Association between antibiotics use and outcome in patients with NSCLC treated with immunotherapeutics
Authors: F. Huemer, G. Rinnerthaler, D. Lang, H. Hackl, B. Lamprecht, R. Greil
Journal: Annals of Oncology (2019)

Conflicting data exist about the impact of antibiotic exposure on clinical outcome during immune-checkpoint blockade (ICB) in advanced non-small-cell lung cancer (aNSCLC). Routy et al. [1.Routy B. Le Chatelier E. Derosa L. et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Science. 2017; 359: 91-97Crossref PubMed Scopus (2643) Google Scholar] and Derosa et al. [2.Derosa L. Hellmann M.D. Spaziano M. et al.Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer.Ann Oncol. 2018; 29: 1437-1444Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar] described a detrimental effect of antibiotic administration on clinical outcome during ICB in aNSCLC, which is in line with our single-center experience at the tertiary cancer center in Salzburg [3.Huemer F. Rinnerthaler G. Westphal T. et al.Impact of antibiotic treatment on immune-checkpoint blockade efficacy in advanced non-squamous non-small cell lung cancer.Oncotarget. 2018; 9: 16512-16520Crossref PubMed Scopus (63) Google Scholar]. Derosa et al. reported an inferior median overall survival (mOS) associated with the use of antibiotics within a time frame of 30 days [hazard ratio (HR) = 4.4] or 60 days (HR = 2.0) preceding ICB initiation in 239 patients with aNSCLC [2.Derosa L. Hellmann M.D. Spaziano M. et al.Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer.Ann Oncol. 2018; 29: 1437-1444Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar]. In contrast, Metges et al. found a survival advantage for patients receiving antibiotics up to 60 days before or during ICB (mOS: 16.2 versus 11.5 months, P = 0.01) in 325 aNSCLC patients [4.Metges J. Michaud E. Lagadec D.D. et al.Impact of anti-infectious and corticosteroids on immunotherapy: nivolumab and pembrolizumab follow-up in a French study.Ann Oncol. 2018; 29: viii400-viii441Google Scholar]. In our bi-centric analysis, including 96 non-squamous aNSCLC patients, no influence of antibiotic exposure on mOS from ICB initiation was found (AB--group: 11.2 versus AB+-group: 12.2 months, HR = 0.84, P = 0.546, Figure 1A). In contrast to Derosa et al. and Metges et al., the defined time frame of antibiotic exposure ranged from one month before to 1 month after ICB start in our analysis. Neither the time point of antibiotic administration (before: 15.5 months, after: 6.3 months, before and after: not reached, P = 0.060), nor a distinct antibiotic class applied as monotherapy (P = 0.954) was associated with mOS. While the detrimental effect of antibiotic exposure on clinical outcome with ICB was corroborated in our aNSCLC cohort in Salzburg (N = 43, AB--group: mOS 13.6 versus AB+-group: 7.5 months, HR = 2.04, P = 0.046, Figure 1B) [3.Huemer F. Rinnerthaler G. Westphal T. et al.Impact of antibiotic treatment on immune-checkpoint blockade efficacy in advanced non-squamous non-small cell lung cancer.Oncotarget. 2018; 9: 16512-16520Crossref PubMed Scopus (63) Google Scholar], an opposite effect was found at the tertiary cancer center in Linz (N = 53; AB--group: mOS 10.8 months versus AB+-group: not reached, HR = 0.33, P = 0.008, Figure 1C). The imbalance of ECOG performance status (PS) at the time point of ICB initiation between the centers in Salzburg and Linz (ECOG PS ≥2: 30% versus 0%, P < 0.001, supplementary Table S1, available at Annals of Oncology online) might have laid the basis for a confounding bias. It is noteworthy that ECOG PS in our bicentric AB+-group was worse in comparison to the Derosa study (ECOG PS ≥2: 13% versus 1%). However, the antibiotic treatment status and ECOG PS remained independently associated with mOS in multivariate analysis in the latter study [2.Derosa L. Hellmann M.D. Spaziano M. et al.Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer.Ann Oncol. 2018; 29: 1437-1444Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar]. Compared with Derosa et al. (20% within 30 days, 28% within 60 days) and Metges et al. (47% within 60 days), 40% of patients had been exposed to antibiotics in our cohort predominantly as empiric antibiotic therapy and for upper respiratory tract infections. Despite the high clinical interest in this topic, only a few retrospective studies have reported an inferior outcome with antibiotics use during ICB and the question arises whether a publication bias exists. In consideration of the limited and conflicting data and due to putative heterogeneity between tertiary cancer centers as depicted in our bi-centric approach, prospective stratification according to the antibiotic treatment status is necessitated in future clinical trials to clarify the impact of antibiotic administration on clinical outcome with ICB. None declared.