FMT in combination with ICI-based therapy shows promise in multiple cancers

medwireNews: Three trials published in Nature Medicine point to the potential of fecal microbiota transplantation (FMT) to enhance the efficacy of immune checkpoint inhibitor (ICI)-based therapy in people with cancer.

The phase 1 PERFORM trial and the phase 2a TACITO trial focused on patients with metastatic renal cell carcinoma (RCC), while the phase 2 FMT-LUMINate trial included those with non-small-cell lung cancer (NSCLC) or melanoma.

Taken together, the studies show the benefit of FMT across tumor pathologies, ICI backbones, and donor types, but larger trials are necessary to confirm these early results.

FMT PERFORMs well in metastatic RCC

Saman Vareki (London Health Sciences Centre, Ontario, Canada) and co-researchers recruited 20 individuals (80% men, median age 60 years) with treatment-naïve metastatic RCC that was classified as intermediate- or poor-risk as per the International Metastatic RCC Database Consortium (IMDC) criteria from a single center.

All patients received one full dose of LND101 – an encapsulated, healthy donor-derived FMT product – a week before initiating treatment with ipilimumab plus nivolumab (n=16), pembrolizumab plus axitinib (n=3), or pembrolizumab plus lenvatinib (n=1), and two half doses during treatment.

The primary endpoint of safety was met, report the investigators. Grade 3 immune-related adverse events (irAEs) occurred in 50% of patients, most commonly colitis in six patients, and there were no grade 4 or 5 events. One participant experienced toxicity related to FMT, a grade 1 case of diarrhea.

Over a median follow-up of 21.9 months, 50% of the 18 evaluable patients achieved an objective response, of which11% were complete responses and the rest were partial. An additional three patients had stable disease for at least 6 months, giving a disease control rate (DCR) of 67%.

The median progression-free survival (PFS) duration was 11.2 months and the median overall survival (OS) was 36.0 months.

Interestingly, just one of the nine participants who had a response experienced grade 3 irAEs compared with eight of the nine nonresponders, “suggesting that healthy donor FMT may enhance efficacy while mitigating irAEs,” say the authors.

TACITO adds to evidence in metastatic RCC

This double-blind study evaluated the impact in patients with metastatic RCC of FMT from donors who had a long-term complete response to ICIs.

A total of 45 patients initiating first-line pembrolizumab plus axitinib were enrolled and randomly allocated to receive either donor FMT (n=23) or placebo (n=22) three times in 6 months, where the first dose was administered via colonoscopy and the subsequent via oral capsules.

The participants were aged a median of 62 years, and the majority were men (73%) and had IMDC intermediate- or poor-risk disease (69%).

They were followed up for a median of 32 months, and although the primary endpoint of 12-month PFS was numerically higher in the donor FMT than placebo group, at 70% and 41%, respectively, the between-group difference did not reach statistical significance.

The median PFS time, however, was significantly longer among patients who received donor FMT than those given placebo, at 24.0 versus 9.0 months, although again, the median OS time was numerically, but not statistically significantly, longer, at 41.0 versus 28.3 months.

The corresponding objective response rates (ORRs) were 52% and 32%.

Gianluca Ianiro (Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy) and colleagues report that AEs “strictly related to the experimental procedures occurred rarely.” One patient in the placebo arm experienced grade 2 diarrhea after colonoscopy and another had grade 3 oral mucositis during frozen capsule ingestion.

Grade 3 or worse AEs related to pembrolizumab and/or axitinib were observed in 28% of the donor FMT group and 16% of those in the placebo FMT group.

FMT-LUMINate shows benefit in other tumor types

Arielle Elkrief (Centre hospitalier de l’Université de Montréal, Québec, Canada) and associates report on the outcomes of 20 patients with advanced NSCLC (55% men, median age 68 years) and 20 with advanced melanoma (65% men, median age 56 years) who received a single dose of healthy donor FMT via oral capsules prior to the start of first-line treatment with a PD-1 inhibitor alone or alongside a CTLA-4 inhibitor, respectively.

At a median follow-up of 24 months, the ORR in the NSCLC cohort was 80%, which exceeded the prespecified rate of 64%, “thereby, meeting the criteria for a positive study outcome,” write the researchers.

The DCR was 95% and the 1-year PFS and OS rates were 65% and 100%, respectively.

In the melanoma cohort, the ORR and DCR were both 75%, and the PFS and OS rates at 1 year were a respective 58% and 79%.

The investigators highlight that the ORRs in the NSCLC and melanoma cohorts exceeded those from historical data, which range from 39–46% and 50–58%, respectively.

“This supports the potential of FMT to overcome primary resistance to ICI and will be assessed as part of the CanBiome2 randomized trial evaluating FMT (LND-101) in combination with ICI in 128 patients,” they say.

With regard to safety, AEs attributable to FMT occurred in 25% of patients with NSCLC and 35% of those with melanoma, and all were of grade 1.

There were no AEs of at least grade 3 that were attributable to FMT plus ICI therapy in the NSCLC cohort, but in the melanoma cohort 60% experienced a grade 3 AE and one (5%) patient had a grade 4 AE.

Elkrief and colleagues observed “a higher-than-expected” incidence of myocarditis in the melanoma cohort, at 15% compared with “an incidence of less than 1% in the literature,” and the trial’s data monitoring and safety committee deemed this “an AE of special interest for monitoring in future FMT trials.”

The team concludes: “Nonetheless, our data provide strong evidence in favor of the efficacy of FMT in the context of immune checkpoint inhibition.”

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