Antibiotic treatment and survival in non-small cell lung cancer patients receiving immunotherapy: a systematic review and meta-analysis

Background: In patients with non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) are an effective mode of treatment. Despite their efficacy, responses to ICIs have been shown to differ based on several factors; for example, antibiotic use prior to and/or during immunotherapy has been associated with lower survival in NSCLC patients. The objective of this study is to provide an updated review of the literature and to fill in important knowledge gaps by accounting for potential confounding in the relationship between ICIs and survival. Methods: We performed a systematic review and meta-analysis on peer-reviewed studies that examined the effects of antibiotic use on overall survival (OS) and progression-free survival (PFS) in NSCLC patients treated with ICIs. We searched MEDLINE for studies published up to June 30th, 2023 that included NSCLC patients treated with anti-programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) agents, who received antibiotics before and/or during immunotherapy, and included a control group who did not receive antibiotics and had available data on the associations between antibiotics and OS and PFS. We calculated aggregated crude OS and PFS for all studies, and only for studies that reported multivariable hazard ratios (HRs). Risk of bias was assessed using a funnel plot. All results were synthesized and displayed using the metaphor statistical package in R, version 4.2.1. Results: Nineteen studies, conducted between 2017 and 2022, met the inclusion criteria, and included 2,932 patients with advanced and/or metastatic NSCLC. Compared to those who did not receive antibiotics, immunotherapy patients who did had a significantly reduced PFS (HR: 1.22, 95% CI: 1.03-1.44) and OS (HR: 1.56, 95% CI: 1.23-1.99). Adjusted HRs were even more pronounced (OS HRadj: 1.67, 95% CI: 1.23- 2.27, PFS HRadj: 1.64, 95% CI: 1.16-2.32). Conclusions: NSCLC patients treated with antibiotics have significantly lowered survival compared with patients not treated with antibiotics. These results support the hypothesis that antibiotic use in conjunction with ICI among NSCLC patients lowers survival. Limitations of this analysis include the use of studies available only on a single database, limiting the literature search to NSCLC patients, which may impact the generalizability of results to other cancer patient populations, and the inability to account for and adjust the estimates for the same variables (e.g., age, sex) across all studies. Nevertheless, our findings underscore the importance of taking antibiotic use into consideration when using ICIs to treat NSCLC and suggest that confounders should be taken into account when designing future similar studies.