De-correlating immune checkpoint inhibitor toxicity and response in melanoma via the microbiome.

Authors

null

Nyelia Williams

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH

Nyelia Williams , Caroline E. Wheeler , Marium Husain , Rebecca Hoyd , Alexa Simon Meara , Mari Lynn , Amna Bibi , Bailey Conrad , Shannon Gray , Michael Bodnar , Namrata Arya , Scott Roberts , Phuong Hoang , Jessica Apparicio , Deanna Merrill , Richard Cheng Han Wu , Claire F. Verschraegen , Christin Elizabeth Burd , Kari Lynn Kendra , Daniel Spakowicz

Organizations

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, The Ohio State University Medical Center, Columbus, OH, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, OH, The Ohio State University, Columbus, OH, The Ohio State University Comprehensive Cancer Center, Columbus, OH, Ohio State College of Medicine, Columbus, OH, University of South Florida, Tampa, FL, Mayo Clinic, Rochester, MN, The James Cancer Hospital and Solove Research Institute, Columbus, OH, The Ohio State University James Cancer Center, Columbus, OH, The Ohio State University Wexner Medical Center, Columbus, OH

Research Funding

Other
Pelotonia

Background: Immune-checkpoint inhibitor (ICI) immunotherapy increases survival in patients with melanoma. Yet only half of the patients respond, and 10-40% of patients experience immune-related adverse events (irAEs). Previous studies have found a correlation between the development of an irAE and treatment response. Modifying the gut microbiome could positively affect response to ICIs and reduce toxicities. We sought to determine if the microbiome at the onset of treatment, during an irAE, and at 12 weeks, can predict the response or toxicity during ICI treatment for metastatic melanoma. Methods: Melanoma patients (pts) > 18 yo treated with ICI enrolled in a prospective observational cohort study at The Ohio State University Comprehensive Cancer Center Skin Cancer Clinic. Excluded were patients on corticosteroids at the start of ICI cycle 1, except for adrenal physiologic replacement. Stools were collected at baseline, within 2 days of an adverse event assessed by physician chart review using CTCAE (Common Terminology Criteria for Adverse Events) v5.0, and at 12 weeks. Response (ORR) to ICIs was assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) q12 weeks and progression-free survival recorded. Metagenomic whole-genome shotgun sequencing was performed on an Illumina NovaSeq 6000 and classified using HUMAnN3. The effect of microbe relative abundances on irAEs was modeled by logistic regression with the R package glmm. Results: Of the 88 patients enrolled, 48 had metastatic disease with 32 assessable for response. ORR at 12 weeks was 28% (1 CR, 8 PR, 17 SD, and 6 PD) and 24 patients showed PFS at 12 months. Grade > 2 irAEs were observed in 11/48 pts. Abundance of Bacteroides dorei (False Discovery Rate Corrected p-value = 9.5E-07) and Blautia species CAG:257 (padj = 0.001) were enriched in responders, Prevotella Stercorea (padj = 1.1E-07) and a phage with a predicted target of Salmonella (padj = 8.3E-09) in non-responders. Responders with an irAE had enrichment of Bacteroides plebeius (padj = 4.2E-13) and Bacteroides coprophilus (padj = 0.0002) whereas responders without irAE had enrichment of Eubacterium siraeum (padj = 7.2E-05). Conclusions: Longitudinal and event-driven biospecimen collection in patients treated with ICIs showed several bacteria and viruses but no fungi associated with response, with and without the development of an irAE. The abundance of the two high-taxonomic rank microbe groups is significantly associated with irAEs. The association with the BacteroidesGenus is consistent with previous studies and is associated with response to ICIs. A microbiome abundant in Bacteroides and lacking Prevotella is associated with response to ICI. An abundance of Bacteroides could be a biomarker for irAEs, and an abundance of Eubacterium, a biomarker for response without irAEs. Future analyses are necessary to assign causal roles for microbe biomarkers with specific irAEs. Clinical trial information: NCT05102773.

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Abstract Details

Meeting

2023 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Melanoma/Skin Cancers

Track

Melanoma/Skin Cancers

Sub Track

Biologic Correlates

Clinical Trial Registration Number

NCT05102773

Citation

J Clin Oncol 41, 2023 (suppl 16; abstr 9569)

DOI

10.1200/JCO.2023.41.16_suppl.9569

Abstract #

9569

Poster Bd #

332

Abstract Disclosures