Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial
Sreya Duttagupta, Meriem Messaoudene, Sebastian Hunter, Antoine Desîlets, Rahima Jamal, Catalin Mihalcioiu, Wiam Belkaïd, Nicolas Marcoux, Marine Fidelle, Déborah Suissa, Mayra Ponce, Mallia Geiger, Julie Malo, Gianmarco Piccinno, Michal Punčochář, Alysé Filin, Vitor Heidrich, Diana Rusu, Babacar Mbaye, Sylvère Durand, I. Ben Aissa, Vadim Puller, Raynald de Lahondès, Normand Blais, Mustapha Tehfé, Scott Owen, Karl Bélanger, Seema Nair Parvathy, Benjamin Shieh, Jacques Raphael, John Gordon Lenehan, Daniel Breadner, J. Rothenstein, Nicholas Rozza, Jade Maillou, Somayeh Nili, Diogjena Katerina Prifti, Federica Pinto, Federica Armanini, Seunghee Kim-Schulze, Thomas U. Marron, G. Kroemer, Lisa Derosa, Laurence Zitvogel, Michael S. Silverman, Nicola Segata, Saman Maleki Vareki, Bertrand Routy, Arielle Elkrief
Abstract
Immune checkpoint inhibitors (ICI) have improved outcomes for patients with non-small cell lung cancer (NSCLC) and melanoma, yet over half of patients exhibit primary resistance. Fecal microbiota transplantation (FMT) may overcome resistance to anti-programmed cell death protein 1 (PD-1) therapy. The clinical activity and safety of FMT plus anti-PD-1 in NSCLC or anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy in melanoma have not been evaluated. Here we report results from FMT-LUMINate, a multicenter, open-label, phase 2 trial assessing healthy donor FMT plus anti-PD-1 in NSCLC (n = 20) or anti-PD-1 plus anti-CTLA-4 (dual ICI) in melanoma (n = 20), in the first-line setting. Eligible patients received a single FMT via oral capsules prior to ICI initiation. The primary endpoint was objective response rate (ORR) in NSCLC. Secondary endpoints included ORR in melanoma, safety and donor-host microbiome similarity. In NSCLC, the ORR was 80% (16/20), meeting the study primary endpoint. In melanoma, the ORR was 75% (15/20). FMT was deemed safe in both cohorts by an independent data and safety monitoring committee, with no grade 3 or higher adverse events (AEs) in NSCLC and 13 (65%) patients experiencing grade 3 or higher AEs in melanoma. Shotgun metagenomic sequencing revealed that responders developed a distinct post-FMT gut microbiome composition, independent of acquired donor-recipient similarity or strain-level engraftment. Responders exhibited significantly greater loss of baseline bacterial species compared to non-responders, with frequent depletion of Enterocloster citroniae, E. lavalensis and Clostridium innocuum. This finding was reproduced across three published FMT oncology trials. We recolonized antibiotic-treated, tumor-bearing mice with post-FMT stool from two responder patients, and reintroduction of the specific bacterial species that were lost after FMT abrogated the antitumor effect of ICI. Taken together, these findings confirm the clinical activity of FMT in combination with ICI and suggest that the elimination of deleterious taxa is required for FMT-mediated therapeutic benefit. ClinicalTrials.gov identifier: NCT04951583 .