Elsevier

Lung Cancer

Volume 130, April 2019, Pages 10-17
Lung Cancer

Antibiotics are associated with attenuated efficacy of anti-PD-1/PD-L1 therapies in Chinese patients with advanced non-small cell lung cancer

https://doi.org/10.1016/j.lungcan.2019.01.017Get rights and content

Highlights

  • The efficacy of ICIs varies among NSCLC patients who have received Abx treatment or not.

  • Concomitant Abx treatment is correlated with worse survival benefits from ICIs therapies.

  • Concomitant Abx treatment is not associated with the occurrence and grades of irAEs.

Abstract

Objectives

Gut microbiome plays a dominant role in modulating therapeutic efficacy of immune checkpoint inhibitors (ICIs) targeting the programmed cell death receptor/ligand-1 (PD-1/PD-L1) pathway, suggesting that co-administration of antibiotics (Abx), which might result in dysbacteriosis, can attenuate the clinical outcomes of ICIs. The current study aimed to investigate the predictive role of Abx on ICIs treatment in patients with advanced non-small cell lung cancer (NSCLC). The impact of proton pump inhibitors (PPIs), another medication that can induce dysbacteriosis, was also investigated.

Materials and methods

We retrospectively reviewed the medical records of eligible patients who received anti-PD-1-based therapies in our hospital. Tumor responses, patients’ survival, the incidence of immune-related adverse events (irAEs) and other baseline variables were examined. The application of Abx or PPIs treatment were also collected. Clinical outcomes and clinicopathologic features were compared according to the status of Abx or PPIs co-administration.

Results

A total of 109 patients were included. Of them, 20 (18.3%) patients were categorized in Abx-treated group. No major difference in baseline characteristics was observed between Abx-treated and -untreated groups. Concomitant Abx treatment was significantly associated with shorter progression-free survival (PFS) (p < 0.0001) and overall survival (OS) (p = 0.0021). And primary disease progression tended to increase in Abx-treated group (p = 0.092). Yet, the occurrence and grades of irAEs were comparable between two groups. In multivariable analysis, Abx treatment was markedly associated with worse PFS (HR=0.32, 95%CI 0.18-0.59, p < 0.0001) and OS (HR=0.35, 95%CI 0.16-0.77, p = 0.009). Regarding the use of PPIs, no significant difference was observed in clinical outcomes between the patients with or without concomitant PPIs treatment.

Conclusions

Abx treatment was significantly associated with attenuated clinical outcomes derived from anti-PD-1-based ICIs in a Chinese cohort of patients with advanced NSCLC.

Introduction

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1(PD-1) and programmed cell death-ligand 1 (PD-L1) axis have dramatically shifted the therapeutic paradigm of non-small cell lung cancer (NSCLC) and now are standard treatment options in both first-line and second-line settings for patients with advanced disease [[1], [2], [3], [4], [5], [6]]. Three monoclonal anti-PD-1/PD-L1 monoclonal antibodies (mAbs) (including nivolumab, pembrolizumab and atezolizumab) have currently been approved for the treatment of advanced NSCLC by the US Food and Drug Administration. However, despite the remarkable success of clinical applications, the efficacy of anti-PD-1/PD-L1 mAbs varies greatly across individual patients [7,8]. In unselected advanced NSCLC populations, the objective response rate [5] is only around 20% [9,10]. Moreover, although responses to PD-1/PD-L1 blockade tend to be more durable than response to chemotherapy [[1], [2], [3], [4]], acquired resistance inevitably develops in most patients [11]. Therefore, the identification of reliable predictors to select those patients that who are more likely to benefit from anti-PD-1/PD-L1 mAbs is of paramount importance.

A number of biomarkers have been identified to predict the response to anti-PD-1/PD-L1 mAbs, such as intratumoral PD-L1 expression, mutational burden, lymphocytic infiltrates and neoantigens [6,10,[12], [13], [14], [15]]. Interestingly, several elegant studies have recently demonstrated the crucial impact of human gut microbiome (GM) on anti-PD-1 immunotherapies [[16], [17], [18]]. The diversity and abundance of the GM can modulate the anti-cancer activity of ICIs in terms of both efficacy and toxicity, highlighting the possibility that concomitant antibiotics (Abx) administration, which can shift GM to long-term alternative dysbiotic states [19,20], may promote resistance to ICIs. Because of its prominent influence on microbial composition, Abx treatment can further disturb the development of systematic immune responses by affecting T cell function, altering cytokine production and interfering with dendritic cells (DCs) action etc. [[21], [22], [23]]. As a consequence, the use of Abx is increasingly being recognized as playing a crucial role in ICIs therapeutic outcomes. A series of previous reports have indicated a negative correlation between Abx uptake and efficacy of several anti-cancer therapies, such as cyclophosphamide, CpG-oligonucleotide immunotherapy, platinum chemotherapy, anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) therapy and anti-PD-1 mAbs [17,[24], [25], [26], [27], [28], [29]]. However, the data on the predictive role of Abx usage in the clinical outcomes of ICIs are scarce, and this issue has not yet been extensively explicated, especially in lung cancer. Furthermore, the human gut microbiota variations appear to vary distinctly depending on ethnicity and geography [30]. For instance, previous literatures demonstrated that Bacteroides shows domination in Chinese and French population in their GM, whereas American community has higher abundance in Firmicutes and Japanese community has abundance in Actinobacteria [[30], [31], [32]]. This phenomenon indicates that the influence of Abx on GM may differ according to ethnicity and geography specific diversity, and further hints at the potential heterogeneous responses to ICIs induced by concomitant Abx treatment in different patient populations. Therefore, more data from diverse patient cohorts are needed to comprehensively reveal the correlation between Abx treatment and ICIs efficacy.

In the present study, we compared the clinical features and responses in a Chinese cohort of NSCLC patients who received ICIs with or without concomitant Abx treatment, and analyzed the prognostic impact of Abx on anti-PD-1-based immunotherapeutic efficacy.

Section snippets

Patients

We conducted a retrospective review of all the patients diagnosed with advanced NSCLC who started anti-PD-1/PD-L1based therapies between January 2016 and January 2018 in Shanghai Pulmonary Hospital, Tongji University. Patients who were evaluable for response assessment were selected for the present study. All of them had received anti-PD-1 mAbs as monotherapy alone or in combination with chemotherapy or anti-angiogenesis, regardless of treatment lines. Electronic medical records were used to

Patient characteristics

A total of 142 consecutive patients with advanced NSCLC received various ICIs approaches at our institution. Among them, 109 patients were evaluable for objective response and finally included in the current study. All the eligible patients did not harbor epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) rearrangements. Of the included patients, 57 received anti-PD-1 mAbs (including pembrolizumab, nivolumab or SHR-1210) as monotherapy. Of the

Discussion

Clinically, patients with lung cancer are usually prone to necessitate Abx treatment, which might be attributed to the immunosuppressive nature of malignancies and anti-cancer therapy induced lymphodepletion. As the therapeutic paradigm for lung cancer has radically evolved with the incorporation of ICIs, the influence of Abx use on ICIs is undeniably an emerging area requiring major focus. Accumulating evidence suggests that loss of diversity and shift in composition of GM can attenuate the

Conflict of interest

The authors declare no potential conflicts of interest.

Funding

This study was supported by grants from the National Natural Science Foundation of China (No. 81772467), the National Key Research and Development Projects of China (No. 2016YFC0902300), the Shanghai Hygiene and Health Committee’s Key Discipline Project of Respiratory Diseases. (No. 2017ZZ02012).

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    These authors contributed equally to this work.

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