Gut microbiome a potential biomarker for nivolumab efficacy in advanced gastric cancer
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The gut microbiome potentially could serve as a biomarker to predict the efficacy of nivolumab among patients with advanced gastric cancer, according to results of the DELIVER trial presented at Gastrointestinal Cancers Symposium.
Gastric cancer-specific gut microbiome additionally appeared to predict immune checkpoint inhibitor response, researchers noted.
“Previous research demonstrated a survival benefit of nivolumab [Opdivo, Bristol Myers Squibb] monotherapy among previously treated patients with advanced gastric cancer,” Yu Sunakawa, MD, PhD, associate professor in the department of clinical oncology at St. Marianna University School of Medicine in Japan, said during his virtual presentation. “However, many patients did not experience response to treatment. Therefore, predictive biomarkers are needed for nivolumab treatment in gastric cancer. We sought to investigate whether genomic information in gut microbiome will serve as predictors for nivolumab in advanced gastric cancer.”
The observational/translational, multicenter study enrolled 501 patients with advanced gastric cancer who received nivolumab between March 2018 and August 2019. Researchers identified gut microbiome biomarkers from fecal samples collected before treatment.
The relationship between the genomic pathway in the gut microbiome and the efficacy of nivolumab served as the primary endpoint. Various associations between gut microbiome markers and clinical outcomes served as secondary endpoints.
The statistical analysis included two steps. For the first step, researchers used the Wilcoxon rank sum test to assess biomarkers among the first 200 patients enrolled (training cohort). For the second step, they used the Bonferroni method to validate the top 30 potential biomarkers in the last 300 patients (validation cohort).
Overall, 180 patients (median age, 70 years; range, 37-90; 76% men) in the training cohort and 257 patients (median age, 71 years; range, 26-90; 72% men) in the validation cohort were available for evaluation.
Disease progression occurred in 62.2% (95% CI, 54.7-69.3) of patients in the training cohort and 53.2% (95% CI, 47-59.4) of patients in the validation cohort.
Patients without disease progression had a more diverse gut microbiome than those with progressive disease, according to Sunakawa.
The Bonferroni method yielded no statistically significant genomic pathways for validation as a primary endpoint. Researchers did, however, observe an association between bacterial invasion of epithelial cells in the KEGG pathway and clinical outcomes of nivolumab in the training cohort — which fell short of statistical significance — and in the validation cohort (P = .014). In addition, they found a relationship between upregulation of the KEGG pathway and progressive disease at first evaluation of nivolumab therapy.
Results of an exploratory analysis indicated that Odoribacter and Veillonella were associated with tumor response to nivolumab among patients in both cohorts.
“Ongoing biomarker analyses are looking at the relationships between the gut microbiome and survival time, as well as scoring by combining gut microbiome with metabolome data,” Sunakawa said.
Perspective
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Ajay Goel, PhD, AGAF
Accumulating evidence has unequivocally indicated that overabundance of specific bacterial populations within our intestinal tracts is linked to various gastrointestinal cancers. These include Helicobacter pylori with gastric cancer and Fusobacterium nucleatum with colorectal cancer. In addition, growing evidence indicates that presence or absence of specific bacterial species in patients with cancer also determines the response of these patients to specific treatments — making this a fascinating topic of research in precision oncology.
This study included two important findings. First, patients who benefited from treatment with nivolumab had a much more diverse bacterial composition than those who exhibited disease progression. Second, presence of two specific bacterial species — Odoribacter and Veillonella — served as a biomarker for response to this anti-PD-1 therapy. Unfortunately, given the lack of statistical significance of results, larger, prospective studies are needed to gain further confidence in these findings. In addition, longer follow-up of these patients will reveal whether the therapeutic response led to any survival gain, which is always an important clinical endpoint.
If validated in subsequent studies, the clinical impact of these findings could be tremendous. This study highlights the need to perform microbial profiling in fecal specimens of patients with gastric and other cancers. Doing so will enable more informed decision-making and potentially spare patients who are unlikely to respond to certain treatments from the toxicity and expense. In addition, given that the presence of specific bacteria is associated with better therapeutic response to nivolumab, simple and inexpensive adjunctive use of probiotics might help improve the overall therapeutic outcomes of patients with gastric cancer.
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Sunakawa Y, et al. Abstract 161. Presented at: Gastrointestinal Cancers Symposium (virtual meeting); Jan. 15-17, 2021.
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