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Abstract
Background The use of immune checkpoint inhibitors (ICI) has increased significantly in the past five years, along with the number of available drugs and regimens. ICIs have dramatically increased survival in cancer patients, however, there has been data to show that they have reduced efficacy in the presence of antibiotics.1 Antibiotic use prior and during ICI therapy was associated with worsening clinical outcomes in patients with renal cell carcinoma,2 melanoma,3 and non-small-cell-lung-cancer.4 Specifically, exposure within 60 days of initiation of ICIs in NSCLC seemed most detrimental, however, some studies have suggested that antibiotics disrupt intestinal microflora for up to six months.5 6 Therefore, we hypothesized that the duration of the antibiotic effect on ICI efficacy may be present for a longer duration.
Methods The electronic medical record was queried at the University of Cincinnati Medical Center for the administration of ICIs and antibiotics. Data was collected on the use, type, and duration of antibiotics before ICI use after administration with relevant demographic and clinicopathologic variables including treatment type, cancer type, staging information, and clinical course including subsequent antibiotic use. Univariant (Fischer’s Exact) and multivariant analysis (multiple logistic regression) were conducted and survival analysis was determined according to log-rank testing.
Results 217 patients were examined. The median age was 64 (range 22-93), 38% were female, 73% had ECOG 0-1, and 77% were white. Cancer types included melanoma 24%, non-small cell lung cancer (NSCLC) 34%, small cell lung cancer 2%, renal cancer 11%, urothelial cancer 10%, head and neck cancers 11%, and 16% other primaries. 20% remained on ICI at the time of data entry. The most common ICIs were pembrolizumab, nivolumab, followed by ipilimumab-nivolumab, ipilimumab, and durvalumab. 81 patients of 218 received antibiotics within 6 months of receiving checkpoint inhibitors. Of antibiotics administered, the most common classes were cephalosporins (86%), fluoroquinolones (28%), and glycopeptides (23%) with substantial overlap. Overall survival and progression-free survival was improved for those who did not receive antibiotics prior to ICI therapy (median OS 6.5 vs. 2.3 years, HR 0.36, p<0.0001; median PFS 1.1 vs 0.5 years, HR 0.6, p=0.0027) (figure 1 and 2 respectively). Linear regression showed no significant association between antibiotic use prior to ICI use and age, sex, race, ICI type, or ECOG status.
Antibiotics up to six months before ICI reduce OSFigure 1: Antibiotics Prior to Checkpoint Inhibitor Therapy Lead to Inferior Overall Survival: Analysis of patients treated with any type of antibiotic lead to worsened overall survival compared to those who did not receive antibiotics or who received a one time dose of cefazolin. Statistical analysis showed by both Log Rank and Wilcoxon testing p-values were <0.0001 with median survival 6.5y vs. 2.3y for those who received antibiotics prior to ICI treatment (HR 3.4, 95% CI 2.2 to 5.3).
Antibiotics up to six months before ICI reduce PFSFigure 2: Antibiotics Prior to Checkpoint Inhibitor Therapy Lead to Inferior Progression-Free Survival: Analysis of patients treated with any type of antibiotic lead to worsened progression-free survival as well compared to those who did not receive antibiotics or who received a one time dose of cefazolin. Statistical analysis showed by both Log Rank and Wilcoxon testing p-values were 0.0027 and 0.0011 respectively. Median PFS from initiation of immunotherapy was 1.1y vs. 0.46y for those who received antibiotics prior to ICI treatment (HR 1.7, 95% CI 1.2 to 2.5).
Conclusions This data adds to the growing body of knowledge that the use of antibiotics prior to ICI treatment leads to inferior overall and progression-free survival.
Acknowledgements We would like to thank the Roman Jandarov, UC Cancer Center, the University of Cincinnati Division of Hematology and Oncology, Department of Internal Medicine of the University of Cincinnati, and the University of Cincinnati Medical Center for their continued support.
Ethics Approval IRB 2019-0610
References
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