Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
J Immunother Cancer. 2024 Jan 31;12(1):e008269. doi: 10.1136/jitc-2023-008269.
The role of antibiotics in malignancies treated with immune checkpoint inhibitors (ICI) remains unclear. Several studies suggested a detrimental impact of antibiotic use on the response to ICI, but were susceptible to confounding by indication. Our objective was therefore to assess whether the relationship between antibiotic use and ICI response is causative or merely associative.
A large, single-center observational cohort study was performed with individuals treated for either non-small cell lung carcinoma (NSCLC) or metastatic melanoma. An effect modification approach was used, aiming to estimate the association between antibiotic use and overall survival (OS) and compare these estimates between individuals receiving first-line ICI treatment versus those receiving first-line tyrosine kinase inhibitors (TKIs). Exposure of interest was antibiotic use within 30 days before the start of anticancer treatment. HRs for OS were estimated for antibiotics versus no antibiotics in each cohort using multivariable propensity adjusted analysis. The "true antibiotic effect" within the ICI versus TKI cohort was modeled using an interaction term.
A total of 4534 patients were included, of which 1908 in the ICI cohort and 817 in the TKI cohort. Approximately 10% of patients in each cohort used antibiotics within 30 days before the start of anticancer treatment. Our results demonstrate a lack of synergistic interaction between current antibiotic use and ICI therapy in relation to OS: although antibiotic use was significantly associated with OS decline in the ICI cohort (HR=1.26 (95% CI 1.04 to 1.51)), a similar magnitude in OS decline was found within the TKI cohort (HR=1.24 (95% CI 0.95 to 1.62)). This was reflected by the synergy index (HR=0.96 (95% CI 0.70 to 1.31)), which implied no synergistic interaction between current antibiotic use and ICI.
This study strongly suggests that there is no causal detrimental association between antibiotic use and ICI therapy outcome when looking at OS in individuals with malignant melanoma or NSCLC. The frequently observed inverse association between antibiotics and ICI response in previous studies is most likely driven by confounding by indication, which was confirmed by the findings in our reference TKI cohort.
抗生素在接受免疫检查点抑制剂 (ICI) 治疗的恶性肿瘤中的作用仍不清楚。一些研究表明抗生素的使用会对 ICI 的反应产生不利影响，但容易受到指示性混杂的影响。因此，我们的目的是评估抗生素的使用与 ICI 反应之间的关系是因果关系还是仅仅是关联关系。
进行了一项大型的单中心观察性队列研究，其中包括接受非小细胞肺癌 (NSCLC) 或转移性黑色素瘤治疗的患者。使用效应修饰方法，旨在估计抗生素使用与总生存期 (OS) 之间的关联，并比较接受一线 ICI 治疗的个体与接受一线酪氨酸激酶抑制剂 (TKI) 治疗的个体之间的这些估计值。感兴趣的暴露是在开始抗癌治疗前 30 天内使用抗生素。使用多变量倾向调整分析，在每个队列中比较抗生素与无抗生素的情况下，OS 的 HR。在 ICI 与 TKI 队列中，使用交互项对“真正的抗生素效应”进行建模。
共纳入 4534 例患者，其中 ICI 队列 1908 例，TKI 队列 817 例。每个队列中约有 10%的患者在开始抗癌治疗前 30 天内使用抗生素。我们的结果表明，当前抗生素的使用与 ICI 治疗之间没有协同作用与 OS 相关：尽管抗生素的使用与 ICI 队列中的 OS 下降显着相关（HR=1.26（95%CI 1.04 至 1.51）），但在 TKI 队列中也发现了类似程度的 OS 下降（HR=1.24（95%CI 0.95 至 1.62））。这反映在协同指数（HR=0.96（95%CI 0.70 至 1.31））中，这意味着当前抗生素的使用与 ICI 之间没有协同作用。
当观察恶性黑色素瘤或 NSCLC 患者的 OS 时，这项研究强烈表明，抗生素的使用与 ICI 治疗结果之间没有因果关系。先前研究中观察到的抗生素与 ICI 反应之间的反向关联很可能是由指示性混杂引起的，这在我们的参考 TKI 队列中的发现得到了证实。
