Immune checkpoint inhibitors (ICIs) have significantly improved the following symptoms: non-small cell lung cancer (NSCLC) and melanoma. However, primary resistance remains common, affecting approximately half of treated patients. Increasing evidence suggests that the gut microbiome is an important regulator of immunotherapy responses. Previous phase I studies suggested that fecal microbiota transplantation (FMT) could overcome resistance to PD-1 blockade, but its efficacy and safety in first-line NSCLC and in combination with dual PD-1/CTLA-4 blockade had not been prospectively evaluated.

Research design and methods

FMT-LUMINate was a multicenter, open-label, phase II study evaluating healthy donor FMT in combination with immune checkpoint inhibition in the first-line setting. Patients received one dose of oral FMT before starting immunotherapy.

• NSCLC cohort (n = 20):
  PD-L1 TPS ≥50%, no actionable carcinogenic changes
  Treatment: FMT → pembrolizumab monotherapy
• Melanoma cohort (n = 20):
  Cutaneous melanoma regardless of BRAF status
  Treatment: FMT → nivolumab + ipilimumab

Primary endpoint: Objective response rate (ORR) in NSCLC
Secondary endpoint: ORR, safety, microbiome dynamics, and donor-host similarity in melanoma

FMT-LUMINate Trial

Main results

NSCLC

• ORR: 80% (16/20), exceeding prespecified efficacy threshold
• Disease control rate: 95%
• 1-year progression-free survival rate: 65%
• 1 year overall survival rate: 100%

melanoma

• ORR: 75% (11 partial responses, 4 complete responses)
• 1-year progression-free survival rate: 58%
• 1 year overall survival rate: 79%

These response rates exceeded previous benchmarks of pembrolizumab monotherapy in PD-L1-rich NSCLC and nivolumab and ipilimumab in melanoma.

FMT-LUMINate Trial

safety

NSCLC cohort

• No grade 3 or higher adverse events
• Toxicity consistent with known safety profile of pembrolizumab

melanoma cohort

• Grade 3 or higher adverse events in 65% of patients
• Serious toxicity with diarrhea/colitis being the most common
• Myocarditis observed in 15%, onset earlier than historically reported
• Severe toxicity concentrated in recipients of Prevotella-enriched donor FMT

Although this combination was deemed acceptable by an independent safety monitoring board, myocarditis was designated as an adverse event of particular interest in future trials.

Mechanistic insights

Mechanistic analysis demonstrated that the clinical response to fecal microbiota transplantation is not caused by acquisition of donor-derived microbial strains or increased similarity between donor and recipient microbiota. Overall microbiome similarity and strain-level engraftment measures were comparable between responders and non-responders, indicating that donor microbial engraftment alone cannot explain treatment efficacy. Instead, responders showed a significantly greater loss of bacterial species present at baseline compared to non-responders. The taxa most consistently depleted in responding patients included Enterocloster spp., Clostridium inocium, Diallister spp., and Streptococcus spp. This baseline bacterial reduction pattern was reproducible in three independent clinical trials evaluating fecal microbiota transplantation in combination with immune checkpoint inhibition, supporting its generalizability.

The functional relevance of this microbial depletion was confirmed in preclinical models. Reintroducing bacterial species removed after fecal microbiota transplantation into tumor-bearing mice abolished the antitumor activity of PD-1 blockade, either alone or in combination with CTLA-4 inhibition. These findings indicate that the full therapeutic effect of fecal microbiota transplantation, when combined with immune checkpoint inhibitors, requires the removal of deleterious bacterial taxa.

At the systemic level, loss of these baseline taxa was associated with distinct immunometabolic changes. Responders showed decreased circulating levels of kynurenine and quinolinic acid, important metabolites of the tryptophan pathway, which are associated with immunosuppression and resistance to immunotherapy. This metabolic change is accompanied by an increase in the effector CD8+ T cell population and a concomitant decrease in regulatory T cells, consistent with the development of a more immunostimulatory systemic immune environment after fecal microbiota transplantation.

clinical significance

FMT-LUMINate provides the first prospective phase II evidence that healthy donor FMT can enhance the efficacy of immunotherapy in:

• PD-L1-high NSCLC treated with anti-PD-1 monotherapy
• Treatment of melanoma by dual blockade of PD-1/CTLA-4

Importantly, therapeutic efficacy appears to depend on the clearance of immunosuppressive enterobacteria rather than simple microbial engraftment. Donor microbiome composition, particularly Prevotella enrichment, may influence toxicity in relation to CTLA-4 blockade.

conclusion

The FMT-LUMINate trial establishes fecal microbiota transplantation as a biologically active immunomodulatory strategy that can enhance the efficacy of checkpoint inhibitors across tumor types and treatment backbones. These findings support the development of next-generation microbiome-based therapeutics aimed at depleting harmful pathogenic organisms, improving donor selection, and personalizing immunotherapy combinations.

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