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Brief Report
September 12, 2019

Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer

Author Affiliations
  • 1Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
  • 2Department of Oncology, Imperial College NHS Trust, Charing Cross Hospital, London, United Kingdom
  • 3Tokyo Medical and Dental University, Tokyo, Japan
  • 4Department of Oncology, Chelsea and Westminster Hospital, London, United Kingdom
  • 5Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
JAMA Oncol. Published online September 12, 2019. doi:https://doi.org/10.1001/jamaoncol.2019.2785
Key Points

Question  Does broad-spectrum antibiotic treatment alter responsive to immune checkpoint inhibitors (ICIs) in routine practice?

Findings  In this observational study that included 196 patients with cancer treated with ICI therapy, antibiotic treatment administered within 30 days from commencement of ICI therapy was associated with significantly worse overall survival and a higher risk of disease refractory to treatment.

Meaning  Antibiotic therapy is associated with a reduced response to ICIs in routine practice, irrespective of tumor site; mechanistic studies exploring this relationship are warranted.

Abstract

Importance  Gut dysbiosis impairs response to immune checkpoint inhibitors (ICIs) and can be caused by broad-spectrum antibiotic (ATB) therapy.

Objective  To evaluate whether there is an association between ATB therapy administered concurrently (cATB) or prior (pATB) to ICI therapy and overall survival (OS) and treatment response to ICI therapy in patients with cancer treated with ICIs in routine clinical practice.

Design, Setting, and Participants  This prospective, multicenter, cohort study conducted at 2 tertiary academic referral centers recruited 196 patients with cancer who received ICI therapy between January 1, 2015, and April 1, 2018, in routine clinical practice rather than clinical trials.

Main Outcomes and Measures  Overall survival calculated from the time of ICI therapy commencement and radiologic response to ICI treatment defined using the Response Evaluation Criteria in Solid Tumors (version 1.1), with disease refractory to ICI therapy defined as progressive disease 6 to 8 weeks after the first ICI dose without evidence of pseudoprogression.

Results  Among 196 patients (137 men and 59 women; median [range] age, 68 [27-93] years) with non–small cell lung cancer (n = 119), melanoma (n = 38), and other tumor types (n = 39), pATB therapy (HR, 7.4; 95% CI, 4.3-12.8; P < .001), but not cATB therapy (HR, 0.9; 95% CI, 0.5-1.4; P = .76), was associated with worse OS (2 vs 26 months for pATB therapy vs no pATB therapy, respectively) (hazard ratio [HR], 7.4; 95% CI, 4.2-12.9) and a higher likelihood of primary disease refractory to ICI therapy (21 of 26 [81%] vs 66 of 151 [44%], P < .001). Overall survival in patients with non–small cell lung cancer (2.5 vs 26 months, P < .001), melanoma (3.9 vs 14 months, P < .001), and other tumor types (1.1 vs 11, P < .001) was consistently worse in those who received pATBs vs those who did not. Multivariate analyses confirmed that pATB therapy (HR, 3.4; 95% CI, 1.9-6.1; P < .001) and response to ICI therapy (HR, 8.2; 95% CI, 4.0-16.9; P < .001) were associated with OS independent of tumor site, disease burden, and performance status.

Conclusions and Relevance  Despite being limited by sample size, geographic origin, and the lack of correlative analyses on patients’ gut microbiota, this study suggests that pATB therapy but not cATB therapy is associated with a worse treatment response and OS in unselected patients treated with ICIs in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICI treatment.

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