Cross Cancer Institute, Edmonton, AB, Canada.
Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione G Pascale, Napoli, Italy.
Lancet. 2023 Dec 16;402(10419):2295-2306. doi: 10.1016/S0140-6736(23)01613-6. Epub 2023 Nov 3.
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 ClinicalTrials.gov, NCT02784171, 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 vs 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.
胸膜间皮瘤通常在晚期、无法治愈的阶段出现。含铂培美曲塞化疗是一种标准治疗方法。我们假设在含铂培美曲塞化疗的基础上加用派姆单抗可以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性、国际、随机的 3 期试验。符合条件的参与者年龄在 18 岁或以上，患有未经治疗的晚期胸膜间皮瘤，东部肿瘤协作组体能状态评分为 0 或 1。患者被随机分配（1:1）接受静脉化疗（顺铂[75mg/m]或卡铂[浓度-时间曲线下面积 5-6mg/mL/min 每分]联合培美曲塞 500mg/m，每 3 周一次，最多 6 个周期），或联合或不联合静脉注射派姆单抗 200mg，每 3 周一次（最多 2 年）。主要终点是所有随机分配患者的总生存期；所有接受至少一剂研究治疗的随机分配患者均进行安全性评估。这项试验在 ClinicalTrials.gov 注册，编号为 NCT02784171，现已关闭入组。
在 2017 年 1 月 31 日至 2020 年 9 月 4 日期间，共纳入 440 名患者并随机分为单纯化疗组（n=218）或化疗联合派姆单抗组（n=222）。333 名（76%）患者为男性，347 名（79%）为白人，中位年龄为 71 岁（IQR 66-75）。在最终分析（数据库锁定 2022 年 12 月 15 日）时，中位随访 16.2 个月（IQR 8.3-27.8），与单纯化疗相比，派姆单抗治疗使总生存期显著延长（派姆单抗组的中位总生存期为 17.3 个月[95%CI 14.4-21.3]，而单纯化疗组为 16.1 个月[13.1-18.2]，死亡风险比为 0.79；95%CI 0.64-0.98，双侧 p=0.0324）。派姆单抗组的 3 年总生存率为 25%（95%CI 20-33%），而单纯化疗组为 17%（13-24%）。派姆单抗组有 60 名（27%）患者和单纯化疗组有 32 名（15%）患者发生与研究治疗相关的 3 或 4 级不良事件。派姆单抗组有 40 名（18%）患者和单纯化疗组有 12 名（6%）患者因与一种或多种研究药物相关的严重不良事件入院。派姆单抗组有 2 名患者和单纯化疗组有 1 名患者发生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，在标准的含铂培美曲塞化疗的基础上加用派姆单抗是可以耐受的，并显著改善了总生存期。该方案为未经治疗的晚期胸膜间皮瘤提供了一种新的治疗选择。
加拿大癌症协会和默克公司。
