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

Abstract

Background: With the advent of immunotherapy, substantial progress has been made in improving outcomes for patients with advanced cancer. However, not all patients benefit equally from treatment, and confounding immune-related issues may have an impact. Several studies suggest that antibiotic use (which alters the gut microbiome) may result in poorer outcomes for patients treated with immune checkpoint inhibitors (ICI).

Materials and methods: This is a large, single-site retrospective review of n = 291 patients with advanced cancer treated with ICI (n = 179 melanoma, n = 64 non-small cell lung cancer, and n = 48 renal cell carcinoma). Antibiotic use (both single and multiple courses/prolonged use) during the periods 2 weeks before and 6 weeks after ICI treatment was investigated.

Results: Within this cohort, 92 patients (32%) received antibiotics. Patients who did not require antibiotics had the longest median progression-free survival (PFS), of 6.3 months, and longest median overall survival (OS), of 21.7 months. With other clinically relevant factors controlled, patients who received a single course of antibiotics had a shorter median OS (median OS, 17.7 months; p = .294), and patients who received multiple courses or prolonged antibiotic treatment had the worst outcomes overall (median OS, 6.3 months; p = .009). Progression-free survival times were similarly affected.

Conclusion: This large, multivariate analysis demonstrated that antibiotic use is an independent negative predictor of PFS and OS in patients with advanced cancer treated with ICIs. This study highlighted worse treatment outcomes from patients with cumulative (multiple or prolonged courses) antibiotic use, which warrants further investigation and may subsequently inform clinical practice guidelines advocating careful use of antibiotics.

Implications for practice: Antibiotic use is negatively associated with treatment outcomes of immune checkpoint inhibitors (ICI) in advanced cancer. Cumulative antibiotic use is associated with a marked negative survival outcome. Judicious antibiotic prescribing is warranted in patients receiving treatment with ICI for treatment of advanced malignancy.

Keywords: Checkpoint inhibitors; Cumulative antibiotics; Immunotherapy; Lung cancer; Melanoma; Renal cancer.

Figure 1

Patient enrolment CONSORT flow‐chart diagram. Patients were identified who had been treated at The Christie NHS Foundation Trust between January 1, 2015, and April 1, 2017. Abbreviations: NSCLC, non‐small cell lung cancer; RCC, renal cell carcinoma.

Figure 2

Survival outcomes for patients based on their exposure to antibiotics. Kaplan‐Meier survival estimators were plotted for patients who had been treated with immune checkpoint inhibitors with and without antibiotics. Patients treated with antibiotics during immune checkpoint inhibitor treatment demonstrated a median progression‐free survival (PFS) of 3.1 months and a median overall survival (OS) of 10.4 months, significantly less than those without antibiotics (p = .003 and .002, respectively). The latter demonstrated a median PFS of 6.3 months and a median OS of 21.7 months. The results have not been adjusted for other prognostic factors.

Figure 3

Survival of patients based upon antibiotic use. Patients were divided into three categories based on whether they had received antibiotics or not during the period of 2 weeks before until 6 weeks after immune checkpoint inhibitor treatment initiation. Kaplan‐Meier estimator graphs illustrate survival outcomes for patients who did not receive antibiotics (blue), patients who received a single course of antibiotics only (red), and patients who received prolonged or multiple courses of antibiotics (black). Other prognostic factors were controlled in this plot. Abbreviations: OS, overall survival; PFS, progression‐free survival.