Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation in Melanoma: Impact of Antibiotic Preconditioning on Microbiome and Immunity
Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metasta...
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| Published in | Cancer discovery Vol. 14; no. 7; pp. 1161 - 1175 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Association for Cancer Research
01.07.2024
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| Subjects | |
| Online Access | Get full text |
| ISSN | 2159-8274 2159-8290 2159-8290 |
| DOI | 10.1158/2159-8290.CD-24-0066 |
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| Abstract | Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials.
Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti–PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.
See author Yongwoo David Seo discuss this research brief, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932607668/63addff7fc |
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| AbstractList | Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials.
Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti–PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.
See author Yongwoo David Seo discuss this research brief, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932607668/63addff7fc Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials. Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutes-enriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an objective response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was under-powered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials. Longitudinal gut microbiome and immune analysis from randomized microbiome modulation in melanoma patients treated with nivolumab reveal novel insights about the impact of antibiotic preconditioning on immunity. Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti–PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials. |
| Author | Fairchild, Justin Sullivan, Ryan J. Cabanski, Christopher R. Hicks, Nathan Henn, Matthew R. Densmore, Julie Hamid, Omid Burton, Elizabeth M. LaVallee, Theresa Ajami, Nadim J. Spencer, Christine N. Wargo, Jennifer A. Alayli, Farah A. Tetzlaff, Michael T. Aunins, John Seo, Yongwoo David Wong, Matthew C. Glitza, Isabella C. Loo, Christopher P. Walsh, Emily McChalicher, Christopher Tawbi, Hussein A. Peterson, Christine B. Wortman, Jennifer R. Gautam, Shikha Boland, Genevieve M. Weiner, Brian Damania, Ashish Ott, Patrick A. Grossmann, Kenneth F. |
| AuthorAffiliation | 7 Portage Biotech, Westport, Connecticut 4 Seres Therapeutics, Cambridge, Massachusetts 17 Coherus BioSciences, Redwood City, California 9 Department of Pathology, University of California San Francisco, San Francisco, California 11 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 10 Cutaneous Oncology, The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, California 15 Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 5 Strategic Translational Research Initiative Development, The University of Texas MD Anderson Cancer Center, Houston, Texas 12 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 13 Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 6 Platform for Innovative Microbiome and Translational Research, Moon Shots Progr |
| AuthorAffiliation_xml | – name: 17 Coherus BioSciences, Redwood City, California – name: 12 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts – name: 2 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – name: 11 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts – name: 10 Cutaneous Oncology, The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, California – name: 3 Parker Institute for Cancer Immunotherapy, San Francisco, California – name: 5 Strategic Translational Research Initiative Development, The University of Texas MD Anderson Cancer Center, Houston, Texas – name: 16 Providence Cancer Institute Franz Clinic, Portland, Oregon – name: 7 Portage Biotech, Westport, Connecticut – name: 14 Broad Institute of MIT and Harvard, Cambridge, Massachusetts – name: 4 Seres Therapeutics, Cambridge, Massachusetts – name: 1 Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas – name: 18 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas – name: 9 Department of Pathology, University of California San Francisco, San Francisco, California – name: 13 Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts – name: 15 Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts – name: 6 Platform for Innovative Microbiome and Translational Research, Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, Texas – name: 8 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/38588588$$D View this record in MEDLINE/PubMed |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3 I.C. Glitza, Y.D. Seo, C.N. Spencer, and J.R. Wortman contributed equally to this article. T. LaVallee, M.R. Henn, H.A. Tawbi, and J.A. Wargo are the co-senior authors of this article. Cancer Discov 2024;14:1161–75 |
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