Negative Association of Antibiotics on Clinical Activity of Immune Checkpoint Inhibitors in Patients With Advanced Renal Cell and Non-Small-Cell Lung Cancer

L. Derosa; M. D. Hellmann; M. Spaziano; D. Halpenny; M. Fidelle; H. Rizvi; N. Long; A. J. Plodkowski; K. C. Arbour; J. E. Chaft; J. A. Rouche; L. Zitvogel; G. Zalcman; L. Albiges; B. Escudier; B. Routy

Disclosures

Ann Oncol. 2018;29(6):1437-1444. 

In This Article

Abstract and Introduction

Abstract

Background: The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI.

Patients and methods: We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed.

Results: Sixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were β-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4–6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1–10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0–2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6–7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC.

Conclusion: ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.

Introduction

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) axis have changed the therapeutic landscape in both renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC). In RCC, higher objective response rate and longer overall survival (OS) were seen with nivolumab (anti-PD-1 mAb) compared with everolimus[1] and represents a therapeutic option in relapsed RCC. The robust clinical effect of anti-PD-1 mAb was observed regarless of PD-L1 expression and standard prognostic factors.[2] In NSCLC, anti-PD-(L)1 mAb improved response rates and survival in a subset of NSCLC patients[3–5] in both first line or second line but few clinical features reliably predict benefit.

Primary resistance to ICI is common in patients with both RCC and NSCLC, ranging from 35% to 44% and remains unpredictable.[1,3] Much recent effort has focused on biomarkers of response to immunotherapy (e.g. PD-L1,[6] mutation burden,[5] gene expression signatures of inflammation[7,8]) but the identification of more reliable predictors associated with resistance (primary or acquired) is also critical to instruct new strategies to improve precision and broaden responder groups.

Building on recent data,[9,10] we hypothesized that the modulation of gut microbiota by antibiotics (ATB) may be associated with resistance to anti-PD-1 mAb. The intestinal microbiota represents a complex ecosystem essential for maintaining gut homeostasis and prevent systemic inflammation.[11,12] The interactions between the host and micro-organisms have been identified as a complex, inter-connected network where certain microbes tailor local and systemic immune system.[13] ATB are known to affect gut microbiota, including loss of distinct species (poor diversity), favoring expansion of others, consequently shifting the metabolic capacity.[14] ATB-induced dysbiosis has been associated with a variety of chronic inflammatory disorders.[15–17] In oncology, converging findings demonstrate the negative impact of ATB-induced dysbiosis in mice. We built upon this experience to expand the series of patients examined using patients with advanced RCC and NSCLC treated with anti-PD-(L)1 therapy at two different centers to evaluate the impact of ATB on resistance.

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