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Fecal Microbiota Transplant Safety Goal Met in Kidney Cancer
TOPLINE:
Healthy donor fecal microbiota transplantation (FMT) combined with immune checkpoint inhibitors (ICI) in metastatic renal cell carcinoma demonstrated safety with a 50% objective response rate and no grade 4-5 toxicities. Successful engraftment of diverse, anti-inflammatory microbiota correlated with improved clinical response and reduced immune-related adverse events.
METHODOLOGY:
- Many patients with metastatic renal cell carcinoma who take ICI experience immune-related adverse events that may require treatment interruption. Recent studies have provided proof of concept for microbiome modulation as a therapeutic adjunct in metastatic renal cell carcinoma, with FMT showing efficacy in resolving TKI-induced toxicities. However, the safety and clinical activity of healthy donor FMT in metastatic renal cell carcinoma remained unexplored, and its mechanism of action was unclear prior to this study.
- The new phase 1 trial enrolled 20 treatment-naive patients with metastatic renal cell carcinoma classified as intermediate-risk or poor-risk disease, who received encapsulated healthy donor FMT (LND101) combined with ipilimumab plus nivolumab (n = 16), pembrolizumab plus axitinib (n = 3), or pembrolizumab plus lenvatinib (n = 1).
- Participants underwent polyethylene glycol bowel preparation before receiving one full dose (36-40 capsules containing 80-100 g of stool) and two half-doses (20-25 capsules each containing 50-60 g of stool) of FMT from rigorously screened healthy donors.
- The primary endpoint was safety assessed through incidence and severity of immune-related adverse events, while secondary endpoints included objective response rate by response evaluation criteria in solid tumors version 1.1, gut microbiome changes, immune correlates, and quality of life.
- Analysis included longitudinal monitoring of stool and blood samples at five timepoints: baseline, week 1 post-FMT, week 4, week 7, and week 10, with a median follow-up of 21.9 months.
TAKEAWAY:
- The safety endpoint was met, with half (10 of 20) of patients experiencing grade 3 immune-related adverse events and no serious FMT-related toxicities or grade 4-5 immune-related adverse events. One patient (5%) reported experiencing an FMT-related grade 1 gastrointestinal event.
- Among evaluable patients (n = 18), the objective response rate was 50% (9 of 18), including two complete responses (11%; 2 of 18), while 67% (12 of 18) achieved clinical benefit defined as complete response, partial response, or stable disease for at least 6 months.
- Higher alpha diversity and greater functional engraftment of short-chain fatty acid-producing and anti-inflammatory taxa correlated with protection from severe immune-related adverse events (P = .041) and improved therapeutic response (P = .006).
- Expansion of Segatella copri above 10 counts per million at 10 weeks post-FMT predicted severe toxicity in patients receiving ipilimumab plus nivolumab, regardless of donor or recipient microbiota origin.
IN PRACTICE:
These findings demonstrate the safety and potential for functional microbiome engraftment to optimize response and minimize toxicity in ICI-treated [metastatic renal cell carcinoma]. Together, our results underscore the importance of functional donor screening and targeted modulation of the microbiome in optimizing the safety and efficacy of next-generation immune-based therapies,” wrote the authors of the study.
SOURCE:
The study was led by Ricardo Fernandes, Behnam Jabbarizadeh, and Adnan Rajeh, London Health Sciences Centre, London, Ontario, Canada. It was published online on January 28 in Nature Medicine.
LIMITATIONS:
According to the authors, the study’s primary limitation was its small sample size, which was not powered to define the ideal donor microbiome composition for enhancing immunotherapy efficacy without additional toxicities. The single-center design and highly selected patient population may limit external generalizability, requiring validation in larger, multicenter trials to refine donor selection criteria and clarify microbiome-immunity mechanisms.
DISCLOSURES:
The clinical trial was primarily funded through philanthropic donations to co-authors Saman Maleki Vareki and Fernandes through the London Health Sciences Foundation clinical trials program. Vareki and Michael Silverman, another co-author, reported having US Patent application no. 63/913,940 related to FMT donor screening. Vareki reported receiving grants from the Lotte and John Hecht Memorial Foundation, the Weston Family Foundation, and the Canadian Institutes of Health Research. Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
Healthy donor fecal microbiota transplantation (FMT) combined with immune checkpoint inhibitors (ICI) in metastatic renal cell carcinoma demonstrated safety with a 50% objective response rate and no grade 4-5 toxicities. Successful engraftment of diverse, anti-inflammatory microbiota correlated with improved clinical response and reduced immune-related adverse events.
METHODOLOGY:
- Many patients with metastatic renal cell carcinoma who take ICI experience immune-related adverse events that may require treatment interruption. Recent studies have provided proof of concept for microbiome modulation as a therapeutic adjunct in metastatic renal cell carcinoma, with FMT showing efficacy in resolving TKI-induced toxicities. However, the safety and clinical activity of healthy donor FMT in metastatic renal cell carcinoma remained unexplored, and its mechanism of action was unclear prior to this study.
- The new phase 1 trial enrolled 20 treatment-naive patients with metastatic renal cell carcinoma classified as intermediate-risk or poor-risk disease, who received encapsulated healthy donor FMT (LND101) combined with ipilimumab plus nivolumab (n = 16), pembrolizumab plus axitinib (n = 3), or pembrolizumab plus lenvatinib (n = 1).
- Participants underwent polyethylene glycol bowel preparation before receiving one full dose (36-40 capsules containing 80-100 g of stool) and two half-doses (20-25 capsules each containing 50-60 g of stool) of FMT from rigorously screened healthy donors.
- The primary endpoint was safety assessed through incidence and severity of immune-related adverse events, while secondary endpoints included objective response rate by response evaluation criteria in solid tumors version 1.1, gut microbiome changes, immune correlates, and quality of life.
- Analysis included longitudinal monitoring of stool and blood samples at five timepoints: baseline, week 1 post-FMT, week 4, week 7, and week 10, with a median follow-up of 21.9 months.
TAKEAWAY:
- The safety endpoint was met, with half (10 of 20) of patients experiencing grade 3 immune-related adverse events and no serious FMT-related toxicities or grade 4-5 immune-related adverse events. One patient (5%) reported experiencing an FMT-related grade 1 gastrointestinal event.
- Among evaluable patients (n = 18), the objective response rate was 50% (9 of 18), including two complete responses (11%; 2 of 18), while 67% (12 of 18) achieved clinical benefit defined as complete response, partial response, or stable disease for at least 6 months.
- Higher alpha diversity and greater functional engraftment of short-chain fatty acid-producing and anti-inflammatory taxa correlated with protection from severe immune-related adverse events (P = .041) and improved therapeutic response (P = .006).
- Expansion of Segatella copri above 10 counts per million at 10 weeks post-FMT predicted severe toxicity in patients receiving ipilimumab plus nivolumab, regardless of donor or recipient microbiota origin.
IN PRACTICE:
These findings demonstrate the safety and potential for functional microbiome engraftment to optimize response and minimize toxicity in ICI-treated [metastatic renal cell carcinoma]. Together, our results underscore the importance of functional donor screening and targeted modulation of the microbiome in optimizing the safety and efficacy of next-generation immune-based therapies,” wrote the authors of the study.
SOURCE:
The study was led by Ricardo Fernandes, Behnam Jabbarizadeh, and Adnan Rajeh, London Health Sciences Centre, London, Ontario, Canada. It was published online on January 28 in Nature Medicine.
LIMITATIONS:
According to the authors, the study’s primary limitation was its small sample size, which was not powered to define the ideal donor microbiome composition for enhancing immunotherapy efficacy without additional toxicities. The single-center design and highly selected patient population may limit external generalizability, requiring validation in larger, multicenter trials to refine donor selection criteria and clarify microbiome-immunity mechanisms.
DISCLOSURES:
The clinical trial was primarily funded through philanthropic donations to co-authors Saman Maleki Vareki and Fernandes through the London Health Sciences Foundation clinical trials program. Vareki and Michael Silverman, another co-author, reported having US Patent application no. 63/913,940 related to FMT donor screening. Vareki reported receiving grants from the Lotte and John Hecht Memorial Foundation, the Weston Family Foundation, and the Canadian Institutes of Health Research. Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
Healthy donor fecal microbiota transplantation (FMT) combined with immune checkpoint inhibitors (ICI) in metastatic renal cell carcinoma demonstrated safety with a 50% objective response rate and no grade 4-5 toxicities. Successful engraftment of diverse, anti-inflammatory microbiota correlated with improved clinical response and reduced immune-related adverse events.
METHODOLOGY:
- Many patients with metastatic renal cell carcinoma who take ICI experience immune-related adverse events that may require treatment interruption. Recent studies have provided proof of concept for microbiome modulation as a therapeutic adjunct in metastatic renal cell carcinoma, with FMT showing efficacy in resolving TKI-induced toxicities. However, the safety and clinical activity of healthy donor FMT in metastatic renal cell carcinoma remained unexplored, and its mechanism of action was unclear prior to this study.
- The new phase 1 trial enrolled 20 treatment-naive patients with metastatic renal cell carcinoma classified as intermediate-risk or poor-risk disease, who received encapsulated healthy donor FMT (LND101) combined with ipilimumab plus nivolumab (n = 16), pembrolizumab plus axitinib (n = 3), or pembrolizumab plus lenvatinib (n = 1).
- Participants underwent polyethylene glycol bowel preparation before receiving one full dose (36-40 capsules containing 80-100 g of stool) and two half-doses (20-25 capsules each containing 50-60 g of stool) of FMT from rigorously screened healthy donors.
- The primary endpoint was safety assessed through incidence and severity of immune-related adverse events, while secondary endpoints included objective response rate by response evaluation criteria in solid tumors version 1.1, gut microbiome changes, immune correlates, and quality of life.
- Analysis included longitudinal monitoring of stool and blood samples at five timepoints: baseline, week 1 post-FMT, week 4, week 7, and week 10, with a median follow-up of 21.9 months.
TAKEAWAY:
- The safety endpoint was met, with half (10 of 20) of patients experiencing grade 3 immune-related adverse events and no serious FMT-related toxicities or grade 4-5 immune-related adverse events. One patient (5%) reported experiencing an FMT-related grade 1 gastrointestinal event.
- Among evaluable patients (n = 18), the objective response rate was 50% (9 of 18), including two complete responses (11%; 2 of 18), while 67% (12 of 18) achieved clinical benefit defined as complete response, partial response, or stable disease for at least 6 months.
- Higher alpha diversity and greater functional engraftment of short-chain fatty acid-producing and anti-inflammatory taxa correlated with protection from severe immune-related adverse events (P = .041) and improved therapeutic response (P = .006).
- Expansion of Segatella copri above 10 counts per million at 10 weeks post-FMT predicted severe toxicity in patients receiving ipilimumab plus nivolumab, regardless of donor or recipient microbiota origin.
IN PRACTICE:
These findings demonstrate the safety and potential for functional microbiome engraftment to optimize response and minimize toxicity in ICI-treated [metastatic renal cell carcinoma]. Together, our results underscore the importance of functional donor screening and targeted modulation of the microbiome in optimizing the safety and efficacy of next-generation immune-based therapies,” wrote the authors of the study.
SOURCE:
The study was led by Ricardo Fernandes, Behnam Jabbarizadeh, and Adnan Rajeh, London Health Sciences Centre, London, Ontario, Canada. It was published online on January 28 in Nature Medicine.
LIMITATIONS:
According to the authors, the study’s primary limitation was its small sample size, which was not powered to define the ideal donor microbiome composition for enhancing immunotherapy efficacy without additional toxicities. The single-center design and highly selected patient population may limit external generalizability, requiring validation in larger, multicenter trials to refine donor selection criteria and clarify microbiome-immunity mechanisms.
DISCLOSURES:
The clinical trial was primarily funded through philanthropic donations to co-authors Saman Maleki Vareki and Fernandes through the London Health Sciences Foundation clinical trials program. Vareki and Michael Silverman, another co-author, reported having US Patent application no. 63/913,940 related to FMT donor screening. Vareki reported receiving grants from the Lotte and John Hecht Memorial Foundation, the Weston Family Foundation, and the Canadian Institutes of Health Research. Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
Fecal Microbiota Transplant Safety Goal Met in Kidney Cancer
Fecal Microbiota Transplant Safety Goal Met in Kidney Cancer