Effect of prior antibiotic or chemotherapy treatment on immunotherapy response in non-small cell lung cancer

Abstract

Background: Treatment outcomes of advanced non-small cell lung cancer (NSCLC) have substantially improved with immune checkpoint inhibitors (ICI), although only approximately 19% of patients respond to immunotherapy alone, increasing to 58% with the addition of chemotherapy. The gut microbiome has been recognized as a modulator of ICI response via its priming effect on the host immune response. Antibiotics as well as chemotherapy reduce gut microbial diversity, hence altering composition and function of the gut microbiome. Since the gut microbiome may modify ICI efficacy, we conducted a retrospective study evaluating the effects of prior antibiotic or chemotherapy use on NSCLC patient response to ICI. Methods: We retrospectively evaluated 256 NSCLC patients treated between 2011–2017 at Moffitt Cancer Center with ICI ± chemotherapy, examining the associations between prior antibiotic or chemotherapy use, overall response rate and survival. Relative risk regression using a log-link with combinatorial expectation maximization algorithm was performed to analyze differences in response between patients treated with antibiotics or chemotherapy versus patients who didn’t receive antibiotics or chemotherapy. Cox proportional hazards models were constructed to evaluate associations between risk factors and overall survival. Results: Only 46 (18% of 256) patients used antibiotics prior to and/or during ICI treatment, and 146 (57%) had prior chemotherapy. Antibiotic users were 8% more likely to have worse overall response rate (RR:1.08; CI:0.93–1.26; p = 0.321), as well as a 35% worse overall survival (HR:1.35; CI:0.91–2.02; p = 0.145), although results were not statistically significant. However, prior use of chemotherapy was significantly associated with poor ICI response (RR:1.24; CI:1.05–1.47; p = 0.013) and worse overall survival (HR:1.47; CI:1.07–2.03; p = 0.018). Conclusions: Patients receiving antibiotics prior to and/or during ICI therapy might experience worse treatment outcomes and survival than unexposed patients, although these associations were not statistically significant and hence warrant further prospective study. Prior chemotherapy significantly reduced ICI response and overall survival. Antibiotic or chemotherapy exposure may negatively impact ICI response, perhaps through disruption of the eubiotic gut microbiome.