The Distribution Characteristics and Dynamic Changes of Gut Microbiota Indicates the Efficacy of Immunotherapy in Advanced EGFR-Mutated Non-Small Cell Lung Cancer

Abstract

Background: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR+) NSCLC remain unknown.

Methods: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR+ NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy.

Findings: The clinical data of 74 advanced EGFR+ NSCLC patients were complete and 18 patients’ fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P=0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites.

Interpretation: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR+ NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites indicates the efficacy of immunotherapy in advanced EGFR+ NSCLC.

Funding: This study was funded by National Natural Science Foundation of China (Grant No. 82102808 to Yi-Chen Zhang); National Natural Science Foundation of China (Grant No. 82373349 to Q. Zhou); Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (2017B030314120, Y.L Wu); Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120 to Yi-Chen Zhang); Guangdong Provincial People's Hospital Young Talent Project (Grant No. KY0120220136 to Yi-Chen Zhang);

Declaration of Interest: Prof. Y.L Wu reports grants and personal fees from AstraZeneca, BMS, Pfizer; and personal fees from Boehringer Ingelheim, Eli Lilly, Hengrui, MSD, Sanofi, Roche, outside the submitted work. Prof. Q. Zhou reports honoraria from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi outside the submitted work. The other authors have no competing interests to declare.

Ethical Approval: The study was approved by the Ethics Committee at Guangdong Provincial People's Hospital, N o. GDREC2019304H(R1). All patients were informed of the study and consented to the enrollment. This study was conducted in accordance with the Helsinki Declaration.

Keywords: Non-Small Cell Lung Cancer, Epidermal Growth Factor Receptor, Gut Microbiota, Metabolites, Antibiotics