Gut Microbiome Makeup May Help Predict Skin-Related Immunotherapy Side Effects in Patients With Gastric Cancer

The makeup of a patient’s gut microbiome may lend insight regarding their risk to skin-related side effects from gastric cancer treatment, according to findings recently presented at the 2022 ASCO Gastrointestinal Cancers Symposium.

The researchers found that when patients present with Arthrobacter – a type of bacteria – and fatty acid metabolism pathways in their gut microbiomes, they were more likely to experience skin-related side effects from treatment with single-agent Opdivo (nivolumab).

Specifically, the IL6R and NLRC5 genomic pathways are predictive of Opdivo-related skin toxicities in this patient population, while SEMA4D and NOTCH1 are predictive of diarrhea. Then, the DELIVER trial validated the correlation with Arthrobacter and fatty acid metabolism.

The PD-1 inhibitor Opdivo 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 Opdivo experience immune-related side effects. 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 (side effects), so patients with high levels of the genus or pathway experienced skin toxicity more frequently,” lead presenter Dr. Yu Sunakawa, of the Department of Clinical Oncology at St. Marianna University School of Medicine in Japan, said in an interview with Oncology Nursing News®, a sister publication of CURE®. “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 Opdivo alone between March 2018 and August 2019. Researchers collected fecal and blood samples before treatment initiation.

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

The primary endpoint was to identify the relationship between Opdivo efficacy and genomic pathways in gut microbiomes; progressive disease was identified in accordance with RECIST criteria – a standard that measures how tumors respond to different cancer treatments. 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 (487 patients).

“The … 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 soon.

This article was originally published on Oncology Nursing News as, “Gut Microbiome May Be Useful in Predicting Toxicities With Nivolumab in Advanced Gastric Cancer.”

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