Certain Pathways in Gut Microbiome May Predict IRAEs With Nivolumab in Advanced Gastric Cancer


Single nucleotide polymorphisms such as NOTCH1, SEMA4D, NLRC5, and IL6R, may be predictive of nivolumab toxicity in advanced gastric cancer.

According to results from the DELIVER trial (JACCRO GC-08; UMIN000030850), observing Arthrobacter and fatty acid metabolism pathways in gut microbiomes may be linked to an increased risk of skin-related adverse events (AEs) in patients with advanced gastric cancer who are receiving single-agent nivolumab (Opdivo).1

Specifically, the IL6R and NLRC5 genomic pathways are predictive of nivolumab-related skin toxicities in this patient population, while SEMA4D and NOTCH1 are predictive of diarrhea. In both training and validation cohorts, the predictive value of Arthrobacter (P = .0212 and P = .0105, respectively) and fatty acid metabolism (P = .0241 and P = .0107, respectively) were validated, according to a presentation at the 2022 Gastrointestinal Cancers Symposium.

The PD-1 inhibitor nivolumab has become integrated as a standard of care for patients with previously treated gastric cancer, and has demonstrated benefits in overall survival. Despite this, about 10% of patients who receive nivolumab experience an immune-related adverse event (irAE). Furthermore, although several studies have shown that there is a link between gut microbiome composition and immunotherapy efficacy, relatively little research has been designed to assess this relationship within the context of advanced gastric cancer.

“Our study demonstrated [that] Arthrobacter and the fatty acid metabolism pathway were identified for candidate markers to predict skin-related adverse events, so patients with high levels of the genus or pathway experienced skin toxicity more frequently,” lead presenter Yu Sunakawa, MD, PhD, of the Department of Clinical Oncology at St. Marianna University School of Medicine in Japan, said in an interview with Oncology Nursing News.® “In near future clinical practice, by measuring the host-related markers such as gut microbiome, or polymorphous, we hope to be able to predict immune related adverse events [to] provide immunotherapy to patients [with cancer] more safely.”

The observational, translational, DELIVER trial enrolled 501 patients with advanced gastric cancer who received nivolumab alone between March 2018 and August 2019. Researchers collected fecal and blood samples before treatment initiation.

There were 2 separate cohorts in this study: a training cohort and a validation cohort. The training cohort included 200 patients, 180 of which presented evaluable and clinical genomic data of gut microbiome. In comparison, the validation cohort included 301 enrolled patients, 257 of which presented genomic data that was evaluable.

Evaluable samples were measured via genome shotgun sequence for genera and pathway, with a median difference of ≥0.01 of normalized value and P value <.05 in the training cohort and confirmed in the validation cohort. Each sample encompassed approximately 5Gbp of metagenomic sequence data and the mapping percentage was approximately 98.2%.

The primary end point was to identify the relationship between nivolumab efficacy and genomic pathways in gut microbiomes; progressive disease was identified in accordance with RECIST criteria. The secondary end point was to identify potentially predictive biomarkers within the gut microbiome, as well as their correspondent clinical outcomes.

A year following last patient enrollment, at a data cutoff date of August 2020, there were 87 confirmed cases of diarrhea, 44 skin eruptions, 29 hypothyroidism events, and 11 adrenal disorders among participants in the safety population (n = 487).

“The polymorphic analysis indicated that [there is] significant association of genetic polymorphism of NOTCH1 and SEMA4D with diarrhea and NLR family domain containing 5 and interleukin-6 receptor gene (IL6R) with skin toxicity,” concluded Sunakawa.

He added that further analysis will be performed using updated clinical toxicity data in [the] near future.


1. Matoba R, Takayama T, Okumara, et al. Host-related biomarkers including gut microbiome to predict toxicities of nivolumab in advanced gastric cancer. J Clin Oncol. 2022;40(suppl; abstr 245). doi:10.1200/JCO.2022.40.4_suppl.245

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