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The effect of antibiotics on clinical outcomes in immune-checkpoint blockade: a systematic review and meta-analysis of observational studies

Abstract

Purpose

Pre-clinical and early clinical data suggests the microbiome plays an important role in oncogenesis and influences response to immune checkpoint blockade (ICB). The objective of this systematic review and meta-analysis was to determine whether antibiotics affect overall survival (OS) and progression free survival (PFS) in patients with solid malignancies treated with ICB.

Patients and methods

A systematic search of EMBASE, MEDLINE and conference proceedings was conducted for observational studies examining the effect of antibiotics on ICB. A random effects study-level meta-analysis was performed with pooling of the hazards ratio (HR) for OS and PFS. Meta-regression was used to determine the impact of the timing of antibiotic exposure on OS.

Results

766 studies were identified, and 18 studies met the inclusion criteria. Of the 2889 patients included, 826 (28.6%) were exposed to antibiotics. The most common malignancies were lung (59%), renal cell carcinoma (RCC) or urothelial carcinoma (16.3%) and melanoma (18.7%). OS was prolonged in those without antibiotic exposure (pooled HR 1.92, 95% CI 1.37–2.68, p < 0.001). The effect of antibiotics on OS was greater in studies defining antibiotic exposure as 42 days prior to initiation of ICB (HR 3.43, 95% CI 2.29–5.14, p < 0.0001). PFS was also longer in patients who did not receive antibiotics (pooled HR 1.65, 95% CI 1.3–2.1, p < 0.0001).

Conclusion

In patients receiving ICB, OS and PFS are longer in patients who are not exposed to antibiotics. Antibiotic use in the 42 days before starting ICB appears to be most detrimental to outcome.

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Abbreviations

CAR-T:

Chimeric antigen receptor T cell

CTLA-4:

Cytotoxic T lymphocyte associated protein 4

ECOG:

Eastern Co-operative Oncology Group

HR:

Hazard ratio

ICB:

Immune checkpoint blockade

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PD-1:

Programmed cell death protein—1

PD-L1:

Programmed death—ligand 1

PFS:

Progression free survival

RCC:

Renal cell carcinoma

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BEW: project design, data extraction, data analysis, manuscript writing. BR: manuscript revision and advice. AN: manuscript revision and advice. VC: project design, data extraction, data interpretation and manuscript revision

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Correspondence to Brooke E. Wilson.

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Wilson, B.E., Routy, B., Nagrial, A. et al. The effect of antibiotics on clinical outcomes in immune-checkpoint blockade: a systematic review and meta-analysis of observational studies. Cancer Immunol Immunother 69, 343–354 (2020). https://doi.org/10.1007/s00262-019-02453-2

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  • DOI: https://doi.org/10.1007/s00262-019-02453-2

Keywords

  • Antibiotics
  • Immunotherapy
  • Immune checkpoint blockade
  • Cancer