transformed outcomes in lung cancer and melanoma, and more than half of patients show primary resistance to them. Gut bacteria are one suspect, so fecal transplantation becomes a candidate for overcoming it. Nobody had tested that combination in the first-line setting. So a phase 2 trial gave a single healthy-donor transplant by oral capsule before treatment, to 20 lung cancer and 20 melanoma patients.
Response rates came in high in both arms. In non-small cell lung cancer the was 80 percent, 16 of the 20 patients, which met the trial’s primary endpoint. In melanoma it was 75 percent, 15 of 20. Sequencing showed responders developed a distinct post-transplant gut microbiome, independent of how similar it became to the donor’s or whether donor strains took hold.
Immune checkpoint inhibitors have improved outcomes in non-small cell lung cancer and melanoma, and over half of patients show primary resistance. The gut microbiome has emerged as one of the few modifiable factors plausibly involved, so is worth testing as a way to overcome that resistance.
FMT-LUMINate was a multicenter, open-label phase 2 trial in the first-line setting. Eligible patients received a single transplant from a healthy donor, via oral capsules, before starting treatment. Twenty patients with lung cancer received it alongside anti-PD-1 therapy, and 20 with melanoma alongside dual anti-PD-1 and anti-CTLA-4 therapy.
The primary endpoint was objective response rate in lung cancer, and it came in at 80 percent, 16 of the 20 patients, meeting the study endpoint. In melanoma the rate was 75 percent, 15 of 20. An independent data and safety monitoring committee deemed the transplant safe in both cohorts, with no grade three or higher adverse events in lung cancer, and 13 patients in melanoma, 65 percent, experiencing them.
The mechanism came out backwards from expectation. Shotgun metagenomic sequencing showed responders developing a distinct post-transplant microbiome composition that was independent of how similar they became to the donor or of any . What distinguished them was losing significantly more of their own baseline species, with frequent depletion of Enterocloster citroniae, E. lavalensis and Clostridium innocuum, a pattern reproduced across three published transplant oncology trials. Read the design before the numbers: single-arm, open-label, 20 patients an arm, with nothing to compare the response rates against.
wat. Four in five lung cancer patients responded after a single capsule transplant, and what marked the responders was losing their own bacteria rather than gaining the donor’s.
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The mechanistic finding is the more surprising half. Responders were not the patients who ended up resembling their donor, they were the patients who lost the most of their own baseline species.
How do we know?
Duttagupta and colleagues ran FMT-LUMINate, a multicenter open-label phase 2 trial, giving a single fecal transplant by oral capsule before first-line checkpoint inhibitor therapy, with objective response rate in lung cancer as the primary endpoint.
What is still unknown
An open-label phase 2 trial with 20 patients per arm and no control group, so the response rates cannot be compared against immunotherapy alone. In melanoma, 65 percent of patients had grade 3 or higher adverse events.
Learn something?
Where to next
How do bacteria in a mouse’s gut change the way it behaves?microbiomeWhat happens to a mouse raised with no gut bacteria at all?microbiome
How many bacteria are there really in your body per human cell?microbiome