Abstract 482P
Background
Clinical trials have shown nivolumab (Nivo) benefits in advanced gastric cancer (AGC), but the lack of established biomarkers, including PD-L1, limits its effectiveness. This study aims to discover novel host-related biomarkers to distinguish AGC patients (pts) who benefit from Nivo.
Methods
We conducted a comprehensive analysis using RNAseq, SNP array, and GC-MS metabolomics on pre-treatment blood samples from 200 pts in the exploratory cohort (A) and 301 pts in the validation cohort (B) of the DELIVER trial, an observational/translational study of Nivo monotherapy in AGC (JACCRO GC-08, UMIN000030850). To find a signature delineating non-progressors (NPs; CR, PR, and SD on RECITST) from progressors, we performed KEGG pathway analysis in cohort A and validated it in cohort B. The prognostic impact of the identified pathway-related gene expression was evaluated using log-rank tests in cohort A, and subsequent validation was conducted in cohort B via log-rank tests and Cox regression analysis. Differential expression analysis was carried out in cohort A to select candidate genes for SNP analysis, with the identified expression differences further validated in cohort B. Nominated SNPs of candidate genes were analyzed for survival correlation across all pts. Since this is an exploratory biomarker study, no correction for multiple comparisons was made.
Results
OXPHOS pathway upregulation emerged as a biomarker for NPs in cohort A, which was validated in cohort B. The average Z score of 407 genes that related to the OXPHOS pathway was significant for overall survival in cohort A when the cut-off value was 2, then confirmed in cohort B. Differential expression analysis revealed overexpression of 8 genes (MTFMT, ZNF322, QRSL1, ZDHHC21, PNPT1, NDUFV2, UQCRQ, ATP7A) in NPs of both cohorts. The SNP analysis showed 2 SNPs in PNPT1 to be associated with survival. Although no metabolites were associated with the OXPHOS pathway, the β-Hydroxybutyrate level varied by PNPT1 genotype.
Conclusions
This translational study revealed, for the first time, that blood-based gene expression profiles in the OXPHOS pathway, along with specific SNPs, may serve as prognostic markers for AGC pts receiving Nivo.
Clinical trial identification
UMIN000030850.
Legal entity responsible for the study
Japan Clinical Cancer Research Organization (JACCRO).
Funding
ONO Pharmaceutical Co., Ltd.
Disclosure
C. Inagaki: Financial Interests, Personal, Invited Speaker: MSD K.K., Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo, Eisai Co., Ltd; Financial Interests, Institutional, Funding: Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Astellas Pharm Inc. H. Yasui: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Chugai Pharma, Bristol Myers Squibb, Daiichi Sankyo, Terumo, Eli Lilly Japan, Merck Biopharma, Yakult Honsha, Bayer Yakuhin, Takeda Pharmaceutical; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical; Financial Interests, Institutional, Invited Speaker: MSD, Daiichi Sankyo, Ono Pharmaceutical, Astellas Pharma, Amgen, AstraZeneca. A. Makiyama: Financial Interests, Personal, Invited Speaker: Eli Lilly, Taiho, Ono, Daiichi Sankyo, Bristol Myers Squibb. Y. Kito: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Ono Pharmaceutical. Y. Sakamoto: Financial Interests, Institutional, Expert Testimony: Eli Lilly Japan K.K., Daiichi Sankyo Co. Ltd., Nippon Kayaku Co., Ltd.; Financial Interests, Institutional, Invited Speaker: MSD K.K., Bristol Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., ONO Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd. E. Inoue: Financial Interests, Personal, Speaker’s Bureau: Eisai Co., Ltd., Chugai Pharmaceutical. W. Ichikawa: Financial Interests, Personal, Invited Speaker: Merck BioPharma, Bristol Myers Squibb, Chugai Pharmaceutical, Yakult Honsha, AstraZeneca, Daiichi Sankyo, Taiho Pharmaceutical; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo, Shionogi, Takeda Pharmaceutical. Y. Sunakawa: Financial Interests, Personal, Invited Speaker: Eli Lilly Japan, Bristol-Byers Squibb, Chugai Pharmaceutical, Takeda, Taiho Pharmaceutical, Merck Biopharma, Daiichi Sankyo, Ono Pharmaceutical; Financial Interests, Personal, Advisory Board: Merck Biopharma; Financial Interests, Personal and Institutional, Research Grant: Chugai Pharmaceutical, Taiho Pharmaceutical, Takeda, Otsuka Pharm, Parexel International Inc., Iqvia, Ono Pharmaceutical, CMIC Shift Zero K.K., PRA Health Sciences, Inc., Amgen; Non-Financial Interests, Project Lead: Japan Clinical Cancer Research Organization. All other authors have declared no conflicts of interest.