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BackgroundIn recent years, the gut microbiome has increasingly emerged as influencing the response to immune checkpoint inhibitors (ICIs).1–3 Antibiotic (ABX) exposure, that leads to microbiome dysbiosis, was further shown in numerous studies to adversely influence the clinical outcomes of cancer patients treated with ICIs, especially in non-small-cell lung cancer (NSCLC).4–6We published in 2020 a meta-analysis confirming that ABX use could hamper survival of NSCLC patients treated with ICIs.7 The present study aims at updating this prior work by incorporating studies published until July 2021 and by studying new clinical outcomes.MethodsPubMed and major oncology conferences’ proceedings were systematically searched to identify studies assessing the impact of ABX on the clinical outcomes of NSCLC patients treated with ICIs. Studies were included when reporting a hazard ratio (HR) or Kaplan–Meier curves for Overall Survival (OS) or Progression-Free Survival (PFS) based on antibiotic exposure, and/or data on treatment response such as Overall Response Rate (ORR) and Progressive Disease Rate (PD) according to antibiotic exposure. Pooled HRs for OS and PFS and Odds Ratios (OR) for ORR and PD were calculated, as well as HRs for OS and PFS according to different time windows of ABX exposure.ResultsOverall, 35 independent cohorts were included for a total of 12,235 patients. The pooled HRs for OS (12,235 patients) and PFS (5,356 patients) were 1.63 [95% Confidence Interval (CI) 1.37–1.94] and 1.49 [95% CI 1.26–1.76], respectively, confirming a significantly reduced survival in patients exposed to ABX. The subgroup analyses of OS and PFS based on the time window of ABX exposure (figures 1 and 2) suggest a harmful effect of ABX when taken around ICI initiation. The pooled OR for ORR (1,992 patients) and PD (1,272 patients) were 0.66 [95% CI 0.44–0.99] and 1.98 [95% CI 1.39–2.8], respectively, reflecting both a decreased odd of treatment response and an almost two-fold increased odd of cancer progression among ABX users (figures 3 and 4). These findings confirm the previously reported deleterious effect of ABX on all clinical outcomes (table 1).Abstract 278 Figure 1Forest plot of hazard ratios for overall survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 278 Figure 2Forest plot of hazard ratios for progression-free survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 278 Figure 3Forest plot of odds ratios for overall response rate of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibioticsAbstract 278 Figure 4Forest plot of odds ratios for progressive disease rate of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibioticsAbstract 278 Table 1Summary of the impact of antibiotic use on all clinical outcomesConclusionsAntibiotics were shown to impair clinical outcomes of NSCLC patients treated with ICIs in this study. Two (non mutually exclusive) mechanisms are increasingly discussed in the literature to explain the role of microbiome on immunotherapy response: the immunomodulatory effects of bacterial molecules,8 and antigenic mimicry between commensal bacteria and tumor antigens cross reactive for the same antigen specific T cells.9 10 ReferencesGopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 5 January 2018;359(6371):97–103.Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 5 January 2018;359(6371):91–7. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 5 January 2018;359(6371):104–8. Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, 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 Off J Eur Soc Med Oncol 1 June 2018;29(6):1437–44.Pinato DJ, Howlett S, Ottaviani D, Urus H, Patel A, Mineo T, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol 1 Décember 2019;5(12):1774–8.Rounis K, Makrakis D, Papadaki C, Monastirioti A, Vamvakas L, Kalbakis K, et al. Prediction of outcome in patients with non-small cell lung cancer treated with second line PD-1/PDL-1 inhibitors based on clinical parameters: results from a prospective, single institution study. PloS One 2021;16(6):e0252537.Lurienne L, Cervesi J, Duhalde L, de Gunzburg J, Andremont A, Zalcman G, et al. NSCLC immunotherapy efficacy and antibiotic use: a systematic review and meta-analysis. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer July 2020;15(7):1147–59.Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science 26 March 2021;371(6536):eabc4552.Fluckiger A, Daillère R, Sassi M, Sixt BS, Liu P, Loos F, et al. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage. Science 21 août 2020;369(6506):936–42.Bessell CA, Isser A, Havel JJ, Lee S, Bell DR, Hickey JW, et al. Commensal bacteria stimulate antitumor responses via T cell cross-reactivity. JCI Insight 23 avr 2020;5(8):135597.

Journal for immunotherapy of cancer, 2021-11, Vol.9 (Suppl 2), p.A301-A302

278 Systematic review and meta-analysis evaluating the impact of antibiotic use on clinical outcomes of non-small-cell lung cancer patients treated with immune checkpoint inhibitors

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.

Biomedicines, 2023-02, Vol.11 (2), p.528

Prognostic Associations of Concomitant Antibiotic Use in Patients with Advanced NSCLC Treated with Atezolizumab: Sensitivity Analysis of a Pooled Investigation of Five Randomised Control Trials

BackgroundImmune 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. Our team published a systematic review and meta-analysis showing that ABX use could indeed decrease the survival of patients diagnosed with non-small-cell lung cancer (NSCLC) and treated with ICIs.1 The present abstract aims at updating this meta-analysis by incorporating new studies that have been published in the period ranging from September 2019 to August 2020.MethodsMedline (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 NSCLC patients treated with ICIs. Studies were found eligible for inclusion when they mentioned a hazard ratio (HR) or Kaplan–Meier curves for overall survival (OS) or progression-free survival (PFS) based on antibiotic exposure. Pooled HRs for OS and PFS and HRs for OS and PFS according to different time windows for ABX exposure were calculated.Results6 eligible new studies were identified between September 2019 and August 2020 while 3 other studies were updated with new information. Altogether, 27 studies reported data for OS (6,436 patients, 826 of whom coming from new studies) and 24 for PFS (3,751 patients, 786 of whom coming from new studies). The pooled HR was 1.75 (95% confidence interval [CI]: 1.38–2.23) for OS and 1.57 (95% CI: 1.28–1.92) for PFS, confirming a significantly reduced survival in patients with NSCLC exposed to ABX. The detailed analysis in subgroups based on the time window of exposure (figure 1, figure 2) suggests that the deleterious effect of ABX is stronger when the exposition happens shortly before and after the initiation of the ICI treatment.Abstract 671 Figure 1Forest plot of hazard ratios for overall survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 671 Figure 2Forest plot of hazard ratios for progression-free survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureConclusionsThe update of the meta-analysis 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.ReferencesLurienne L, Cervesi J, Duhalde L, de Gunzburg J, Andremont A, Zalcman G, et al. NSCLC immunotherapy efficacy and antibiotic use: a systematic review and meta-analysis. J Thorac Oncol 2020;15:1147–1159.

Journal for immunotherapy of cancer, 2020-11, Vol.8 (Suppl 3), p.A708-A708

671 Update of a systematic review and meta-analysis studying the association between antibiotic use and clinical outcomes of non-small-cell lung cancer patients treated with immune checkpoint inhibitors

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278 Systematic review and meta-analysis evaluating the impact of antibiotic use on clinical outcomes of non-small-cell lung cancer patients treated with immune checkpoint inhibitors

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Prognostic Associations of Concomitant Antibiotic Use in Patients with Advanced NSCLC Treated with Atezolizumab: Sensitivity Analysis of a Pooled Investigation of Five Randomised Control Trials

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671 Update of a systematic review and meta-analysis studying the association between antibiotic use and clinical outcomes of non-small-cell lung cancer patients treated with immune checkpoint inhibito...

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