Antibiotic use reduces efficacy of tyrosine kinase inhibitors in patients with advanced melanoma and non-small cell lung cancer

Abstract

Background: Antibiotic (ABX) use and disruption of the gut microbiome has been demonstrated to reduce the efficacy of immune checkpoint inhibitors and chemotherapeutics in cancer patients. Little is known about the impact of ABX use in patients treated with targeted therapies, such as tyrosine kinase inhibitors (TKI). Methods: Retrospective data analysis was performed on advanced melanoma and non-small cell lung cancer (NSCLC) patients treated with TKIs between January 2015 and April 2017 at The Christie NHS Foundation Trust, UK. Demographics, prior systemic treatment, extent of disease, lactate dehydrogenase level (LDH), presence of brain metastases, performance status, comorbidities, TKI agent and the use of ABX (class, route, duration) were collected. Progression free survival (PFS) and overall survival (OS) were compared between the ABX+ group (defined as patients treated with ABX within 2 weeks of TKI initiation or 6 weeks after) and the ABX – group (patients with no ABX during specified period). Statistical analyses were performed with univariate and multivariable models. Results: In total, 168 patients were included; 89 patients (53%) with advanced NSCLC and 79 patients (47%) with melanoma. Over a third of patients, (57/168, 34%) received ABX in the specified period (ABX+). On univariable analysis, ABX use was associated with shorter PFS (208 days vs 357 days, p = 0.008) and OS (294 days vs 438 days, p = 0.024). Increased age, poorer performance status, and higher LDH were also associated with shorter PFS and OS. On multivariable analysis, ABX use was independently associated with shorter PFS (HR 1.57, 95% CI 1.05-2.34, p = 0.028) and OS (HR 2.19, 95% CI 1.44-3.32, p = 0.0002). The negative impact of ABX on OS was particularly pronounced for patients with worse performance status (HR 3.82, 95% CI 1.18-12.36, p = 0.025). Conclusions: To our knowledge, this is the largest multivariable analysis showing ABX use independently reduces PFS and OS in patients treated with TKIs. It is the first analysis to demonstrate this phenomenon across two distinct tumour sites. The data suggests that ABX use could be an independent predictor of shorter PFS and OS in cancer patients treated with TKIs, and warrants further validation in a larger cohort.