We present the results of a randomized, open-label pilot study investigating the combination of oral vancomycin and stereotactic body radiotherapy (SBRT) in early-stage non-small cell lung cancer (NSCLC). Our findings highlight vancomycin's safety, evidenced by the absence of Grade 3 or 4 adverse events, and its potential to enhance the antitumor efficacy of SBRT. The observed enhancement is linked to vancomycin's modulation of the gut microbiota, which triggers significant metabolic changes and immune activation, thereby contributing to improved progression-free survival (PFS) and overall survival (OS). Patients received vancomycin (125 mg, four times daily for five weeks, starting one week prior to SBRT), which induced restructuring of the gut microbiome and significant changes in the gut metabolome. Key changes included reductions in short-chain fatty acids (SCFAs) and shifts in other immunomodulatory metabolites. These metabolic shifts were associated with the activation of dendritic cells and T cells, creating a pro-inflammatory environment conducive to strengthening SBRT's antitumor efficacy. The combination of vancomycin and SBRT presents a novel, low-toxicity therapeutic approach for early-stage NSCLC, showing promising initial outcomes. While the results are encouraging, further research with larger cohorts is necessary to verify these findings and elucidate the underlying mechanisms that contribute to the observed clinical benefits.

The authors have declared no competing interest.

NCT03546829

NIH/NCI funded this study through grant 1R01CA219871-01A1

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University of Pennsylvania Institutional Review Board IRB PROTOCOL#: 827551

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