive unresectable or metastatic melanoma using SER-401, a Firmicutes-enriched spore formulation. Baseline gut microbiota were characterized (high versus low Ruminococcaceae abundance), and patients were randomized to SER-401 arm (oral vancomycin pre-conditioning + SER-401, followed by nivolumab + SER-401); versus placebo (with placebo-antibiotic pre-conditioning + placebo microbiome-modulation - PMM, followed by nivolumab + PMM) (NCT03817125). Accrual was negatively impacted by the COVID-19 pandemic, with 14 patients enrolled. Treatment with SER-401 and nivolumab was safe, though increased Ruminococcaceae abundance above baseline was not achieved in most patients; ORR was 25% (95% confidence interval [CI] 3.2-65.1%, SER-401 arm) versus 67% (95% CI 22.3-95.7%, placebo arm). Important insights were gained via translational analyses, and additional placebo-controlled biomarker-driven microbiome trials are needed in this age of precision medicine.