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).
Keywords: Immune Checkpoint Inhibitor, Skin Cancer, Combination therapy
Introduction
Immune checkpoint inhibitor (ICI) therapy with antibody agents against programmed death 1 (PD1), lymphocyte activation gene 3 (LAG3), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has greatly improved survival outcomes for patients with advanced melanoma.1–5 With respect to anti-PD1 monotherapy, studies showed significant benefit with pembrolizumab and nivolumab. The objective response rate (ORR) was 32.9% with 3-weekly pembrolizumab in the KEYNOTE-006 study,5 the median progression-free survival (mPFS) was 9.4 months, and the median overall survival (mOS) was 32.7 months.3 The CheckMate 067 trial demonstrated an ORR of 44% in the nivolumab alone group, a mPFS of 6.9 months, and a mOS of 36.9 months.2 4
Despite these impressive results, not all patients derive benefit from ICIs, with nearly half experiencing primary resistance to anti-PD1 therapy alone.1–5 The gut microbiome has been implicated for its role in primary resistance to ICI through dysregulation of the immune response. Microbiome profiling of gut bacteria helped identify certain taxa associated with response, resistance, and immune-related adverse events (irAEs).6–9 In the first of their kind studies, two trials demonstrated that in patients with advanced melanoma refractory to ICI, fecal microbiota transplantation (FMT) using stool from patients with long-term responses to ICI therapy combined with anti-PD1 rechallenge circumvented resistance in a small number of patients.10 11
In a phase I safety trial, MIMic (NCT 03772899), we enrolled 20 adult patients with advanced melanoma across 3 academic centers in Canada.12 Patients naïve to anti-PD1 therapy in the advanced/metastatic setting and not appropriate for combination immunotherapy were eligible. Patients received an oral FMT from one of three healthy donors.12 13 ICI therapy was single-agent anti-PD1 with either 4-weekly nivolumab or 3-weekly pembrolizumab by physician’s choice. The primary endpoint was safety, with secondary endpoints including ORR, mPFS, and mOS. We anticipated that primary resistance may be avoided with a shift towards a more healthy gut microbiome prior to commencing ICI.
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).
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). The microbiome composition of R patients was enriched with Ruminococcus, Faecalibacterium, and Eubacterium, with downregulation in Enterocloster species, consistent with data suggesting improved responses to ICI.6–9 Our results showed that FMT with healthy donor stool safely improved microbiome health and suggested improved outcomes compared with both randomized controlled-trial (RCT) data and real-world data. Here, we present the survival analysis for the entire cohort at more than 3 years after enrollment and treatment of the last patient.
Methods
MIMic was a multicenter, single-arm phase I safety trial evaluating the addition of oral FMT using healthy donor stool to single-agent anti-PD1 immunotherapy in patients with advanced cutaneous melanoma. Patients were recruited at outpatient cancer centers from three academic centers in Canada. Key inclusion criteria were patients aged ≥18 years, measurable disease as per RECIST 1.1 criteria, most appropriate for single-agent anti-PD1 therapy, and with an Eastern Cooperative Oncology Group (ECOG) 0–2. Previous BRAF±MEK inhibitor therapy was allowed for those with a BRAF V600 mutated tumor. Key exclusion criteria were prior ICI therapy in the advanced setting, active CNS disease, daily use of corticosteroids >10 mg, antibiotics within 2 weeks before FMT, ongoing use of probiotic supplements, or contraindications to FMT such as toxic megacolon.
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. After FMT, a minimum duration of 7 days was required before the first dose of anti-PD1 allowing microbial engraftment. Anti-PD1 therapy was given at standard dosing of either nivolumab (4 weekly) or pembrolizumab (3 weekly) for up to 24 months, at the discretion of the treating oncologist. Both treatments were publicly funded through the provincial healthcare systems. Patients received anti-PD1 as per standard of care with imaging every 3 months to assess response. A complete methodology was previously published.12
The MIMic trial was approved by the insitutional research board (IRB) at each participating center. The study was conducted in accordance with Good Clinical Practice guidelines as defined by the International Council for Harmonization and the Declaration of Helsinki. All patients provided written informed consent. A data safety monitoring committee verified the safety of trial participants. The study is registered at ClinicalTrials.gov (NCT 03772899).
Responses were evaluated using RECIST 1.1 criteria, and iRECIST when applicable. Those with a CR or a partial response (PR) as best overall response were considered responders (R). Non-responders (NR) were patients without CR/PR, but included those with stable disease ≥6 months (SD). The ORR was calculated as the proportion of patients achieving CR/PR. PFS was considered the time between FMT and the date of first-documented disease progression, or death due to any cause, whichever occurred first. OS was considered as the time between FMT and the date of last contact or death. Patients who did not progress or die at the time of data evaluation were censored on the date of their last evaluable tumor assessment or clinical follow-up, whichever occurred last.
The times to event distributions, including mPFS, mOS, median melanoma-specific survival (mMSS), and median duration of response, were estimated using the Kaplan-Meier method and performed with GraphPad Prism V.10.3.1 (San Diego, California). A post hoc analysis of specific cohorts included mPFS and mOS as per the Kaplan-Meier method, with p values determined using the log-rank test. A p≤0.05 was considered statistically significant. Continuous variables were summarized using the number, median, minimum and maximum values, and percentage as appropriate.
Metagenomic sequencing data were reanalyzed using raw FASTQ files. Initial preprocessing involved trimming sequencing primers, removing reads <75 bp, and discarding low-quality reads (quality score <Q20). Contaminant DNA was filtered out by mapping reads against the human-associated reads (hg19) and phiX174 Illumina spike-in using Bowtie214 V.2.5.4 with very-sensitive-local parameters. Reads were paired and prepared for downstream analyses.
Microbial taxonomic profiling was performed using MetaPhlAn V.4.1.115 with the mpa_vJun23 reference database determining species-level relative abundances. Functional profiling was conducted using HUMAnN V.3.916 to identify gene families based on the UniRef90 database, followed by mapping to enzyme commission (EC) numbers using level4ec_uniref90 utility.
Microbial and survival statistical analysis was executed using R V.4.3.3. Patients were stratified into two groups based on PFS less than or greater than mPFS, categorizing them as short-term survivors (STS) and long-term survivors (LTS), respectively. Differential analysis identified significant microbial species or ECs associated with outcomes at specific sampling points: timepoint 2 (S2, post-FMT) was used for associations with FMT toxicity, and time point 3 (S3, post-anti-PD1 dose 1) with PFS. The Wilcoxon test was used to determine significance between groups. Heatmaps were generated using the pheatmap library V.1.0.12, and additional visualizations were created with ggplot2 V.3.5.1.
Results
Between June 2019 and September 2021, 20 patients received FMT and anti-PD1 therapy. The median age was 75.5 years (48–90) with 60% of patients biologically male. 95% had an ECOG 0–1. 90% had stage IV disease, 45% with lung metastases, and 15% with CNS metastases. 4 (20%) had a baseline lactate dehydrogenase (LDH) >upper limit of normal. 30% were BRAF V600 mutated, although none received prior targeted therapy for advanced disease. Only two patients received subsequent systemic therapy; one received eight months of temozolomide, and the other anti-BRAF-MEK therapy, nivolumab plus ipilimumab, and a BRAF-MEK rechallenge. Both patients had CNS disease and received palliative radiation to the brain metastases. Patient and tumor characteristics are listed in table 1.
Table 1.
Patient characteristics in the MIMic trial (N=20)
| Characteristic | n |
| Median age in years (range) | 75.5 (48–90) |
| Sex (n, %) | |
| Female | 8 (40) |
| Male | 12 (60) |
| ECOG performance status (n, %) | |
| 0–1 | 19 (95) |
| 2 | 1 (5) |
| AJCC eighth edition staging at enrollment (n, %) | |
| Stage III unresectable (M0) | 2 (10) |
| Skin, soft tissue±nonregional nodes (M1a) | 3 (15) |
| Metastases to the lung (M1b) | 9 (45) |
| Visceral metastases with no CNS involvement (M1c) | 3 (15) |
| CNS metastases (M1d) | 3 (15) |
| Baseline LDH (n, %) | |
| Normal | 16 (80) |
| >ULN | 4 (20) |
| BRAF status (n, %) | |
| V600 Mutated | 6 (30) |
| Wild-type | 14 (70) |
| Patients with subsequent lines of therapy (n, %) | |
| 0 | 18 (90) |
| 1 | 1 (5)* |
| ≥2 | 1 (5)† |
*BRAF wild-type.
†BRAF V600 mutated.
AJCC, American Joint Committee on Cancer; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; LDH, Lactate Dehydrogenase; RECIST, Response Evaluation Criteria in Solid Tumors; ULN, upper limit of normal.
After 40 months of follow-up from the date of FMT for the last patient enrolled and median duration of follow-up of 52.8 months (2.1-NR), the mPFS was 29.6 months (1.8-NR) and mOS was 52.8 months (1.8-NR) (figure 1A,B). At the time of data censoring (January 21, 2025), eight patients were alive with the longest ongoing follow-up at 62.2 months. None were on active therapy and seven without disease progression. Median time on treatment was 12.9 months (0.7–24.0). Median time to response was 3.0 months (1.3–6.0), and median duration of response was 49.9 months (14.0–NR) for the 13 responders. The mMSS was 55.0 months and not significantly different than the mOS (p=0.4778) (online supplemental figure S1). The estimated 1-year and 2-year MSS and OS rates were the same at 95% and 74%, but diverged at year 3 at 63% and 53%, respectively.
Figure 1.
Survival outcomes for patients with advanced melanoma treated with FMT and anti-PD1 therapy. (A) Median progression-free survival (PFS) and (B) median overall survival (OS) for the entire MIMic cohort (n=20). (C) Median PFS and (D) median OS for the 13 responders (R) compared with the 7 non-responders (NR). (E) Median PFS and (F) median OS for the 12 patients without FMT-specific Toxicity (NFT) compared with the 8 patients who experienced FMT-specific toxicity (FT). Estimated survival at 1, 2, and 3 years indicated by horizontal lines. FMT, fecal microbiota transplantation.
jitc-13-8-s001.pdf (375.9KB, pdf)
A post hoc analysis of subgroups including response status, development of FT, sex, treatment location by city, and individual healthy stool donor was completed to determine differences in mPFS and mOS. The mPFS for R patients was 52.8 months compared with 5.2 months for NR patients (p=0.0016), and mOS was 52.8 months vs 17.6 months, respectively (p=0.0628) (figure 1C and D). Of the 13 R patients, 2 died from melanoma and 2 others were presumed to have died from melanoma near the time of progression, 3 died of causes unrelated to melanoma, and 6 remained alive and without progression on the date of censoring (online supplemental table S2). The time on treatment ranged from 4.7 to 24.0 months with only 4 completing 2 years of therapy. As reported in the initial publication, eight patients experienced FT, defined as those experienced after FMT and prior to first dose of anti-PD1. All were GI-related and grade 1–2 per NCI-CTCAE v5. The eight patients with FT were all responders, and their details are shown in online supplemental table S3. The mPFS was 52.8 months for FT vs 15.9 months for no FT (NFT) (p=0.0364). The mOS for FT patients was 53.9 months compared with 24.6 months for NFT patients (p=0.0610) (figure 1E,F). Analysis of mPFS and mOS for patient sex, treatment location, and individual donor revealed no statistically significant difference in outcomes (online supplemental figure S2A-F).
Functional enzyme analysis revealed that FT patients harbored microbiomes enriched in glycan-modifying enzymes (eg, chondroitin-sulfate ABC endolyase), fermentative metabolism (eg, lactoyl-CoA dehydratase), and selenocysteine biosynthesis, consistent with enhanced engraftment and mucosal immune conditioning. In contrast, NFT patients displayed higher levels of oxidative and xenobiotic-associated enzymes (eg, sarcosine oxidase), suggesting divergent microbiome-host interactions potentially linked to differential clinical outcomes (figure 2A). Patients with FT exhibited a distinct microbial profile enriched in beneficial, short-chain fatty acid (SCFA)-producing taxa such as Blautia wexlerae, Roseburia hominis, and Intestinimonas butyriciproducens (figure 2B). This group demonstrated significantly improved mPFS, suggesting that mild early-onset GI toxicity reflects successful microbiota engraftment and immune priming, ultimately correlating with enhanced ICI efficacy.6 8 17
Figure 2.
Post hoc analysis of patients receiving FMT combined with anti-PD1 therapy and toxicity related to FMT. (A) Functional metagenomic profiling of patients who experienced FMT-specific toxicity (FT) compared with patients without FMT-related toxicity (NFT) from baseline (S1) to after FMT (S2). (B) Change in abundance of key taxa from baseline sample (S1) to after FMT sample (S2) for FT patients compared with NFT. FMT, fecal microbiota transplantation.
Seven of 10 LTS reported FMT-related toxicity and all experienced irAEs. Only one STS reported FMT-related toxicity but had an OS of 55.0 months (online supplemental table S4). Microbiome analysis of STS and LTS demonstrated taxonomic differences between the groups. LTS were enriched post-FMT for several commensal bacteria, including Alistipes communis, Faecalibacterium prausnitzii, and Bacteroides ovatus, species associated with favorable outcomes to ICI. STS experienced enrichment of Hungatella hathewayi associated with poor gut health and reduced ICI response (figure 3A). Functional metagenomic profiling revealed that STS harbored microbiota enriched for oxidative and stress-related pathways, including formate–tetrahydrofolate ligase and 2-aminophenol dioxygenase, associated with pro-inflammatory or dysbiotic microbial metabolism.18 19 In contrast, LTS showed enrichment in enzymes involved in amino acid and SCFA biosynthesis including hydroxybutyryl-CoA dehydrogenase and D-proline reductase, suggesting a role for metabolically supportive and immunomodulatory bacterial functions in enhancing ICI efficacy20–22 (figure 3B).
Figure 3.
FMT-induced taxonal and enzymatic pathway activation for short-term versus long-term survivors (STS/LTS) based on median progression-free survival (mPFS). (A) Microbiome analysis showing statistically significant taxonomic differences by key species based on mPFS for patients with PFS less than the mPFS considered STS, compared with patients with PFS beyond mPFS considered LTS. (B) Functional metagenomic profiling of STS compared with LTS from baseline sample (S1) compared with after FMT and first dose of anti-PD1 therapy sample (S3). FMT, fecal microbiota transplantation.
Discussion
Early results from the MIMic trial demonstrated that combining oral FMT capsules with healthy donor stool and anti-PD1 as first-line therapy in patients with advanced melanoma is safe.12 Furthermore, the effects of FMT on the gut microbiome at a taxonal level demonstrated a positive and sustained shift in R patients. The ORR of 65% was higher than expected from RCTs and real-world data (17.2%–51.6% ORR).2–5 23–25 Here, we present the survival results for the entire cohort and key post hoc subgroups. Similar to the response rates, mPFS and mOS were much higher than expected compared with RCTs and real-world data (11.8–12.5 months mPFS and 30.0–39.6 months mOS).23–25 The estimated survival at years 1 (95%), 2 (74%), and 3 (53%) was higher than in RCTs (68%–72%, 55%–63%, and 40%–52%).2 3 By year 3, the MSS exceeded that of the OS, similar to the trend seen in the 10-year results of CheckMate 067.2 There was no statistically significant difference between the mOS and mMSS in our study, likely related to the small cohort, only three patients had a non-melanoma death, and the high number of patients alive at the time of censoring. The improvements in clinical outcomes observed in this small single-arm study support the role of FMT before anti-PD1 in patients with advanced melanoma who are treatment-naïve in the advanced setting. There was no clear donor effect for the entire cohort who received stool from one of three male donors.
Post hoc analysis of our results showed a significant increase in mPFS for R patients compared with NR patients. Although the improvement in mOS was large in R patients compared with NR, it only approached significance, possibly due to the small sample size. All eight patients with FT were responders, including the four with a CR. The mPFS for patients with FT was significantly better than for NFT. There was no statistically significant difference in mOS for those with FT compared with NFT, although it also approached significance. However, 5 of the 13 patients who were responders did not experience FMT-related toxicity. Since R patients experienced stable engraftment of donor taxa over time, it is possible that there was an important difference in compatibility between donor and recipient leading to FMT-related toxicity, although only grade 1–2. FMT-related toxicity may be a marker of an improvement in microbial fitness.
Microbiome and functional analyses revealed that LTS harbored enriched communities of SCFA-producing taxa and associated metabolic pathways, including butyrate metabolism and glycan degradation, while STS showed enrichment in stress-associated microbial functions such as oxidative metabolism and nucleotide salvage. Similarly, patients who experienced FT demonstrated a distinct enrichment of immunomodulatory bacteria and glycan-modifying enzymatic functions and experienced superior clinical outcomes. These converging patterns suggest that early post-FMT immune activation, possibly driven by successful engraftment of metabolically fit microbiota, may contribute to both toxicity and long-term therapeutic benefit.
Limitations of this trial are the small sample size, lack of an anti-PD1 alone comparator arm, and patient selection for single-agent anti-PD1 therapy over combination therapy. This small cohort does not have the statistical power required to determine differences in outcomes, and the results are only hypothesis generating. Without a control arm, it is not possible to account for factors other than FMT that may have impacted results. The patients enrolled were not appropriate for combination immunotherapy, possibly leading to bias in patient selection.
The benefits of combining our FMT product LND101 with ICIs are now being assessed in the pan-Canadian ME.17 phase II randomized trial (NCT06623461), conducted by the Canadian Cancer Trials Group and will include investigator’s choice of an ICI backbone (anti-PD1, anti-PD1+anti-CTLA-4, or anti-PD1+anti-LAG-3) with or without FMT.
Conclusions
ICIs significantly improve outcomes for many patients with advanced melanoma, including some with a durable response and improved long-term survival. The gut microbiome influences the response to ICIs and microbiome manipulation with oral FMT capsules in this small cohort was safe and appeared to improve clinical outcomes and possibly avoid primary resistance. A study is underway to characterize the actual benefit, if present, of this combination therapy.
jitc-13-8-s002.pdf (304.7KB, pdf)
Acknowledgments
We would like to thank the patients and their families. We also thank the Clinical Research Unit at the Verspeeten Family Cancer Centre-LHSC for managing the trial.
Footnotes
@smimmunology
Contributors: SMV conceived the study; SMV and JGL designed the study and co-wrote the protocol; JGL, WHM, RJ, DSE, DL, KB and KE recruited and treated patients; SMV and BR designed and supervised the translational studies; SNP and MS prepared and administered FMT capsules; JGL, DKH, SMV, BR, AE, KJB and BJ collected/analyzed data. KJB, BJ and JGL generated figures; DKH, JGL and SMV wrote the manuscript. All authors contributed to reviewing and approving the final manuscript. JGL is the guarantor.
Funding: This trial was funded by a grant from the Lotte and John Hecht Memorial Foundation awarded to SMV (4324), a grant from the Division of Medical Oncology at Western University awarded to JGL and SMV (no grant number), and a Canadian Cancer Society Impact grant supported by the Lotte and John Hecht Memorial Foundation awarded to BR, SMV, and AE (706672).
Competing interests: BR has received research funding from Kanvas Bioscience as well as consulting fees from Merck, AstraZeneca, Novartis, and BMS. He is the cofounder of Curebiota. RJ has received honoraria from Pfizer, BMS GmbH & Co. KG, Merck KGaA, and Novartis as well as consulting fees from medison pharma, Pfizer, Merck GKaA, and Novartis. The institution receives research funding from Merck Sharp & Dohme, BMS, Iovance Biotherapeutics, Pfizer, BioNTech SE, Astellas Pharma, Pacylex, Novartis, VelosBio/Merck, alkermes, Surface Oncology, Boehringer Ingelheim, Immunocore, Evelo Biosciences, AstraZeneca/MedImmune, Roche/Genentech, and Takeda. SMV was a member of the Board of Directors at IMV and receives consulting fees from Kanvas Bioscience and FedBio. All other authors have declared no conflicts of interest.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
Data availability statement
Data are available on reasonable request. Data are available from the corresponding author on reasonable request. Metagenomic sequencing data are available in NCBI Sequence Read Archive under the accession number PRJNA928744.
Ethics statements
Patient consent for publication
Not applicable.
Ethics approval
This study involves human participants and was approved by the Western University Health Sciences Research Ethics Board (HSREB) Project ID 113131. All participants provided written informed consent.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
jitc-13-8-s001.pdf (375.9KB, pdf)
jitc-13-8-s002.pdf (304.7KB, pdf)
Data Availability Statement
Data are available on reasonable request. Data are available from the corresponding author on reasonable request. Metagenomic sequencing data are available in NCBI Sequence Read Archive under the accession number PRJNA928744.