Host-related biomarkers including gut microbiome to predict toxicities of nivolumab in advanced gastric cancer: DELIVER trial (JACCRO GC-08).
Authors: Sunakawa Yu , Matoba Ryo , Takayama Toshizo , Okumura Naoki , Sugimoto Naotoshi , Miura Kou , Yuki Satoshi , Shindo Yoshiaki , Kuramochi Hidekazu , Sato Sho , Ogura Takashi , Kinami Shinichi , Nagao Narutoshi , Ueda Shugo , Inoue Eisuke , Kawakami Hisato , Muro Kei , Nakajima Takako Eguchi , Ichikawa Wataru , Fujii Masashi 
Published: January 2022

245 Background: Nivolumab monotherapy demonstrated survival benefit in previously treated gastric cancer (GC) patients (pts) (Kang YK, et al. Lancet 2017) and was involved into standard of care in advanced GC. Immune-related adverse events (irAEs) were observed in about 10% of pts treated with immune-check point inhibitor. Several studies revealed that the toxicities of anti-PD-1-based immunotherapy was associated with composition of gut microbiome, but little is known about GC. We therefore investigated whether host-related factors including genomic information in gut microbiome will serve as predictors for nivolumab-induced toxicities in advanced GC. Methods: The observational/translational study (DELIVER trial: UMIN000030850) has enrolled 501 pts with advanced GC treated with nivolumab alone from March 2018 to August 2019 to evaluate real-world data and discover host-related biomarkers using fecal and blood samples which were collected before treatment with nivolumab [Takahashi Y, et al. Gastric Cancer 2021]. In the biomarker part, the relationship between markers of microbiome/genetic polymorphisms and AEs was evaluated as previously planned for the secondary endpoint. Genomic data in fecal samples and single nucleotide polymorphisms (SNPs) in blood samples were measured by genome shotgun sequence and microarray, respectively, at central lab. Genera and pathway with a median difference of ≥0.01 of normalized value and P-value < 0.05 of t-test were picked up from the first 200 pts (training cohort) and then confirmed in the last 301 pts (validation cohort). Comparison analysis between pts with and without each AE was performed for SNPs in all pts. Results: In the safety population with 487 pts, at the time of 1 year after last patient enrollment, each AE was 87 for diarrhea, 44 for skin eruptions, 29 for hypothyroidism, and 11 for adrenal disorders. In the analysis of gut microbiome, 180 of 200 pts and 257 of 301 pts were available for massive metagenomic in the training cohort and validation cohort, respectively. Four hundred-forty pts were available for analyzing SNPs. Arthrobacter and fatty acid metabolism pathway were identified for candidate markers to predict skin AEs in the training cohort ( p= 0.021 and p= 0.024, respectively) and then confirmed in the validation cohort ( p= 0.011 and p= 0.011, respectively). Patient with high level of the genus or pathway experienced skin AEs more frequently. The SNPs analysis indicated the significant association of genetic polymorphisms of NLRC5 and IL6R with skin toxicities and NOTCH1 and SEMA4D with diarrhea. Conclusions: Genus of Arthrobacter and fatty acid metabolism pathway in gut microbiome predict skin toxicities in advanced GC treated with nivolumab. In addition, some SNPs may potentially become markers for skin toxicities and diarrhea of nivolumab. Clinical trial information: UMIN000030850.