Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum–pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum–pemetrexed would improve overall survival in patients with pleural mesothelioma. We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m] or carboplatin [area under the concentration-time curve 5–6 mg/mL per min] with pemetrexed 500 mg/m, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with , , and is closed to accrual. Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66–75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3–27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4–21·3] with pembrolizumab 16·1 months [13·1–18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64–0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20–33%) with pembrolizumab and 17% (13–24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group. In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum–pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma. The Canadian Cancer Society and Merck & Co.

中文翻译：

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加拿大、意大利和法国未经治疗的晚期胸膜间皮瘤的 Pembrolizumab 加化疗与化疗对比：一项 3 期、开放标签、随机对照试验

胸膜间皮瘤通常处于晚期、无法治愈的阶段。铂类培美曲塞化疗是标准治疗方法。我们假设在铂类培美曲塞中添加派姆单抗将改善胸膜间皮瘤患者的总生存期。我们在加拿大、意大利和法国的 51 家医院进行了这项开放标签、国际随机 3 期试验。符合资格的参与者年龄为 18 岁或以上，患有先前未经治疗的晚期胸膜间皮瘤，东部肿瘤合作组表现状态评分为 0 或 1。患者被随机分配 (1:1) 接受静脉化疗（顺铂 [75 mg/m2]）或卡铂[浓度-时间曲线下面积 5–6 mg/mL/min] 联合培美曲塞 500 mg/m，每 3 周一次，最多 6 个周期），联合或不联合每 3 周静脉注射 200 mg 帕博利珠单抗（最多 2 次）年）。主要终点是所有随机分配的患者的总生存率；对所有接受至少一剂研究治疗的随机分配患者的安全性进行了评估。该试验已在 、 、 登记，并且已停止计提。2017年1月31日至2020年9月4日期间，入组了440名患者，并随机分配接受单独化疗（n=218）或联合帕博利珠单抗化疗（n=222）。333 名患者（76%）为男性，347 名患者（79%）为白人，中位年龄为 71 岁（IQR 66-75）。根据最终分析（数据库锁定 2022 年 12 月 15 日），中位随访时间为 16·2 个月 (IQR 8·3–27·8)，派姆单抗组的总生存期显着更长（中位总生存期为 17·3 个月 [ 95% CI 14·4–21·3] 派姆单抗单独化疗 16·1 个月 [13·1–18·2]，死亡风险比 0·79；95% CI 0·64–0·98，2单侧p=0·0324)。派姆单抗组的 3 年总生存率为 25%（95% CI 20-33%），单纯化疗组的 3 年总生存率为 17%（13-24%）。派姆单抗组 222 名患者中有 60 名患者（27%）发生了与研究治疗相关的 3 级或 4 级不良事件，而单纯化疗组 211 名患者中有 32 名患者（15%）发生了与研究治疗相关的不良事件。派姆单抗组 222 名患者中有 40 名 (18%) 因与一种或多种研究药物相关的严重不良事件入院，而单纯化疗组 211 名患者中有 12 名 (6%) 因与一种或多种研究药物相关的严重不良事件入院。派姆单抗组的两名患者和单独化疗组的一名患者发生了与一种或多种药物相关的 5 级不良事件。在晚期胸膜间皮瘤患者中，在标准铂类培美曲塞化疗中添加派姆单抗是可以耐受的，并且可以显着改善总生存期。该方案是针对先前未经治疗的晚期胸膜间皮瘤的新治疗选择。加拿大癌症协会和默克公司。