Background:Immune checkpoint inhibitors (ICIs) have considerably improved patient outcomes in various cancer types, but their efficacy remains poorly predictable among patients. The intestinal microbiome, whose balance and composition can be significantly altered by antibiotic use, has recently emerged as a factor that may modulate ICI efficacy. The objective of this systematic review and meta-analysis is to investigate the impact of antibiotics on the clinical outcomes of cancer patients treated with ICIs.Methods:PubMed and major oncology conference proceedings were systematically searched to identify all studies reporting associations between antibiotic use and at least one of the following endpoints: Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR) and Progressive Disease (PD) Rate. Pooled Hazard Ratios (HRs) for OS and PFS, and pooled Odds Ratios (ORs) for ORR and PD were calculated. Subgroup analyses on survival outcomes were also performed to investigate the potential differential effect of antibiotics according to cancer types and antibiotic exposure time windows.Results:107 articles reporting data for 123 independent cohorts were included, representing a total of 41,663 patients among whom 11,785 (28%) received antibiotics around ICI initiation. The pooled HRs for OS and PFS were respectively of 1.61 [95% Confidence Interval (CI) 1.48-1.76] and 1.45 [95% CI 1.32-1.60], confirming that antibiotic use was significantly associated with shorter survival. This negative association was observed consistently across all cancer types for OS and depending on the cancer type for PFS. The loss of survival was particularly strong when antibiotics were received shortly before or after ICI initiation. The pooled ORs for ORR and PD were respectively of 0.59 [95% CI 0.47-0.76] and 1.86 [95% CI 1.41-2.46], suggesting that antibiotic use was significantly associated with worse treatment-related outcomes.Conclusion:As it is not ethically feasible to conduct interventional, randomized, controlled trials in which antibiotics would be administered to cancer patients treated with ICIs to demonstrate their deleterious impact versus control, prospective observational studies and interventional trials involving microbiome modifiers are crucially needed to uncover the role of microbiome and improve patient outcomes. Such studies will reduce the existing publication bias by allowing analyses on more homogeneous populations, especially in terms of treatments received, which is not possible at this stage given the current state of the field. In the meantime, antibiotic prescription should be cautiously considered in cancer patients receiving ICIs.Systematic review registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42019145675.

Background: Immune checkpoint inhibitors (ICIs) have been a significant milestone for the treatment of advanced non-small cell lung cancer (NSCLC). However, the efficacy of ICIs can vary substantially between patients, with disparities in treatment outcomes being potentially driving by changes in the microbiome. Antibiotics can cause dysbiosis and are hypothesised to impact the efficacy of ICIs Methods: Data were pooled from five randomised clinical control trials, IMpower130, IMpower131, IMpower150, OAK, and POPLAR, assessing atezolizumab in advanced NSCLC. Cox proportional hazard models were used to determine whether antibiotic use within 6-weeks before and after randomisation was associated with progression-free survival (PFS) and overall survival (OS) outcomes, with data further stratified by programmed death ligand-1 (PD-L1) status. Results: Antibiotic use was significantly associated with worsened PFS (hazard ratio (HR) = 1.19 [1.08–1.30], p ≤ 0.001) and OS (HR = 1.27 [1.13–1.42], p ≤ 0.001) in patients treated with atezolizumab and those not treated with atezolizumab (PFS, HR = 1.21 [1.08–1.36] p < 0.001, OS, HR = 1.33 [1.16–1.51] p < 0.001). These associations were relatively consistent in both PD-L1 positive and PD-L1 negative. Conclusions: Antibiotic use within a ±6-week window was significantly associated with worse PFS and OS.

Homeostasis of the intestinal microbiota is currently recognized as a major contributor to human health. Furthermore, intestinal dysbiosis is associated with a multitude of consequences, including intestinal colonization by antibiotic-resistant or pathogenic bacteria, such as Clostridioides difficile, and reduced efficacy of promising anticancer immunotherapies. By far, the most immediate and drastic exposure leading to dysbiosis is antibiotic treatment. Many attempts have been made to prevent or repair antibiotic-associated dysbiosis. Here, we review these innovations and the difficulties associated with their development.

Immune checkpoint inhibitors (ICI) have improved patient outcomes in a variety of cancers but with variable efficacy. In the past 24 months, several observational studies, mostly retrospective, suggested that antibiotic (ABX) use may be associated with a lowered efficacy of ICI and survival of patients. ABX-induced disruption of the gut microbiota and the complex interplay between the immune system and the microbiota have been advanced as the likely mechanisms underlying the observed effect. We aim at reviewing the meta-analyses that summarized the findings reported in literature. We systematically searched Medline, the Cochrane Library, and oncology conferences proceedings to identify the systematic reviews and meta-analyses as well as all the recent studies that were not included in them. We identified 4 meta-analyses published since 2019 studying the overall survival (OS) and progression-free survival (PFS) of cancer patients treated with ICI (mainly anti-PD(L)1 antibodies as monotherapy or combined with anticancer drugs) and ABX. In all, ABX use is reported to have a negative impact on the survival of patients treated with ICI regardless of cancer type. The pooled hazard ratio (HR) ranged from 1.47 to 1.84 for PFS and 1.69 to 2.37 for OS, revealing a significantly reduced survival in patients with cancer exposed to ABX. In all meta-analyses, the use of ABX around the ICI treatment start appeared to be most detrimental to the outcomes.Table: 1043P1st AuthorHuangWilsonLurienneXuCancerNon-small-cell lung cancer (NSCLC), Melanoma, Renal cell carcinoma (RCC), Urothelial Carcinoma (UC), MixedNSCLC, Melanoma, RCC, UC, MixedNSCLCNSCLC, Melanoma, RCC, MixedHR OS [95% CI]2.37 [2.05; 2.75]1.92 [1.37; 2.68]1.69 [1.25; 2.29]1.90 [1.55; 2.34]HR PFS [95% CI]1.84 [1.49; 2.26]1.65 [1.30; 2.10]1.47 [1.13; 1.90]1.53 [1.30; 1.79] Open table in a new tab The independently-developed meta-analyses vary in the scope of studies included and their methodology but they commonly conclude on a significant deleterious effect of ABX use on the survival of patients treated with ICI. The topic deserves further research to understand the mechanisms at stake and improve care of patients.

Immune checkpoint inhibitors (ICIs) have dramatically improved patient outcomes in a variety of tumor types, but with variable ef ficacy. Recent research has suggested that antibiotic-induced disruption of the microbiota may impact ICI ef ficacy. We performed a systematic review and meta-analysis of studies that assessed the impact of antibiotic use on the survival of patients diagnosed with NSCLC and treated with ICI. We systematically searched Medline, the Cochrane Library, and major oncology conferences pro-ceedings. Eligible studies mentioned hazard ratio or Kaplan-Meier curves for progression-free survival (PFS) or overall survival (OS) based on antibiotic exposure before or during ICI treatment. We identi fied 23 eligible studies. The impact of antibiotics was then evaluated in 2208 patients for PFS and 5560 for OS. For both PFS and OS meta-analyses, the between-study heterogeneity was high (Hig-gins and Thompson I 2 of 69% and 80%, respectively). The pooled hazard ratio was 1.47 (95% con fidence interval [CI]: 1.13-1.90) for PFS and 1.69 (95% CI: 1.25-2.29) for OS revealing a signi ficantly reduced survival in patients with NSCLC exposed to antibiotics. The median OS was reduced on average by 6.7 months (95% CI: 5.1-8.4) in the patients exposed to antibiotics. The effect seems to depend on the time window of exposure with stronger effects reported when the patients took antibiotics [-60 days; +60 days] around ICI initiation. In patients with NSCLC, the findings of the meta-analysis indicate that antibiotic use before or during treatment with ICI leads to a median OS decreased by more than 6 months. Speci fically, exposure shortly before or after ICI initiation seems to be particularly detrimental, whereas antibiotic use later during disease course does not seem to alter survival. Because PFS and OS were dif ficult to compare between studies owing to het-erogeneity and the multiple confounding factors identi fied, further studies are needed to strengthen the understanding of this phenomenon. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Immune checkpoint inhibitors (ICIs) have been shown to improve patients' clinical outcomes in a variety of cancers, but with variable efficacy. Prior research has also suggested that systemic antibiotic (ABX) exposure may impact the intestinal microbiota and result in suboptimal ICI treatment outcomes. Six meta-analyses studying the progression-free survival (PFS) and overall survival (OS) of cancer patients treated with ICIs and exposed to ABX were published between 2019 and 2020. The present abstract aims at updating those meta-analyses by incorporating all new studies that have been published up to September 2020. Medline (through PubMed), the Cochrane Library and major oncology conferences proceedings were systematically searched to identify studies assessing the impact of ABX use on the clinical outcomes of cancer patients treated with ICIs. Studies were found eligible for inclusion when they mentioned Hazard Ratios (HRs) or Kaplan–Meier curves for OS or PFS based on antibiotic exposure. Pooled HRs for OS and PFS as well as HRs for OS and PFS according to cancer type and to ABX exposure time window were calculated. Eligible results from 70 independent cohorts were published between 2018 and September 2020 and included in this meta-analysis. Altogether, 63 independent cohorts reported data for OS (22,977 patients) and 45 for PFS (14,547 patients). The pooled HR was 1.65 (95% confidence interval [CI]: 1.46-1.88) for OS and 1.44 (95% CI: 1.27-1.64) for PFS, confirming a significantly reduced survival in patients with cancer exposed to ABX. The detailed analysis in subgroups based on the exposure time window suggests that the deleterious effect of ABX is stronger when the exposition happens shortly before and after the start of the ICI treatment. This update of meta-analyses confirms the previously reported deleterious effect of ABX on ICI treatment outcomes, taking into account the latest publications in the field. The topic deserves further research to uncover if the effect will stand with 1st line use of ICI together with chemotherapies and/or other approved combinations, elucidate the mechanisms at stake and improve care of patients.