60MO - Gut microbiota and efficacy of immune-checkpoint inhibitors (ICIs) in patients (pts) with advanced solid tumor: SCRUM-Japan MONSTAR-SCREEN

Background

MONSTAR-SCREEN is the nationwide cancer genome screening project of prospectively assessing gut microbiota and circulating tumor DNA in 2,000 pts with advanced solid tumor at 31 Japanese institutions. Recently, several studies have showed that gut microbiota modulates efficacy of ICIs across cancer types. Here we report an initial analysis of association between alpha diversity index (ADI) of fecal microbiome and efficacy of ICIs between Sep 2019 and Sep 2020.

Methods

The 16S ribosomal RNA gene sequencing to V3-V4 region was conducted for assessing the ADI, which was represented as an operational taxonomic unit (OTU) score. Objective response rate (ORR) was assessed by RECIST version 1.1 and progression-free survival (PFS) on ICIs was estimated using the Kaplan-Meier method. Microsatellite instability (MSI) and blood tumor mutational burden (bTMB) status were measured by FoundationOneLiquid plus a 1.125Mb bTMB assay at the same time points as the feces collection. In addition, tissue TMB (tTMB) were measured by FoundationOneCDx using pretreatment tissue samples.

Results

A total of 167 pts were included. Most common cancer types were as follows; head and neck cancer (N=43), malignant melanoma (N=26) and gastric cancer (N=25). Of these, 136 (81%) pts received ICI alone, while 31 (19%) did ICI and chemotherapy combination. We determined the optimal cutoff value of 240 by combined sensitivity with specificity for the ORR. The ORR in high OTU (OTU-H > 240, N=52) was 35%, while that with low OTU (OTU-L < 240, N=115) was 17% (p=0.01). In addition, OTU-H pts had a significantly a longer PFS on ICIs than OTU-L (8.6 vs. 2.6 months; hazard ratio, 0.48; 95% CI, 0.30–0.78; p=0.002). Multivariate analyses for the ORR and PFS demonstrated the OTU was the only significant independent factor beyond MSI, bTMB, and tTMB status.

Conclusions

Diversity of gut microbiota by the OTU was significantly associated with higher ORR and longer PFS on ICIs in pts with advanced solid tumor. These results indicated the potential of the OTU as a putative tumor-agnostic biomarker for the efficacy of ICIs beyond MSI, bTMB and tTMB status. Further study with shotgun and single cell metagenome analyses are ongoing.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

SCRUM-Japan.

Funding

SCRUM-Japan funding.

Disclosure

R. Yamashita: Financial Interests, Personal, Advisory Board: Takeda. Y. Nakamura: Financial Interests, Institutional, Research Grant: Genomedia; Financial Interests, Institutional, Research Grant: Guardant Health; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Chugai. H. Taniguchi: Financial Interests, Personal, Speaker’s Bureau: Merck Biopharma; Financial Interests, Personal, Speaker’s Bureau: Takeda; Financial Interests, Personal, Speaker’s Bureau: Taiho; Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: RDKK; Financial Interests, Institutional, Research Grant: Sysmexy; Financial Interests, Institutional, Research Grant: Chugai. S. Kadowaki: Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharma; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Speaker’s Bureau: Merck KGaA; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Chugai Pharma; Financial Interests, Institutional, Research Grant: Nobelpharma. M. Hosokawa: Financial Interests, Institutional, Member of the Board of Directors: bitBiome, Inc.. T. Kodama: Financial Interests, Personal, Full or part-time Employment: Chugai Pharmaceutical Co., Ltd.. K. Kato: Financial Interests, Institutional, Research Grant: Ono; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Personal, Advisory Board: Ono; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Beigene; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Speaker’s Bureau: Eli lilly; Financial Interests, Personal, Speaker’s Bureau: Ono; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Ono. T. Satoh: Financial Interests, Personal and Institutional, Research Grant: Ono Pharmaceutical; Financial Interests, Personal and Institutional, Research Grant: Chugai Pharmaceutical; Financial Interests, Personal and Institutional, Research Grant: Yakult Honsha; Financial Interests, Institutional, Research Grant: Giliad; Financial Interests, Institutional, Research Grant: Bristol-Myers; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Personal and Institutional, Research Grant: Eli Lilly; Financial Interests, Personal, Invited Speaker: Ono pharmaceutical; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical; Financial Interests, Personal, Invited Speaker: Yakult Honsha; Financial Interests, Personal, Invited Speaker: Bristol-Myers; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Research Grant: BeiGene. Y. Komatsu: Financial Interests, Personal, Research Grant: Ono Pharmaceutical Co., Ltd; Financial Interests, Personal, Research Grant: Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Research Grant: Chugai Pharmaceutical Co., Ltd; Financial Interests, Personal, Research Grant: Eli Lilly and Company; Financial Interests, Personal, Research Grant: Mediscience Planning Inc.; Financial Interests, Personal, Research Grant: NanoCarrier Co.,Ltd.; Financial Interests, Personal, Research Grant: Yakult; Financial Interests, Personal, Research Grant: Daiichi Sankyo Company, Limited; Financial Interests, Personal, Research Grant: IQVIA Services Japan K.K; Financial Interests, Personal, Research Grant: Japanese Foundation for Multidisciplinary Treatment of Cancer; Financial Interests, Personal, Research Grant: Nationel Cancer Center Japan; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical Co., Ltd; Financial Interests, Personal, Speaker’s Bureau: Bayer Yakuhin, Ltd.; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly and Company; Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Speaker’s Bureau: Taiho Pharmaceutical Co., Ltd. M. Shiota: Financial Interests, Personal, Speaker’s Bureau: Janssen Pharmaceutical K.K.; Financial Interests, Personal, Speaker’s Bureau: Astellas Pharma Inc.; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Institutional, Research Grant: Daiichi Sankyo. H. Yasui: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Astellas Pharma; Financial Interests, Institutional, Research Grant: BeiGene; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical; Financial Interests, Personal, Invited Speaker: Chugai Pharma; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb Japan; Financial Interests, Personal, Invited Speaker: Terumo; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan; Financial Interests, Personal, Invited Speaker: Merk Biopharma; Financial Interests, Personal, Invited Speaker: Yakult Honsha; Financial Interests, Personal, Invited Speaker: Bayer Yakuhin; Financial Interests, Personal, Invited Speaker: Takeda Pharmaceutical. K. Yamazaki: Financial Interests, Personal, Speaker’s Bureau: Chugai Pharma; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Yakult Honsha; Financial Interests, Personal, Speaker’s Bureau: Takeda; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Speaker’s Bureau: Merck Serono; Financial Interests, Personal, Speaker’s Bureau: Taiho Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Personal, Speaker’s Bureau: Sanofi; Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb. T. Yoshino: Financial Interests, Personal, Speaker’s Bureau: Taiho; Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Merck Biopharma; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Speaker’s Bureau: Ono; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Sumitomo Dainippon; Financial Interests, Institutional, Research Grant: Ono; Financial Interests, Institutional, Research Grant: Chugai; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Parexel International; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Sanofi. All other authors have declared no conflicts of interest.