Abstract CT022: Evaluation of oral microbiome profiling as a response biomarker in squamous cell carcinoma of the head and neck: Analyses from CheckMate 141

Abstract

Introduction: Recent studies indicated that specific intestinal microbiota may modulate efficacy of anti-PD-1 and anti-CTLA-4 immunotherapy in preclinical tumor models (Sivan et al, Science. 2015;350:1084-9; Vétizou et al, Science. 2015;350:1079-84). However, little is known regarding the association of the oral microbiome with checkpoint blockade immunotherapy. In CheckMate 141 (NCT02105636), a randomized global phase 3 study comparing nivolumab with investigator’s choice (IC) therapy in patients with platinum-refractory squamous cell carcinoma of the head and neck (SCCHN), nivolumab improved median overall survival compared with IC (7.5 vs 5.1 months; P=0.01) (Ferris et al, NEJM. 2016;375:1856-67). This analysis assessed if oral microbiome profiling would yield prognostic biomarkers of response to anti-PD-1 immunotherapy in patients with SCCHN treated in CheckMate 141. Methods: Saliva samples were obtained at screening (nivolumab n=85, IC n=31) and week 7 of treatment (nivolumab n=77, IC n=28), and profiled using high-throughput 16S ribosomal RNA sequencing. Bacterial abundance was estimated using a combined differential abundance modeling approach, normalized using cumulative sum scaling to correct for sequencing depth, and analyzed using a linear model for association with response (complete response/partial response vs stable disease vs progressive disease), tumor PD-L1 expression, HPV16 status, treatment history, and patient demographics. Results: Among 221 saliva samples analyzed, bacteria from 13 phyla and 542 species were detected. At baseline, no significant associations were detected in richness of bacterial diversity with best overall response, tumor PD-L1 expression, or HPV16 status. No associations in microbial alpha and beta diversity were detected with treatment modality (nivolumab vs IC) or treatment duration (baseline vs week 7). Patients with prior radiation therapy (n=97) had lower abundance of bacteria from the families Prevotellaceae and Flavobacteriaceae than patients without prior radiation therapy (n=17). The abundance of bacteria from the families Desulfobulbaceae and Flavobacteriaceae was higher in European (n=56) than North American (n=46) patients. Conclusion: Differences in certain bacterial species were observed in patients with prior radiation therapy and between different geographical locations. However, no significant associations were detected between oral bacterial diversity and clinical response, tumor PD-L1 expression, HPV16 status, or treatment modality. This exploratory analysis is the first to evaluate the oral microbiome as a biomarker in a randomized, phase 3 clinical trial for immunotherapy in SCCHN and may serve as a basis for future assessments and experimental design. Correlation of salivary and intestinal microbiota with that from tumor specimens is warranted. Citation Format: Robert L. Ferris, George Blumenschein, Kevin Harrington, Jérôme Fayette, Joël Guigay, A. Dimitrios Colevas, Lisa Licitra, Everett Vokes, Maura Gillison, Caroline Even, Cheryl Ho, Makoto Tahara, Robert Haddad, Mark Lynch, Manish Monga, Somnath Bandyopadhyay, Omar Jabado, Henry Kao. Evaluation of oral microbiome profiling as a response biomarker in squamous cell carcinoma of the head and neck: Analyses from CheckMate 141 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT022. doi:10.1158/1538-7445.AM2017-CT022

The Challenge for Development of Valuable Immuno-oncology Biomarkers

“…In this study, patients who responded to therapy harbored gut microbiota with greater diversity, particularly greater amounts of clostridia bacterium, and tumors from these responding patients showed significantly increased immune infiltrates. In contrast, among saliva samples analyzed from patients with squamous carcinoma of the head and neck, no significant associations were detected among bacterial diversity with best overall response, tumor PD-L1 expression, or HPV16 status (46). These findings underscore the importance of taking both the tumor and host factors into consideration in the search for biomarkers(47), with further studies needed to determine the relevance of the immiune microbiome in predicting toxicity from and response to immunotherapy.…”

Immune biomarkers of response to immune-checkpoint inhibitors in head and neck squamous cell carcinoma

“…Retrospective analysis from a noncontrolled cohort [73]. Microbiota16S rRNA high throughput sequencing of saliva and stoolOral microbiota: nonpredictiveIntestinal microbiota: no data yetRetrospective analysis of prospective randomized clinical trial [133]. aPredictive values in HPV – and HPV + subgroups were defined positive or negative if a statistically significant correlation between response and the immune biomarker was described in the referenced studies; uncertain if no significant correlation was found; no data if no studies had evaluated the role of the biomarker in this setting at the time of this publication.bThe positive correlation between PD-L1 expression and treatment response was not consistent across the studies.…”

“…Whether the microbiota has a role in predicting response to immunotherapy in HNSCC is yet to be determined. Only one substudy from CHECKMATE-141 explored the role of the oral microbiota measured in the saliva as a predictive biomarker in patients with R/M HNSCC treated with nivolumab, showing no significant correlation with treatment efficacy or survival [9, 133]. However, the study had several limitations, including the lack of uniformity in sample collection, the small number of responses for correlation and importantly, the omission of intestinal microbiota.…”

Novel strategies in immune checkpoint inhibitor drug development: How far are we from the paradigm shift?

“…For example in melanoma patients whose baseline microbiota was enriched with Faecalibacterium genus and other Firmicutes showed a longer PFS and OS than those whose baseline microbiota was enriched with Bacteroides upon ipilimumab treatment 145 . One substudy from the Checkmate‐141 trial, however, explored the oral microbiota as a predictive biomarker in patients with advanced SCC of the head and neck treated with nivolumab and reported no significant correlation with treatment efficacy or survival 146 . Recent studies have also suggested that the immune microbiome plays a role in the development of toxicity 147–149 .…”