Association of Antibiotic Exposure With Survival and Toxicity in Patients With Melanoma Receiving Immunotherapy

Abstract

BACKGROUND Gut microbial diversity is associated with improved response to immune checkpoint inhibitors (ICI). Based on the known detrimental impact that antibiotics have on microbiome diversity, we hypothesized that antibiotic receipt prior to ICI would be associated with decreased survival. METHODS Patients with stage III and IV melanoma treated with ICI between 2008 and 2019 were selected from an institutional database. A window of antibiotic receipt within 3 months prior to the first infusion of ICI was pre-specified. The primary outcome was overall survival (OS) and secondary outcomes were melanoma-specific mortality and immune-mediated colitis requiring intravenous (IV) steroids. All statistical tests were two-sided. RESULTS There were 568 patients in our database, of which 114 received antibiotics prior to ICI. 35.9% of patients had stage III disease. On multivariable Cox proportional hazards analysis of patients with stage IV disease, the antibiotic-exposed group had statistically significantly worse OS (hazard ratio [HR] 1.81, 95% confidence interval [CI] 1.27-2.57, p<.001). The same effect was observed among antibiotic-exposed patients with stage III disease (HR 2.78, 95% CI 1.31-5.87, p=.007). When limited to only patients who received adjuvant ICI (N = 89), antibiotic-exposed patients also had statistically significantly worse OS (HR 4.84, 95% CI 1.09-21.50, p=.04). The antibiotic group had a greater incidence of colitis (HR 2.14, 95% CI 1.02-4.52, p=.046). CONCLUSION Patients with stage III and IV melanoma exposed to antibiotics prior to ICI had statistically significantly worse OS than unexposed patients. Antibiotic exposure was associated with greater incidence of moderate to severe immune-mediated colitis. Given the large number of antibiotics prescribed annually, physicians should be judicious with their use in cancer populations likely to receive ICI.

Is the survival of patients treated with ipilimumab affected by antibiotics? An analysis of 1585 patients from the French National hospital discharge summary database (PMSI)

“…In a multivariate analysis of patients with stage IV melanoma, overall survival was significantly worse in the antibiotic-exposed group than in the non-exposed group (HR = 1.81, [1.27; 2.57]). 40 Our study had several strengths. Firstly, to the best of our knowledge, it constituted the largest yet study (in terms of the sample size) to have addressed this issue.…”

“…In a multivariate analysis of patients with stage IV melanoma, overall survival was significantly worse in the antibiotic-exposed group than in the non-exposed group (HR = 1.81, [1.27; 2.57]). 40 …”

Biomarkers for precision immunotherapy in the metastatic setting: hope or reality?

“…Modulation of the gut microbiome to enhance therapeutic response is being tested in multiple ongoing clinical studies [130]. Accordingly, antibiotic consumption before ICPIs had worse OS than unexposed patients [131].…”

Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors

“…Clearly, harm from antibiotics is not limited to cancer patients with advanced metastatic disease. 39 Nevertheless, antibiotic classes should be carefully considered. Some antibiotics can provide a positive 'eubiotic' effect on the gut microbiota by reducing the abundance of unfavorable gut bacteria.…”