1547P - SNP discovery based on transcriptome sequencing of whole blood RNA to find predictive biomarkers for nivolumab in gastric cancer

Background

Nivolumab (Nivo) monotherapy showed a survival benefit for patients (pts) with advanced gastric cancer (AGC), while its efficacy is limited, raising an urgent need to discover biomarkers. Here, we performed SNP discovery based on gene ontology (GO) terms analysis from transcriptome sequencing of whole blood RNA to find predictive biomarkers of Nivo in AGC.

Methods

We analyzed differential gene expression and SNPs data in pts with available pre-treatment blood samples from the DELIVER trial (JACCRO GC-08), an observational/translational study (UMIN000030850) that enrolled 501 AGC pts treated with Nivo alone. The GO-terms analysis was performed to identify genes associated with outcomes (CR/PR vs. SD/PD, non-PD vs. PD, non-hyper progressive disease [HPD] vs. HPD) in the exploratory cohort (the first 200 pts), and then the results were confirmed in the validation cohort (the last 301 pts). For the validated genes, SNP analysis was carried out to further assess genetic relatedness.

Results

When comparing pts with non-PD and PD, 205 genes in metabolic-related GO-Terms were upregulated in pts with non-PD; 12 SNPs in 12 genes (BICD1, PKD2, GOPC, TXK, SYPL1, PAQR8, ZC3H3, RNF138, ZFP90, ZC3H3, DDX60, FAM175B) were correlated to non-PD. In tumor response, 107 genes in nucleic acid-related GO-Terms were upregulated in pts with CR/PR; 5 SNPs in 4 genes (PDE3B, ZNF333, ACACB, ZNF780A) were correlated to CR/PR. In comparison between pts with non-HPD and pts with HPD, 306 genes in immune-related GO-Terms were enriched in pts with non-HPD and the median expression value of this genes set was significantly higher in pts with non-HPD; 16 SNPs in 12 genes (COX10-AS1, PASK, DOCK10, CDS2, PASK, CSGALNACT1, ARHGAP26, HLA-DQA1, DIAPH2, NFATC1, ARHGAP6, LCP2, RASA3) were correlated to non-HPD.

Conclusions

Our translational study demonstrated for the first time that gene expression of whole blood and SNPs as host-related markers can potentially predict response to Nivo in AGC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

St. Marianna University School of Medicine.

Funding

Ono Pharmaceutical Co., LTD., Bristol Myers Squibb.

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. R. Matoba: Financial Interests, Personal, Member of Board of Directors: DNA Chip Research Inc.; Financial Interests, Personal, Stocks/Shares: DNA Chip Research Inc. H. Iijuma: No financial interest, Personal, Full or part-time Employment: DNA Chip Research Inc. H. Yasui: Financial Interests, Institutional, Funding: Ono Pharmaceutical; Financial Interests, Personal, Speaker, Consultant, Advisor: Ono Pharmaceutical, Bristol Myers Squibb Japan. 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, Daiichi Sankyo. Y. Sakamoto: Financial Interests, Institutional, Expert Testimony: Eli Lilly Japan K.K., Daiichi Sankyo Co. Ltd., Merck Biopharma Japan Co. Ltd., Novartis Pharmaceutical Co. Ltd.; Financial Interests, Institutional, Invited Speaker: MSD K.K., Hisamitsu Pharmaceutical Co. Ltd., Bristol Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd. E. Inoue: Financial Interests, Personal, Expert Testimony: Bristol Myers Squibb Co., Ltd., Eisai Co., Ltd., Nippontect Systems Co., Ltd., Cyberdyne Inc. W. Ichikawa: Financial Interests, Personal, Invited Speaker: Merck, 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 Myers 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 Pharmaceutical, 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.