Effect of Antibiotic Therapy on Immunotherapy Outcomes for Non-Small Cell Lung Cancer: Analysis From the Veterans Health Administration

Abstract

<h3>Purpose/Objective(s)</h3> Dysregulation of gut microbiota induced by antibiotic therapy (Abx) may alter the anticancer immune response. Multiple small studies have associated Abx use with inferior outcomes in patients with non-small cell lung cancer (NSCLC) who were treated with immune checkpoint inhibitors (ICI). We investigated this association in a larger population of patients treated with ICI within the Veterans Health Administration. <h3>Materials/Methods</h3> We conducted a nested cohort study of Veterans diagnosed with NSCLC between 2010-2018 and treated with ICI. Abx exposure was defined as receipt of an Abx prescription within a window extending from 30 days before to 30 days after first ICI administration. Overall survival (OS), measured from start of ICI, was compared. Cox proportional hazard multivariate analysis (MVA) was used to identify factors associated with OS. A separate cohort of Veterans with stage IV NSCLC who received docetaxel without ICI was similarly analyzed. <h3>Results</h3> 3,634 Veterans received ICI, mostly nivolumab (59.1%) or pembrolizumab (35.1%), with a median age of 69, male gender in 97.0%, white race in 73.0%, adenocarcinoma in 47.8%, and stage IV disease at diagnosis in 40.9%. In this nested cohort, 1,240 (34.1%) were exposed to Abx, with beta-lactams (30.1% of Abx recipients) the most common agent. Abx receipt was associated with male gender, greater comorbidity burden, and non-receipt of chemotherapy (all <i>p</i>≤0.044). Abx were associated with worse OS on MVA (HR 1.38, 95%CI 1.27-1.49, <i>p</i><0.001) and in a propensity-matched matched subset (HR 1.37, 95%CI 1.26-1.50, <i>p</i><0.001). Among 764 Veterans with stage IV disease receiving docetaxel, Abx were also associated with worse OS on MVA (HR 1.26, 95%CI 1.11-1.44, <i>p</i><0.001) and in a propensity-score matched subset (HR 1.22, 95%CI 1.07-1.40, <i>p</i>=0.004). In a <i>post-hoc</i> pooled analysis of the 1,681 Abx-exposed Veterans from the ICI and stage IV docetaxel cohorts, ICI receipt was associated with worse OS as compared to docetaxel receipt (HR 1.15, 95%CI 1.00-1.31, <i>p</i>=0.044); no such difference was observed in a pooled analysis of 2,910 unexposed Veterans (HR 0.99, 95%CI 0.88-1.12, <i>p</i>=0.904). However, a test for heterogeneity of Abx effect by ICI/docetaxel did not attain statistical significance (interaction <i>p</i>=0.062). <h3>Conclusion</h3> Abx are associated with worse OS among NSCLC patients receiving either ICI or cytotoxic chemotherapy; however, this decrement appears larger among ICI recipients. These findings suggest Abx may have a detrimental effect on immunotherapy outcomes.