1O - Exploration of Gut Microbiota Biomarkers in Treatment-Naïve Advanced NSCLC Patients Undergoing Chemo-Immunotherapy: Insights from the Phase III trial, JCOG2007 (NIPPON)

Background

Immunotherapy has transformed treatment for advanced non-small cell lung cancer (NSCLC). However, reliable biomarkers for treatment selection remain scarce. Gut microbiota (GM) has emerged as a potential biomarker, but its role in chemo-immunotherapy for NSCLC is unclear.

Methods

The phase III trial (JCOG2007, NIPPON) compared pembrolizumab plus platinum doublet chemotherapy (PC) and nivolumab-ipilimumab plus platinum doublet chemotherapy (NIC) in treatment-naïve advanced NSCLC patients without driver gene alterations. As an ancillary biomarker study, 270 patients with baseline fecal samples were analyzed for GM composition out of 295 patients enrolled in JCOG2007. 16S rDNA sequencing was performed for the subsequent GM diversity and differential abundance analysis.

Results

The beta diversity analysis of the overall cohort (n=270) revealed distinct microbial structures between responders and non-responders, categorized by overall survival (OS) at 12 or 18 months. Subsequent LEfSe analysis identified specific bacterial genera that differed between the groups, with Fusicatenibacter, Butyricicoccus, and Blautia being enriched in patients with longer OS. Regarding adverse events (AEs), lower microbial alpha diversity and the presence of certain taxa were linked to a higher risk of severe AEs (≥ grade 4). Additionally, favorable genera, including Fusicatenibacter and Butyricicoccus, were associated with a lower risk of severe AEs. Lastly, regimen-specific analysis showed that higher abundance of Fusicatenibacter and Butyricicoccus in the NIC arm were linked to better OS compared to the CP arm (Hazard Ratio (HR) for OS = 0.56 and 0.52, respectively). Conversely, the higher abundance of Prevotellaceae NK3B31 was associated with higher mortality risk in the NIC arm (HR for OS = 2.33).

Conclusions

GM may serve as a biomarker for chemo-immunotherapy in advanced NSCLC. Differences in microbial diversity and specific bacterial genera were associated with prognosis and severe AEs, with potential regimen-specific effects. These findings support integrating GM profiling into clinical practice to optimize first-line treatment strategies.

Legal entity responsible for the study

Japan Clinical Oncology Group.

Funding

This work was supported by AMED (Grant Number: JP23ck0106669h0003) and a Japanese Respiratory Society Fellowship Grant.

Disclosure

T. Hakozaki: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Ono Pharmaceutical. K. Tanaka: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, Takeda Pharmaceutical, Pfizer, MSD, Novartis, Bristol Myers Squibb. Y. Shiraishi: Financial Interests, Personal and Institutional, Funding: Chugai Pharmaceutical; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Taiho Pharmaceutical, Kyowa Kirin. Y. Okuma: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Nippon Boehringer Ingelheim, Novartis, Ono Pharmaceutical, Takeda, Taiho Pharmaceutical. T. Aiba: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co. Ltd. J. Tanizaki: Financial Interests, Personal, Invited Speaker: Boehringer-Ingelheim Japan Inc., Bristol Myers Squibb Co. Ltd, Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Eli Lilly Japan K.K, Janssen Pharmaceutical K.K, MSD K.K, Nihon Medi-Physics Co., Ltd, Nippon Kayaku Co., Ltd, Taiho Pharmaceutical Co. Ltd. K, Ono Pharmaceutical Co. Ltd, Pfizer Japan Inc., AstraZeneca K.K., Takeda Pharmaceuticals; Financial Interests, Personal, Advisory Board: AstraZeneca K.K., AbbVie GK, Genmab, Taiho Pharmaceutical Co. Ltd. K, Daiichi Sankyo Co., Ltd; Financial Interests, Institutional, Local PI: AbbVie, AstraZeneca K.K., Shanghai Junshi, Roche, EMD Serono, Merck, Boehringer Ingelheim; Non-Financial Interests, Personal, Member: ASCO, JSMO, Japan Lung Cancer Society, ESMO, IASLC. K. Azuma: Financial Interests, Personal, Invited Speaker, Lecture fee: AstraZeneca, MSD, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Takeda Pharmaceutical. R. Morita: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Chugai Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Eli Lilly Japan, MSD, Amgen, Merck; Financial Interests, Personal, Advisory Board: Daiichi Sankyo. S. Niho: Financial Interests, Personal and Institutional, Funding: GSK, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, MSD, Ono Pharmaceutical, Eisai, Kyorin, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Novartis, Amgen, Merck, Nippon Kayaku, Kyowa Kirin; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo. T. Yokoyama: Financial Interests, Personal and Institutional, Funding: MSD, Chugai Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim Japan, Takeda, Delta-Fly Pharma, Janssen, AbbVie, Daiichi Sankyo, Parexel International; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Pfizer Japan, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Nippon Kayaku, MSD, Novartis, Merck. R. Toyozawa: Financial Interests, Personal and Institutional, Funding: AbbVie, Amgen, AnHeart Therapeutics, Daiichi Sankyo, Eli Lilly Japan, Novartis Pharma, Pfizer Japan, Takeda Pharmaceutical; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda Pharmaceutical. H. Horinouchi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, BMS/Ono, Merck Sharp & Dohme, Roche/Chugai, Novartis, Pfizer, Boehringer Ingelheim, Kyowa-Kirin, Nihon Kayaku, AbbVie; Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, BMS/Ono, Merck Sharp & Dohme, Roche/Chugai, Amgen, Nihon Kayaku; Financial Interests, Personal, Steering Committee Member: Roche/Chugai; Financial Interests, Institutional, Research Grant: Roche/Chugai, Merck Sharp & Dohme, Daiichi Sankyo, Ono Pharmaceutical, AstraZeneca; Financial Interests, Institutional, Local PI: AbbVie. I. Okamoto: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Bristol Myers Squibb, Takeda Pharmaceutical, Daiichi Sankyo, MSD, Pfizer, Taiho Pharmaceutical, Novartis; Financial Interests, Institutional, Local PI: Chugai Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, GSK, MSD, Taiho Pharmaceutical, Novartis. Y. Hosomi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Eisai, Kyowakirin, Nippon Kayaku, Novartis, Ono Pharmaceutical, Takeda, Taiho pharmaceutical. Y. Ohe: Financial Interests, Personal, Advisory Board: Amgen, AnHeart Therapeutics Inc., AstraZeneca, BMS, Celltrion, Nippon Kayaku, ONO, Pfizer, Takeda, PharmaMar, AnHeart; Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, MSD, Novartis, Ono, Takeda; Financial Interests, Institutional, Local PI: AstraZeneca, Janssen, Amgen; Financial Interests, Personal and Institutional, Coordinating PI: Takeda, ONO; Non-Financial Interests, Personal, Leadership Role: JSMO, JLCS, JCOG; Non-Financial Interests, Personal, Member: ASCO. All other authors have declared no conflicts of interest.