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Abstract
Background Pioneering studies in metastatic melanoma patients have suggested that fecal microbial transplantation (FMT) may overcome resistance to immune checkpoint inhibitors (ICI).1 2 We are conducting a single-arm phase IIa basket trial (MITRIC; NCT05286294) evaluating the safety, feasibility and efficacy of FMT to cancer patients not responding to ICI.
Methods MITRIC will enroll up to 20 patients with progressive disease on ICI therapy who will receive FMT from ICI-responders (>12 months response). Eligible patient groups are metastatic melanoma, cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma (HNSCC; >20% PD-L1), renal clear cell carcinoma, non-small cell lung cancer (>20% PD-L1) and micro-satellite instability high (MSI-H) solid cancers. Up to five FMT administrations of are given (first two by colonoscopy, 3rd-5th by clyster; figure 1). ICI treatment is kept unchanged from when progressive disease was recorded. The primary objectives are safety and objective tumor response (iRECIST). Secondary objectives include feasibility, clinical benefit rate (CBR), implant engraftment, patient reported outcomes and biomarkers.
Results Preliminary results are reported. As of 24 June 2024 nine patients with metastatic melanoma (n=6), renal clear cell carcinoma (n=1), MSI-H pancreatic cancer (n=1) or HNSCC (n=1) have been enrolled. Median age is 57 years, 7/9 patients are male. All enrolled patients received the first FMT, 8/9 received the 2nd FMT (after 4 weeks). Five patients (56%) have recorded stable disease (SD) as best response and 4 patients (44%) progressive disease. The CBR (SD> 6 months) is 1/8 (12.5%). Patient number 9 has ongoing SD not yet reaching 6 months. FMT-related adverse events (n=3) were all grade 1. Immune-related adverse events (irAEs) were all grade 1–2 and occurred in 3/9 patients. One patient experienced worsening of existing vitiligo (grade 2) and recurrent immune-related hepatitis (grade 2), eventually causing discontinuation of anti-PD-1. This patient had clinical benefit (SD >6 months, disappearance of non-target lung lesions). A different patient developed immune-related colitis grade 2 shortly after reintroduction of ICI (resolved after infliximab) and only received one FMT-treatment. This patient had progressive disease per iRECIST, but with regression of non-target lesions in bone and lymph nodes. 16S rRNA sequencing has been performed on fecal samples from 7 patients. Beta diversity analysis (Bray-Curtis dissimilarity between recipients and donors) suggested engraftment in 4/7 patients one week after the first FMT.
Conclusions FMT combined with continued ICI is feasible and safe in heavily pretreated patients. The first nine patients have not developed objective responses.
Trial Registration Clinicaltrials.gov: NCT05286294.
References
Davar D, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021;371:595–602.
Baruch EN, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021;371:602–609.
Ethics Approval The study was approved by the Regional Committee for Medical Research Ethics south-east B, Norway (reference# 2021/263149) and the Institutional Review Board. Written informed consent was obtained from all study participants.
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