Michael Harrop
Well-known member
https://jitc.bmj.com/content/13/8/e012659
Background
Microbiome manipulation research is focused on developing techniques to modify the gut microbiome and augment responses to immune checkpoint inhibitors (ICI). Fecal microbiota transplantation (FMT) represents a potential strategy to overcome primary or acquired resistance to ICI.
20 patients with advanced melanoma were enrolled in a phase I multicenter trial to evaluate the safety and response to anti-PD1 combined with FMT using healthy donor stool as first-line treatment (MIMic, NCT03772899). Combination therapy was safe, and the objective response rate (ORR) was 65%. We now report survival data based on over 3 years of follow-up.
Patients with advanced melanoma and treatment-naïve for advanced disease received a single FMT with healthy donor stool followed by standard anti-PD1 therapy. Progression-free survival (PFS) and overall survival (OS) were measured from the date of FMT to event. Radiographic response was measured using RECIST 1.1 criteria. Both median PFS (mPFS) and median OS (mOS) were determined using the Kaplan-Meier method. Post hoc analyses assessed the impact of specific factors on survival outcomes. Minimum follow-up was 40 months from the date of FMT of the last patient, with the longest surviving patient in complete response at 62.2 months.
At the time of data analysis, eight patients were alive and seven patients were without progression. No patients remain on anti-PD1 therapy. Only two patients received additional lines of therapy. The mPFS was 29.6 months and mOS 52.8 months. The 1, 2, and 3 years estimated survival rates were 95%, 74% and 53%, respectively. Post hoc analysis demonstrated significantly improved mPFS in responders and patients with FMT-specific toxicity. Combining first-line anti-PD1 therapy and oral FMT with healthy donor stool in this small cohort was safe and demonstrated an improvement in ORR, mPFS, and mOS, compared with randomized trials.
Our sample size was small, and results were only hypothesis generating. The potential benefit of microbiome manipulation using oral FMT from healthy donors prior to ICI in patients with advanced melanoma will be evaluated in the ME.17 randomized phase 2 Canadian study (NCT06623461).
Patients received an oral FMT from one of three healthy donors
We demonstrated successful microbial engraftment of donor stool, which was linked to clinical response.12 Alpha-diversity increased in all patients post-FMT. However, the acquired similarity between donor and recipient was sustained over time only in responders (R).
Patients were pretreated with a PEG-based bowel preparation the day before FMT. No antibiotics were used. The microbial FMT product contained stool from a single healthy donor following our stringent selection criteria.12 13 Three male donors were used for the study. Patients consumed 35–40 capsules, equivalent to 80–100 g of stool, as a single treatment.
FMT-specific toxicities (FT) were gastrointestinal (GI)-related and grade 1–2 in severity per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5). There was no increase in the incidence of irAEs combining FMT and anti-PD1. Five (25%) patients experienced grade 3 toxicity, and there were no grade 4 or 5 irAEs. The ORR as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and iRECIST criteria was higher than expected at 65%, with 4 patients having a complete response (CR).
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