Journal: Nature medicine
This phase 2, multicenter, open-label trial (FMT-LUMINate; NCT04951583) evaluated whether a single fecal microbiota transplant (FMT) from healthy donors, given as oral capsules before starting immune checkpoint inhibitors, could enhance outcomes in treatment‑naïve patients with:
- • Non–small cell lung cancer (NSCLC) receiving anti–PD-1 monotherapy (n=20)
- • Melanoma receiving dual checkpoint blockade with anti–PD-1 plus anti–CTLA-4 (n=20)
Design and endpoints
- • Intervention: One FMT dose prior to initiating standard ICI therapy.
- • Primary endpoint: Objective response rate (ORR) in NSCLC.
- • Secondary endpoints: ORR in melanoma, safety, and microbiome dynamics (donor–recipient similarity and compositional changes).
Efficacy
- • NSCLC: ORR 80% (16/20), meeting the primary endpoint.
- • Melanoma: ORR 75% (15/20).
These response rates suggest substantial antitumor activity when FMT is combined with first‑line ICI.
Safety
- • NSCLC cohort: No grade ≥3 adverse events attributed to FMT plus anti–PD-1.
- • Melanoma cohort: Grade ≥3 adverse events occurred in 65% (13/20), consistent with known toxicity of dual ICI; FMT was considered safe by an independent data and safety monitoring committee.
Microbiome findings
- • Responders developed a distinct post-FMT gut microbiome profile that did not depend on strong donor–recipient similarity or clear strain-level engraftment.
- • A key signature of response was greater loss of baseline bacterial species versus non‑responders, particularly depletion of:
- • Enterocloster citroniae
- • Enterocloster lavalensis
- • Clostridium innocuum
- • This pattern of losing specific “deleterious” taxa was reproduced across three other published FMT-oncology studies.
Mechanistic validation (preclinical)
- • In antibiotic-treated, tumor-bearing mice recolonized with post-FMT stool from two human responders, reintroducing the specific bacterial species that had been depleted after FMT abrogated the antitumor effect of ICI.
- • This supports a causal role for elimination of these taxa in restoring ICI sensitivity.
Clinical and biological implications
- • Demonstrates clinically meaningful activity and acceptable safety of FMT given once before first‑line ICI in NSCLC and melanoma.
- • Suggests that FMT’s benefit may derive less from adding “beneficial” bacteria and more from removing inhibitory taxa that promote primary resistance to checkpoint blockade.
- • Points toward future strategies focused on targeted depletion or modulation of specific gut bacteria to enhance immunotherapy efficacy.