Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer 

SUMMARY: The American Cancer Society estimates that in 2020, there will be an estimated 1.8 million new cancer cases diagnosed and 606,520 cancer deaths in the United States. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Biomarkers predicting responses to ICI’s include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL‐derived Interferon‐γ, Neutrophil‐to‐Lymphocyte ratio, and peripheral cytokines, have also been proposed as predictors of response. It has been postulated that concomitant medications during therapy with ICIs such as baseline steroid use as well as treatment with antibiotics may negate or lessen the efficacy of ICIs.
Preclinical studies have suggested that immune-based therapies for cancer may have a very complex interplay with the host’s microbiome and there may be a relationship between gut bacteria and immune response to cancer. The crosstalk between microbiota in the gut and the immune system allows for the tolerance of commensal bacteria (normal microflora) and oral food antigens and at the same time enables the immune system to recognize and attack opportunistic bacteria. Immune Checkpoint Inhibitors strongly rely on the influence of the host’s microbiome, and the gut microbial diversity enhances mucosal immunity, dendritic cell function, and antigen presentation. Broad-spectrum antibiotics can potentially alter the bacterial composition and diversity of our gut microbiota, by killing the good bacteria. It has been postulated that this may negate the benefits of immunotherapy and influence treatment outcomes.
This present study was conducted to assess the impact of antibiotic use at the time of ICI treatment, on the outcomes for patients with advanced or metastatic solid tumors. This United Kingdom single institution retrospective analysis included 291 (N=291) patients with advanced cancer, treated with ICI (Melanoma N=179, Non‐Small Cell Lung Cancer N=64, and Renal Cell Carcinoma N=48), who received an ICI agent between January 1, 2015, and April 1, 2017. Antibiotic use (both single and multiple courses as well as prolonged use) during the periods 2 weeks before and 6 weeks after ICI treatment was investigated and data collected. The authors chose this time period, because the potential duration of modification of gut microbiota following antibiotic therapy can vary, for different classes of antibiotics.
Ninety two (N=92) patients in the analyzed cohort had antibiotic therapy during ICI treatment. The use of antibiotics during treatment with ICIs was significantly associated with shorter Progression Free Survival (median PFS 3.1 versus 6.3 months; P=0.003) and Overall Survival (median OS 10.4 versus 21.7 months; P=0.002). Administration of a single course of antibiotics was associated with a non-significant reduction in PFS and OS, whereas patients who had received cumulative courses of antibiotics had significantly worse PFS (median PFS, 2.8 months; P=0.026) and OS (median OS, 6.3 months; P=0.009). Cumulative use of antibiotics was an independent significant prognostic factor for clinical outcomes among patients treated with ICIs. 
It was concluded from this large, multivariate analysis that antibiotic use is an independent negative predictor of PFS and OS in patients with advanced cancer treated with Immune Checkpoint Inhibitors, with worse treatment outcomes among patients who had received multiple or prolonged courses of antibiotics. The authors added that this is the first study to suggest an adverse effect of cumulative antibiotic use, in patients receiving treatment with Immune Checkpoint Inhibitors for advanced cancer. Cumulative Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer. Tinsley N, Zhou C, Tan G, et al. Oncologist. 2020;25:55-63.