• 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • br Fig Kaplan Meier curves for PFS and OS


    Fig. 1. Kaplan-Meier curves for PFS and OS according to antibiotic use in the EIOP.
    PFS = Progression Free Survival.
    Atb = Antibiotics.
    EIOP = Early Immunotherapy Period.
    OS = Overall Survival.
    Fig. 2. Kaplan-Meier curves for PFS and OS according to AIER during the WIOP.
    PFS = Progression Free Survival.
    AIER = Antibiotic/Immunotherapy Exposure Ratio.
    OS = Overall Survival.
    Table 4
    Multivariate analyses.
    PFS1, months OS2, months
    1 Progression Free Survival.
    2 Overall Survival.
    3 Hazard Ratio.
    4 Confidence Interval.
    5 Immunotherapy.
    6 Antibiotic.
    7 Performance Status.
    NSCLC, and the consequent need of further research.
    This study has some limitations. First, it is a retrospective analysis of a single Institution population, with a small number of patients. This might limit the possibility of generalizing its results. Second, as this is a retrospective work on an unselected population, we did not perform either biologic analyses on stool samples, or translational correlations on animal models. This prevents from identifying a biologic rationale and confirmation for our observations. Indeed, in absence of a trans-lational correlative, the possibility that patients receiving repeated courses of (-)-Bicuculline methiodide have a worse prognosis because of frequent in-fections and not for the use of antibiotics itself, cannot be excluded. In the end, AIER is a merely empiric variable, based on a theoretical ra-tionale, which will require additional studies to prove its scientific basis. Moreover, the cutoff chosen for stratification derives from the analysis of the population itself, being defined as the median value of the observed cases. This cutoff may be different when analyzing other case series, and the results may change consequently.
    Despite these limitations, the present work presents some inter-esting points. For the first time it proposes the AIER as a new variable that may condition the impact of antibiotic use on the efficacy of IO. Although the selection of a specific cut-off may be questionable, we conducted our analysis in the attempt of testing the potential applica-tions of this new variable. Indeed, a definite cut-off is essential for any tool aiming to be useful in clinical practice, whereas continuous 
    variables are barely applicable. The AIER has been tested on an un-selected, intentionally heterogeneous population, which reflects the characteristics of patients in clinical practice. The variability in treat-ments, disease extension and patient PS, and the prolonged time span of data collection, instead of being a bias, may constitute a strong point of the analysis, depicting a realistic population of outpatient cases with NSCLC.
    In conclusion, this work suggests that the recently emerged concept that antibiotics impair IO efficacy may be considered from a different point of view. In particular, the most relevant factor modulating this effect may be the duration of the antibiotic use in relation with the duration of IO, instead of the prescribed antibiotic type or the time between the beginning of the antibiotic use and the beginning of IO. Given the limited number of patients and the retrospective nature of the analysis, this hypothesis deserves confirmation and further investiga-tion in larger case series. Furthermore, a translational and biological correlation with stool analyses and animal models may contribute to give a strong scientific evidence to our observation, which still remains a hypothesis-generating finding. However, if this relevance is con-firmed, the AIER may become a new variable to help predicting the response to IO in NSCLC patients. Finally, it suggests that clinicians should weigh the risk/benefit ratio of prescribing antibiotics carefully, in particular for repeated or long courses, to patients with metastatic NSCLC.
    5. Funding
    This study did not receive any external funding.
    6. Conflict of interest statement
    CP declares travel accommodations and honoraria with MSD International GmbH, BMS, Eli Lilly. DS declares travel accommodations and honoraria with AstraZeneca, MSD International GmbH, BMS. FdB provided consultation, attended advisory boards and/or provided lec-tures for the following organizations, from whom received honoraria or education grants: Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Eli Lilly, F. Hoffmann-La Roche, Ignyta, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer. MCG declares personal financial interests with the following organizations: AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda; she also declares Institutional financial interests with the following organiza-tions: Eli Lilly, MSD, Pfizer (MISP), AstraZeneca, MSD International