The Association Between Antibiotic Use and Outcome Among Metastatic Melanoma Patients Receiving Immunotherapy

Florence Poizeau, MD, MSc; Sandrine Kerbrat, MSc; Frédéric Balusson, MSc; Pierre Tattevin, MD, PhD; Matthieu Revest, MD, PhD; Vincent Cattoir, PharmD, PhD; David Luque-Paz, MD, MSc; Thierry Lesimple, MD; Marc Pracht, MD; Monica Dinulescu, MD; David Russo, MD; Emmanuel Oger, MD, PhD; Alain Dupuy, MD, PhD

Disclosures

J Natl Cancer Inst. 2022;114(5):686-694. 

In This Article

Abstract and Introduction

Abstract

Background: Several observational studies have reported a decreased response to immune checkpoint inhibitors (ICI) following antibiotic use. ICI activity has been hypothesized to be impaired by antibiotic-induced gut dysbiosis.

Methods: Patients with advanced melanoma receiving an anti-PD-1 antibody as a first-line therapy between 2015 and 2017 in France were selected using the French Health Insurance database. We compared overall survival and time-to-treatment discontinuation according to antibiotic exposure in the 3 months prior to the initiation of anti-PD-1 antibody. To disentangle a causal effect of antibiotics from a confounding bias, we balanced characteristics of patients exposed and nonexposed to antibiotics using an overlap weighting method based on a propensity score. We also evaluated a control cohort of patients with advanced melanoma receiving first-line targeted therapy, as there is no rationale for decreased efficacy of targeted therapy following antibiotic treatment.

Results: The anti-PD-1 antibody cohort comprised 2605 individuals. Antibiotic exposure in the 3 months prior to anti-PD-1 antibody initiation was not associated with shorter overall survival (weighted hazard ratio = 1.01, 95% confidence interval = 0.88 to 1.17) or time-to-treatment discontinuation (weighted hazard ratio = 1.00, 95% confidence interval = 0.89 to 1.11). Consistent results were observed when the time frame of antibiotics was narrowed to 1 month prior to anti-PD-1 initiation or when exposure was restricted to antibiotics leading to more profound gut dysbiosis. Similar results were observed in the targeted therapy cohort.

Conclusions: In a large cohort of advanced melanoma patients, we showed that antibiotic use preceding anti-PD-1 antibody was not associated with worse outcome. Physicians should not delay immunotherapy for patients who have recently received antibiotics.

Introduction

Tumor immunotherapy using immune checkpoint inhibitors (ICI) has dramatically changed the prognosis of metastatic melanoma as well as several other cancers.[1] However, only approximately 35% to 45% of patients benefit from immunotherapy.[2–4] Identification of factors that affect the efficacy of ICI has therefore become a new challenge. One of the most disturbing findings that has emerged in the past 3 years is the suspected detrimental effect of antibiotics: across several cancers, antibiotics administered before ICI have been associated with shorter progression-free and overall survival.[5–11] Because the role of the gut microbiota in response to ICI has been substantiated by experimental data in mice,[12] the hypothesis of an impairment of ICI efficacy consecutive to antibiotic-induced gut dysbiosis has been raised.[13] Among patients receiving ICI, dysbiosis could consecutively lead to cancer progression and death. Alongside this neat causal hypothesis, however, one alternative line of explanation, namely confounding by indication, has not been ruled out or even appropriately discussed in the vast majority of reports. Thus, more aggressive disease or a comorbid burden among patients receiving antibiotics could lead to the poorer prognosis observed, independently from any causal effect of antibiotic exposure.[14,15] In other words, patients with more active or advanced metastatic cancer, with a poorer prognosis, are more likely to require medical care, including antibiotic courses. Because it is very challenging to control for, confounding by indication has been considered as the "most stubborn bias."[16]

We addressed the question of the impact of exposure to antibiotics on ICI efficacy and survival in a cohort of advanced melanoma patients using data prospectively collected in the French Health Insurance database. To ensure the best comparability between patients exposed and nonexposed to antibiotics, we used a propensity score weighting method and included a large homogeneous single-cancer population. We defined 2 cohorts according to the first-line treatment used: anti-PD-1 antibody or targeted therapy. The hypothesis of a deleterious effect of antibiotic-induced gut dysbiosis has been raised for ICI, although no suspicion of such an effect has emerged in the literature on targeted therapy. Therefore, studying these 2 cohorts in parallel offered the opportunity to disentangle causal effect from bias.

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