Gut Microbiota in Advanced NSCLC Receiving Chemoimmunotherapy: An Ancillary Biomarker Study From the Phase III Trial JCOG2007 (NIPPON)
- PMID: 40058642
- DOI: 10.1016/j.jtho.2025.02.026
Gut Microbiota in Advanced NSCLC Receiving Chemoimmunotherapy: An Ancillary Biomarker Study From the Phase III Trial JCOG2007 (NIPPON)
Abstract
Introduction: Immunotherapy has transformed the treatment for NSCLC. Nevertheless, reliable biomarkers for treatment selection remain scarce. Gut microbiota has emerged as a potential biomarker, but its role in chemoimmunotherapy for NSCLC is unclear.
Methods: The phase III trial (JCOG2007, NIPPON) compared pembrolizumab plus platinum doublet chemotherapy (PC) with nivolumab and ipilimumab plus platinum doublet chemotherapy (NIC) in treatment-naive patients with advanced NSCLC without driver gene alterations. As an ancillary biomarker study, 270 patients with baseline fecal samples were analyzed for gut microbiota composition from 295 patients enrolled. 16S ribosomal DNA sequencing was performed for the diversity and differential abundance analysis.
Results: The beta diversity analysis of the overall cohort (n = 270) revealed distinct microbial structures between the subpopulations defined by whether overall survival (OS) exceeds 12 or 18 months. Subsequent linear discriminant analysis effect size analysis identified specific bacterial genera that differed between the subpopulations, 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 serious (≥grade 4) AEs. In addition, favorable genera, including Fusicatenibacter and Butyricicoccus, were associated with a lower risk of serious AEs. Last, regimen-specific analysis demonstrated that higher abundance of Fusicatenibacter and Butyricicoccus was linked to better OS in the NIC arm compared with that in the CP arm (hazard ratio 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 (hazard ratio for OS = 2.33).
Conclusions: Gut microbiota may serve as a biomarker for chemoimmunotherapy in advanced NSCLC. Differences in microbial diversity and specific bacterial genera were associated with prognosis and serious AEs, with potential regimen-specific effects. These findings support integrating gut microbiota profiling into clinical practice to optimize first-line treatment strategies.
Keywords: Biomarker; Gut microbiota; Immune checkpoint inhibitor; Ipilimumab; Non–small cell lung cancer.
Copyright © 2025 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Disclosure Dr. Hakozaki received personal fees from Chugai Pharmaceutical and Pharmaceutical outside the submitted work. Dr. Tanaka received personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, Takeda Pharmaceutical, Pfizer, Merck Sharp & Dohme, Novartis, and Bristol Myers Squibb outside the submitted work. Dr. Shiraishi received grants from Chugai Pharmaceutical and personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Taiho Pharmaceutical, and Kyowa Kirin, all outside the submitted work. Dr. Okuma has received personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Nippon Boehringer Ingelheim, Novartis, Ono Pharmaceutical, Takeda, and Taiho Pharmaceutical outside the submitted work. Dr. Tanizaki has received personal fees as an invited speaker from AstraZeneca K.K., Boehringer-Ingelheim Japan, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Janssen Pharmaceutical, Merck Sharp & Dohme, Nihon Medi-Physics, Nippon Kayaku, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical and has also received personal fees for serving on the advisory board of AstraZeneca and AbbVie, all outside the submitted work. Dr. Azuma has received lecture fees from AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, Merck Sharp & Dohme, Bristol Myers Squibb, and Takeda Pharmaceutical, all outside the submitted work. Dr. Morita has received personal fees from Daiichi Sankyo, Chugai Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Eli Lilly Japan, Merck Sharp & Dohme, Amgen, and Merck and personal fees for serving on an advisory board from Daiichi Sankyo, all outside the submitted work. Dr. Niho has received grants from Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Boehringer Ingelheim, Shionogi, Kyowa Kirin, Teijin, GlaxoSmithKline, Daiichi Sankyo, Ono Pharmaceutical, and Kyorin; personal fees from AstraZeneca, Pfizer, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, Merck Sharp & Dohme, Ono Pharmaceutical, Eisai, Kyorin, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Novartis, Amgen, Merck, Nippon Kayaku, and Kyowa Kirin; and consulting fees from AstraZeneca and Daiichi Sankyo, all outside the submitted work. Dr. Toyozawa has received research grants from AbbVie, Amgen, AnHeart Therapeutics, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp & Dohme, Novartis Pharma, Pfizer Japan, and Takeda Pharmaceutical and has received honoraria for lectures from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Merck Sharp & Dohme, Nippon Kayaku, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda Pharmaceutical, and Thermo Fisher Scientific, all outside the submitted work. Dr. Yokoyama has received grants from AbbVie GK, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Delta-Fly Pharma, Janssen, Merck Sharp & Dohme, Parexel International, and Takeda and honoraria for lectures from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma, Merck Sharp & Dohme, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, and Takeda, all outside the submitted work. Dr. Horinouchi has received research funding from Merck Sharp & Dohme, AbbVie, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Janssen, Chugai Pharmaceutical, and Roche; personal fees from AstraZeneca, Merck Sharp & Dohme, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Roche, Amgen, and AbbVie; and personal fees from AstraZeneca, Chugai Pharmaceutical, Roche, Ono Pharmaceutical, Bristol Myers Squibb, and AbbVie (served on the advisory board), all outside the submitted work. Dr. Okamoto has received grants from the National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development during the conduct of the study; grants from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Merck Sharp & Dohme, Eli Lilly, Astellas, Bristol Myers Squibb, Novartis, Chugai Pharmaceutical, Pfizer, and AbbVie; consulting fees from AstraZeneca, Bristol Myers Squibb, and AbbVie; and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Merck Sharp & Dohme, Eli Lilly, Bristol Myers Squibb, Novartis, Chugai Pharmaceutical, and Pfizer, all outside the submitted work. Dr. Hosomi has received personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly, Kyowakirin, Nippon Kayaku, Novartis Ono Pharmaceutical, Takeda, and Taiho Pharmaceutical, outside the submitted work. Dr. Ohe has received grants from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, LOXO, Kirin, Sumitomo, Pfizer, Taiho Pharmaceutical, Novartis, Takeda, Kissei, Daiichi Sankyo, and Janssen; personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim, Bayer, Pfizer, Merck Sharp & Dohme, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Hakko Kirin, Eisai, and Daiichi Sankyo; payment for expert testimony from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, AnHeart Therapeutics, and PharmaMar; personal fees for serving on the advisory board from Haihe Biopharma; and served with the Japanese Society of Medical Oncology, the Japan Lung Cancer Society, and the Japan Clinical Oncology Group, all outside the submitted work. The remaining authors declare no conflict of interest.
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