Rousseau Adrien, Simon-Tillaux Noémie, Michiels Stefan, Derosa Lisa, Laparra Ariane, Planchard David, Remon Jordi, Barlesi Fabrice, Lavaud Pernelle, Frelaut Maxime, Parisi Claudia, Gazzah Anas, Besse Benjamin, Foulon Stéphanie
Department of Cancer Medicine, Gustave Roussy, Thoracic Group and International Center for Thoracic Cancers, Paris-Saclay University, Villejuif, France.
Oncostat U1018, Institut National de la Santé et de la Recherche Médicale (INSERM), Ligue Contre le Cancer, Paris-Saclay University, Villejuif, France.
JAMA Netw Open. 2025 Sep 2;8(9):e2529225. doi: 10.1001/jamanetworkopen.2025.29225.
Antibiotics, steroids, and proton pump inhibitors (PPIs) are suspected to decrease the efficacy of immunotherapy.
To explore the association of comedications with overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC).
DESIGN, SETTING, AND PARTICIPANTS: This nationwide retrospective cohort study used target trial emulations of patients newly diagnosed with NSCLC from January 2015 to December 2022, identified from the French national health care database. Eligible patients were treated with pembrolizumab in a first-line setting and alive 2 months after initiating pembrolizumab. Exclusion criteria included hospitalization for infectious disease, autoimmune disorders, or peptic ulcer disease.
Antibiotic and PPI exposures were defined as at least 2 prescriptions 60 days before to 42 days after pembrolizumab start. Steroid exposure was defined as at least 2 prescriptions 30 days before to 30 days after pembrolizumab start.
The primary outcome was OS. Patients exposed were compared with those without exposure, using inverse probability of treatment weighting (IPTW) to adjust for confounding.
Between January 2015, and December 2022, 41 529 patients were treated with first line pembrolizumab for advanced disease (27 826 male [67.0%]; median [range] age, 65 [19-97] years; 14 835 [35.7%] treated with pembrolizumab alone; 26 694 [64.3%] treated with pembrolizumab plus chemotherapy). At treatment initiation, 12 898 (41.9%) patients were exposed to antibiotics, 18 210 (59.1%) to steroids, and 16 783 (53.7%) to PPIs. After IPTW, antibiotics (except for macrolide and penicillin) were associated with shorter OS (hazard ratio [HR], 1.08; 95% CI, 1.05-1.12; P < .001), but it varied by antibiotic type. Steroids were not associated with OS (HR, 0.98; 95% CI, 0.95-1.02; P = .37); however, there was an interaction with pembrolizumab regimen (ie, pembrolizumab alone or with chemotherapy) (P for interaction < .001), and there was a dose-dependent association according to daily prednisone-equivalent dose (P for trend < .001). Steroids were associated with worse OS when prescribed at doses greater than 20 mg per day for pembrolizumab alone (P for trend = .005) and greater than 30 mg per day for pembrolizumab combined with chemotherapy (P for trend < .001). PPIs were associated with worse OS (HR, 1.13; 95% CI, 1.10-1.17; P < 001).
In this cohort study of patients with advanced NSCLC treated with pembrolizumab, exposure to some classes of antibiotics, to steroids (>20 mg per day of prednisone equivalent), and to PPIs was associated with worse OS, indicating that comedications should be monitored carefully in patients with immunotherapy.
抗生素、类固醇和质子泵抑制剂（PPI）被怀疑会降低免疫疗法的疗效。
探讨联合用药与晚期非小细胞肺癌（NSCLC）患者总生存期（OS）之间的关联。
设计、背景和参与者：这项全国性回顾性队列研究采用了目标试验模拟法，研究对象为2015年1月至2022年12月新诊断为NSCLC的患者，这些患者来自法国国家医疗数据库。符合条件的患者在一线治疗中接受派姆单抗治疗，且在开始使用派姆单抗2个月后仍存活。排除标准包括因传染病、自身免疫性疾病或消化性溃疡疾病住院治疗。
抗生素和PPI暴露定义为在派姆单抗开始前60天至开始后42天内至少有2次处方。类固醇暴露定义为在派姆单抗开始前30天至开始后30天内至少有2次处方。
主要结局为总生存期。使用治疗权重逆概率（IPTW）对暴露组和未暴露组患者进行比较，以调整混杂因素。
2015年1月至2022年12月期间，41529例晚期疾病患者接受了一线派姆单抗治疗（男性27826例[67.0%]；年龄中位数[范围]为65岁[19 - 97岁]；14835例[35.7%]仅接受派姆单抗治疗；26694例[64.3%]接受派姆单抗联合化疗）。在开始治疗时，12898例（41.9%）患者暴露于抗生素，18210例（59.1%）暴露于类固醇，16783例（53.7%）暴露于PPI。经过IPTW后，抗生素（大环内酯类和青霉素类除外）与较短的总生存期相关（风险比[HR]，1.08；95%置信区间，1.05 - 1.12；P <.001），但因抗生素类型而异。类固醇与总生存期无关（HR，0.98；95%置信区间，0.95 - 1.02；P = 0.37）；然而，与派姆单抗治疗方案（即单独使用派姆单抗或联合化疗）存在相互作用（交互作用P <.001），并且根据每日泼尼松等效剂量存在剂量依赖性关联（趋势P <.001）。当单独使用派姆单抗时，如果类固醇剂量大于每天20毫克（趋势P = 0.005），以及当派姆单抗联合化疗时，如果类固醇剂量大于每天30毫克（趋势P <.001），则与较差的总生存期相关。PPI与较差的总生存期相关（HR，1.13；95%置信区间，1.10 - 1.17；P < 0.001）。
在这项对接受派姆单抗治疗的晚期NSCLC患者的队列研究中，暴露于某些类别的抗生素以及类固醇（泼尼松等效剂量>每天20毫克）和PPI与较差的总生存期相关，这表明在接受免疫治疗的患者中应仔细监测联合用药情况。
