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Observational Study
. 2021 May:149:73-81.
doi: 10.1016/j.ejca.2021.02.040. Epub 2021 Apr 7.

The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression

Nobuaki Ochi  1 , Eiki Ichihara  2 , Nagio Takigawa  1 , Daijiro Harada  3 , Koji Inoue  4 , Takuo Shibayama  5 , Shinobu Hosokawa  6 , Daizo Kishino  7 , Shingo Harita  8 , Naohiro Oda  9 , Naofumi Hara  10 , Katsuyuki Hotta  11 , Yoshinobu Maeda  10 , Katsuyuki Kiura  12
Affiliations
Observational Study

The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression

Nobuaki Ochi et al. Eur J Cancer. 2021 May.

Abstract

Background: Immune checkpoint inhibitors (ICIs) are essential for treatment of various malignancies, including non-small-cell lung cancer (NSCLC). Recently, several studies have shown that the gut microbiome plays an important role in ICI treatment of solid cancers, and antibiotic (ATB) use had a negative impact on the outcomes of ICI treatment via dysbiosis in the gut. However, whether this is applicable to NSCLC remains unclear. The impact of ATBs based on PD-L1 expression also remains unclear.

Methods: We retrospectively reviewed the medical records of patients with NSCLC who received ICI monotherapy (anti-PD-1 or anti-PD-L1 antibody) at nine institutions from December 2015 to May 2018. Outcomes with use of ATBs during the 2 months before or a month after initiation of ICI treatment, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analysis was also conducted using a Cox proportional hazards model.

Results: A total of 531 patients were included in this study, among whom 98 (18.5%) received ATBs before or after ICI treatment. ATB use was significantly associated with a shorter median OS (11.7 months in the ATB group vs. 16.1 months in the non-ATB group; p = 0.028), whereas the difference in PFS was not significant (3.5 months in both the groups; p = 0.287). We next investigated the association based on PD-L1 expression in the 265 patients for whom PD-L1 expression was determined. There was no significant difference in the median OS or PFS between patients with NSCLC and PD-L1 expression <50% receiving ATBs and those not receiving ATBs (PFS: 3.3 vs. 2.8 months, p = 0.88; OS: 9.5 vs. 17.1 months, p = 0.24). Conversely, patients with NSCLC and PD-L1 expression ≥50% receiving ATBs showed significantly shorter median PFS and OS (PFS: 4.2 vs. 9.4 months, p = 0.012; OS: 11.9 vs. 28.4 months, p = 0.011). The impact of ATBs in patients with NSCLC and PD-L1 expression ≥50% was more significant than that in the entire cohort.

Conclusions: Our results indicate that the impact of ATB use on the efficacy of ICIs differed based on PD-L1 expression in patients with advanced NSCLC. A negative impact of ATB use was found in patients with NSCLC and PD-L1 expression ≥50% but not in those with PD-L1 expression <50%.

Keywords: Antibiotics; Anti–PD-1 antibody; Anti–PD-L1 antibody; Immune checkpoint inhibitor; PD-L1 expression.

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Conflict of interest statement

Conflict of interest statement E.I. received honoraria from Boehringer Ingelheim and additional research funding from MSD. N.T. received honoraria and research funds from Eli Lilly Japan, AstraZeneca, Daiichi-Sankyo, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer, Boehringer Ingelheim and Ono Pharmaceutical. T.N. received honoraria from MSD, Bristol Myers Squibb and Eisai. N.T. received research funds from Kyowa Hakko Kirin, Nippon Kayaku, Takeda Pharmaceutical and Astellas Pharma. D.H. received research funds from Eli Lilly, MSD, Chugai, Pfizer, BMS, AstraZeneca, Novartis, Kissei and Takeda and honoraria from MSD, Ono Pharmaceutical, BMS, Kyowa Hakko Kirin, AstraZeneca, Boehringer Ingelheim and Lilly. S.H. received honoraria from Bristol Myers Squibb and MSD. T.S. received research funding from Ono Pharmaceutical and Shionogi Pharmaceutical. K.H. received honoraria from Taiho Pharmaceutical and Chugai Pharmaceutical. K.H. received additional research funding from MSD and Chugai Pharmaceutical. Y.M. received honoraria from Chugai Pharmaceutical and Bristol Myers Squibb. Y.M. received honoraria from Chugai Pharmaceutical and Bristol Myers Squibb. K.K. received honoraria from Chugai Pharmaceutical. All other authors declare no conflicts of interest with regard to this study.

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