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Fecal microbiome transplant (FMT) produced mixed results for stimulating response to immunotherapy in advanced melanoma, according to two preliminary studies.

In one trial, a donor FMT plus a PD-1 inhibitor led to objective responses in two-thirds of patients with newly diagnosed advanced melanoma, about 50% higher than observed in trials of single-agent immunotherapy. Three- fourths of the patients obtained clinical benefit, reported Saman Maleki, PhD, of Western University in London, Ontario.

FMT was associated with increased microbiome diversity in recipients, although increased diversity did not appear to improve response. Engraftment retention was associated with clinical response FMT, he said in a presentation at the Society for Immunotherapy of Cancer (SITC) meeting in Boston.

"The combination of healthy donor fecal microbiome transplant with anti-PD1 therapy is safe in melanoma in the front line, as it was the first time it was tested in this setting," said Maleki. "Donor fecal microbiome transplant can induce response to anti-PD1 therapy and potentially reduce primary resistance to immunotherapy."

A second small clinical study showed no benefit of FMT, as patients who received placebo plus immunotherapy had a numerically higher response rate and longer progression-free survival (PFS).

"The trial demonstrated the feasibility of such a multicenter, randomized, placebo-controlled trial, delivering an oral microbiome intervention in conjunction with immunotherapy for cancer patients," said Isabella Glitza Oliva, MD, PhD, of the MD Anderson Cancer Center in Houston. "In depth analysis of longitudinal microbiome data suggest the importance of choosing the right preconditioning antibiotic regimen, in terms of duration, timing, and time of antibiotic."

"We all agree that more work is needed to study preconditioning dosing strategies, as well as other nuances and environmental and patient-related factors, in order to truly optimize the potential effect of an oral microbiome intervention," she stated.

An has shown that the gut microbiome influences the induction and activity of CD8+ and CD4+ T cells and affect that function of checkpoint inhibitors. Recently two different research groups showed that via FMT from patients who had previously responded to cancer immunotherapy to anti-PD1 therapy.

Continuing the line of research, Maleki and colleagues conducted a prospective clinical trial to evaluate the effect of donor FMT on anti-PD1 therapy in untreated advanced melanoma. Investigators enrolled 20 patients, who underwent bowel prep without antibiotics. A week before starting anti-PD1 therapy, patients received encapsulated fecal microbiota from three healthy donors. One patient had received adjuvant anti-PD1 therapy, but none had received an anti-PD1 agent for metastatic disease.

No FMT-related grade ≥3 adverse events (AEs) occurred. Grade 1/2 AEs consisted primarily of diarrhea (six patients) and flatulence (four). No unexpected AEs occurred during anti-PD1 therapy.

Efficacy data showed three complete responses and 10 partial responses for an overall response rate (ORR) of 65%. Two other patients had stable disease, resulting in a clinical benefit rate of 75%.

The results compared favorably with two prior trials of single-agent anti-PD1 therapy in similar patients, Maleki noted. The of nivolumab (Opdivo) resulted in an ORR of 45%, and KEYNOTE-006 with pembrolizumab (Keytruda) produced an ORR of 44%.

FMT led to increased microbiome diversity, mirroring that of the donors, and thereafter the diversity remained stable over time. Responses were observed with fecal microbiota obtained from all three donors.

"What was really key was engraftment and retention of the donor microbiome in terms of responders versus nonresponders," said Maleki. "Responders had engraftment that lasted over time, whereas we did not see that in nonresponders."

In particular, responding patients' microbiome had enrichment of Ruminococcus callidus, Alistipes communis, and Ruminococcaceae.

Post-FMT analysis of plasma metabolites showed an increase in histidine, which has been reported as a favorable prognostic factor for patients treated with anti-PD1 agents, said Maleki.

Oliva reported findings from a multicenter, randomized trial that was terminated early because of slow accrual during the COVID-19 pandemic. Patients received SER-401, an investigational fecal microbiome preparation enriched with Ruminococcaceae and other spore-forming microbes.

In contrast to the patients in Maleki's study, those enrolled in the SER-401 trial underwent preconditioning with vancomycin on the basis of clinical experience in ulcerative colitis. All patients received nivolumab following administration of the investigational therapy.

"Our hypothesis was that SER-401 treatment would increase the relative abundance of spore forming bacteria, in particular Ruminococcaceae, above preantibiotic baseline and placebo values," said Oliva.

Data analysis comprised 14 patients, eight assigned to SER-401 and six to placebo. All patients had a median follow-up of 15.9 months.

As expected, the abundance of Ruminococcaceae declined after preconditioning but recovered by cycle 1, day 1 in the SER-401 group.

The efficacy data showed one complete response and one partial response (ORR 25%) in the SER-401 arm versus four partial responses (ORR 66.6%) in the placebo arm. Three patients in the SER-401 arm and one in the placebo arm had stable disease. Median PFS was 5.2 months with SER-401 versus 15.0 months with placebo.

"This study really highlights the complexities involved in the dynamic of gut microbiome modulation with a human investigational therapeutic, such as SER-401, and specifically demonstrates the careful consideration needed in choosing a preconditioning regimen and dosing strategies," said Oliva.