Cumulative antibiotic use and efficacy of immune checkpoint inhibitors in patients with advanced cancer.

Tinsley, Nadina; Zhou, Cong; Villa, Shaun; Tan, Grace; Lorigan, Paul; Blackhall, Fiona; Elliott, Tony; Krebs, Matthew; Carter, Louise; Thistlethwaite, Fiona; Hughes, Andrew; Cook, Natalie

doi:10.1200/jco.2018.36.15_suppl.3010

Cited by 26 publications

(31 citation statements)

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“…Our findings are not unlike those reported at the recent American Society of Clinical Oncology meetings for metastatic renal cell carcinoma 17 and a cohort of patients with heterogenous diagnoses. 18 Similar observations were also observed in another study that involved renal cell and non-small cell lung cancer. 19 These detrimental effects of antibiotics associated with treatment outcome were prominently seen, especially in those who received broad-spectrum antibiotics such as the quinolones and 3rd or 4th generation cephalosporins, even in multivariate analysis.…”

Section: Discussionsupporting

confidence: 82%

Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors

et al. 2018

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We carried out a retrospective cohort study on patients with advanced cancer treated with immune checkpoint inhibitors (ICIs) to determine whether antibiotics affect treatment outcome. Sixty consecutive patients were identified, and 17 received systemic antibiotics within 2 weeks before and/or after first dose of ICI. Antibiotic-treated patients were significantly younger (p = 0.0008) and less likely to receive nivolumab (p = 0.08) or had neutrophil:lymphocyte ratio < 5 (p = 0.08). They had a lower response rate (RR) (29.4% vs 62.8%) (p = 0.024) and more inferior progression-free survival (PFS) (p = 0.048). Narrowspectrum antibiotics did not affect the RR. However, broad-spectrum antibiotics were associated with a lower RR (25% vs 61%) (p = 0.02) and a trend towards longer time to response (median: 14 weeks vs 12 weeks) (p = 0.1). They also had shorter PFS (p = 0.012). Multivariate analysis identified antibiotics as the only factor affecting RR (p = 0.0038) and PFS (p = 0.01). We next examined the 21 patients whose PFS lasted for 12 weeks or more. Five of the 21 patients received broad-spectrum antibiotics within 10 weeks before disease progression. There was a trend towards shorter PFS in these patients (p = 0.1). Finally, antibiotic-treated patients experienced shorter overall survival (OS) (median: 24 months vs 89 months) (p = 0.003). Multivariate analysis found age (p = 0.035) and antibiotics (p = 0.038) to be the only factors affecting OS. Our results point to a detrimental effect of broad-spectrum antibiotics on treatment outcome to ICI therapy.

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Section: Discussionsupporting

confidence: 82%

Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors

et al. 2018

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“…The first study to include melanoma patients showed that the duration of ATB was important, as cumulative ATB use, defined by ATB duration of over 10 days or two or more successive courses of ATB was associated with even lower PFS and OS [54]. When examining the timing of ATB treatment, it appeared that patients treated with ATB before ICI initiation had a shorter PFS and OS compared with those who were treated with ATB after the first administration of ICI.…”

Section: Atb-related Dysbiosis and Impact Of Atb On Efficacy Of Immunmentioning

confidence: 99%

The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?

Elkrief

Derosa

Kroemer³

et al. 2019

Annals of Oncology

173

136

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Immune-checkpoint inhibitors (ICI) now represent the standard of care for several cancer types. In pre-clinical models, absence of an intact gut microbiome negatively impacted ICI efficacy and these findings permitted to unravel the importance of the commensal microbiota in immuno-oncology. Recently, multiple clinical studies including more than 1800 patients in aggregate demonstrated the negative predictive impact of treatments with broad-spectrum antibiotics (ATB) on cancer patients receiving ICI. Altogether, these results have led to the hypothesis that ATB-induced dysbiosis might influence the clinical response through the modulation of the gut microbiome. Controversy still remains, as ATB treatment might simply constitute a surrogate marker of unfit or immunodeficient patients. In this review, we summarize recent publications addressing the impact of the gut microbiome on ICI efficacy, discuss currently available data on the effect of ATB administered in different time-frames respect to ICI initiation, and finally, evoke the therapeutic implications of these findings.

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“…Finally, 19 studies were included in our quantitative analysis ( Figure 1). 10,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] A total of 2,740 patients [mean: 144; median with range: 109 (30-360)] were included in our analysis. The included studies were published between 2017 and 2019 (17/19 studies, 89%, were published in 2018 and 2019) from the United States, the United Kingdom, China, Japan, Canada, Switzerland, Greece, Korea, Austria, and France.…”

Section: Study Selection and Associated Characteristicsmentioning

confidence: 99%

Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients

et al. 2019

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The gut microbiota plays a critical role in the anti-tumor immune response. There is increasing data showing that antibiotics (ATBs) change the composition of the gut microbiota and affect the efficacy of immune checkpoint inhibitors (ICIs). However, this is the first meta-analysis to evaluate the association between ATB use and ICI efficacy in cancer patients to provide a better understanding of the strength of this association. We performed a literature search for relevant studies that evaluated the relationship between ATB use and ICI efficacy using the PubMed, Embase, and conference databases. The primary outcomes consisted of overall survival (OS) and progression-free survival (PFS) measured by hazard ratios (HR) and corresponding 95% confidence intervals (CI). Subgroup and sensitivity analyses were also performed. A total of 19 eligible studies comprising 2,740 cancer patients treated with ICIs were included in the analysis. Our results indicated that ATB use was negatively associated with OS in cancer patients (HR = 2.37; 95% CI = 2.05–2.75; P < .001), without heterogeneity (I2 = 0.0%; P = .851). Moreover, ATB use significantly reduced PFS in patients treated with ICIs (HR = 1.84; 95% CI = 1.49–2.26; P < .001; I2 = 56.2%). Similar results were obtained in the subgroup analyses stratified by the time of ATB use and cancer type. Sensitivity analyses confirmed the stability of our results. Therefore, the findings of our meta-analysis indicated that ATB use is negatively associated with OS and PFS in cancer patients treated with ICI immunotherapy.

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Cumulative antibiotic use and efficacy of immune checkpoint inhibitors in patients with advanced cancer.

Cited by 26 publications

References 0 publications

Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors

Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors

The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?

Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients

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