Impact of prior antibiotic use on the efficacy of nivolumab for non‑small cell lung cancer

Hakozaki, Taiki; Okuma, Yusuke; Omori, Miwako; Hosomi, Yukio

doi:10.3892/ol.2019.9899

Cited by 83 publications

(102 citation statements)

References 44 publications

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“…In contrast, two retrospective reviews reported negative findings, with antibiotic use not influencing responses to nivolumab in patients with lung cancer .…”

Section: Discussionmentioning

confidence: 94%

Cumulative Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer

et al. 2019

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Background With the advent of immunotherapy, substantial progress has been made in improving outcomes for patients with advanced cancer. However, not all patients benefit equally from treatment, and confounding immune‐related issues may have an impact. Several studies suggest that antibiotic use (which alters the gut microbiome) may result in poorer outcomes for patients treated with immune checkpoint inhibitors (ICI). Materials and Methods This is a large, single‐site retrospective review of n = 291 patients with advanced cancer treated with ICI (n = 179 melanoma, n = 64 non‐small cell lung cancer, and n = 48 renal cell carcinoma). Antibiotic use (both single and multiple courses/prolonged use) during the periods 2 weeks before and 6 weeks after ICI treatment was investigated. Results Within this cohort, 92 patients (32%) received antibiotics. Patients who did not require antibiotics had the longest median progression‐free survival (PFS), of 6.3 months, and longest median overall survival (OS), of 21.7 months. With other clinically relevant factors controlled, patients who received a single course of antibiotics had a shorter median OS (median OS, 17.7 months; p = .294), and patients who received multiple courses or prolonged antibiotic treatment had the worst outcomes overall (median OS, 6.3 months; p = .009). Progression‐free survival times were similarly affected. Conclusion This large, multivariate analysis demonstrated that antibiotic use is an independent negative predictor of PFS and OS in patients with advanced cancer treated with ICIs. This study highlighted worse treatment outcomes from patients with cumulative (multiple or prolonged courses) antibiotic use, which warrants further investigation and may subsequently inform clinical practice guidelines advocating careful use of antibiotics. Implications for Practice Antibiotic use is negatively associated with treatment outcomes of immune checkpoint inhibitors (ICI) in advanced cancer. Cumulative antibiotic use is associated with a marked negative survival outcome. Judicious antibiotic prescribing is warranted in patients receiving treatment with ICI for treatment of advanced malignancy.

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“…In contrast, two retrospective reviews reported negative findings, with antibiotic use not influencing responses to nivolumab in patients with lung cancer .…”

Section: Discussionmentioning

confidence: 94%

Cumulative Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer

et al. 2019

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“…Among the publications retrieved using electronic search, 15 studies were eligible for quantitative analysis, for a total of 2,363 patients [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Survival of Patients Treated with Antibiotics and Immunotherapy for Cancer: A Systematic Review and Meta-Analysis

Petrelli

Iaculli²,

Signorelli

et al. 2020

Preprint

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Antibiotics (ABs) are common medications used for treating infections. In cancer patients treated with immune checkpoint inhibitors (ICIs), concomitant exposure to ABs may impair the efficacy of ICIs and lead to a poorer outcome compared to AB non-users. We report here the results of a meta-analysis evaluating the effects of ABs on the outcome of patients with solid tumors treated with ICIs. PubMed, the Cochrane Library, and Embase were searched from inception until September 2019 for observational or prospective studies reporting prognosis of adult patients with cancer treated with ICIs and with or without ABs. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI), and an HR > 1 associated with a worse outcome in ABs users compared to no-ABs users. Fifteen publications were retrieved for a total of 2363 patients. In the main analysis (n = 15 studies reporting data), OS was reduced in patients exposed to ABs before or during treatment with ICIs (HR = 2.07, 95%CI 1.51–2.84; P<.01). Similarly, PFS was inferior in ABs users in n = 13 studies with data available (HR = 1.53, 95%CI 1.22–1.93; p<.01). In cancer patients treated with ICIs, AB use significantly reduces OS and PFS. Short duration/course of ABs may be considered in clinical situations in which they are strictly needed.

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“…Among them, two studies [23,24] were prospective (labeled with *). Across all studies, it clearly demonstrated that only antibiotic exposure within 2 months prior to the initiation of ICIs universally exhibited negative impact on treatment response of ICIs (Figure 4b and c), except one study [10] (Supplemental Figure 3).…”

Section: The Potential Impact Of Antibiotics On the Therapeutic Effecmentioning

confidence: 95%

“…However, several key questions remain to be addressed: 1) whether there is shared feature of gut microbiome that links to ICI response and AEs across various solid tumors; 2) whether antibiotics can affect cancer immunotherapy. This is important considering there are controversial results [6,9] , [10,11], and antibiotic is such an inevitable gut microbiome modi er in the clinical setting; 3) whether diet, as one of the most important lifestyle factors, will have impact on cancer immunotherapy. We aim to investigate existing evidence that could help address these questions at the human level using a systematic review.…”

Section: Introductionmentioning

confidence: 99%

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Relating Gut Microbiome and Its Modulating Factors to Immunotherapy in Solid Tumors: A Systematic Review

Huang

Liu

et al. 2020

Preprint

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Background: Gut microbiome is proved to affect the activity of immunotherapy in certain tumors. However, little is known if there is universal impact on both the treatment response and adverse effects (AEs) of immune checkpoint inhibitors (ICIs) across multiple solid tumors, and whether such impact can be modulated by common gut microbiome modifiers, such as antibiotics and diet.Methods: A systematic search in PubMed followed by stringent manual review were performed to identify clinical cohort studies that evaluated the relevance of gut microbiome to ICIs (response and/or AEs, 12 studies), or association of antibiotics with ICIs (17 studies), or impact of diet on gut microbiome (16 studies). Only original studies published in English before April 1st, 2020 were used. Qualified studies identified in the reference were also included.Results: At the phylum level, patients who had enriched abundance in Firmicutes and Verrucomicrobia almost universally had better response from ICIs, whereas those who were enriched in Proteobacteria universally presented with unfavorable outcome. Mixed correlations were observed for Bacteroidetes in relating to treatment response. Regarding the AEs, Firmicutes correlated to higher incidence whereas Bacteroidetes were clearly associated with less occurrence. Interestingly, across various solid tumors, majority of the studies suggested a negative association of antibiotic use with clinical response from ICIs, especially within 1-2 month prior to the initiation of ICIs. Finally, we observed a significant correlation of plant-based diet in relating to the enrichment of “ICI-favoring” gut microbiome (P = 0.0476).Conclusions: Gut microbiome may serve as a novel modifiable biomarker for both the treatment response and AEs of ICIs across various solid tumors. Further study is needed to understand the underlying mechanism, minimize the negative impact of antibiotics on ICIs, and gain insight regarding the role of diet so that this important lifestyle factor can be harnessed to improve the therapeutic outcomes of cancer immunotherapy partly through its impact on gut microbiome.

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Impact of prior antibiotic use on the efficacy of nivolumab for non‑small cell lung cancer

Cited by 83 publications

References 44 publications

Cumulative Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer

Cumulative Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer

Survival of Patients Treated with Antibiotics and Immunotherapy for Cancer: A Systematic Review and Meta-Analysis

Relating Gut Microbiome and Its Modulating Factors to Immunotherapy in Solid Tumors: A Systematic Review

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