Mesothelioma Research Programme, Leicester Cancer Research Centre, University of Leicester, Leicester, UK; University Hospitals of Leicester NHS Trust, Leicester, UK.
Cancer Research UK, Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
Lancet Oncol. 2021 Nov;22(11):1530-1540. doi: 10.1016/S1470-2045(21)00471-X. Epub 2021 Oct 14.
No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients.
This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450.
Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2-16·8). Median progression-free survival was 3·0 months (95% CI 2·8-4·1) in the nivolumab group versus 1·8 months (1·4-2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53-0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5-12·1) in the nivolumab group versus 6·9 months (5·0-8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52-0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group.
Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy.
Stand up to Cancer-Cancer Research UK and Bristol Myers Squibb.
尚未有任何三期临床试验显示，对于接受过基于铂类的化疗后进展的胸膜或腹膜恶性间皮瘤患者，使用抗 PD-1 抗体纳武利尤单抗可改善其生存。本研究旨在评估纳武利尤单抗在这些患者中的疗效和安全性。
这是一项在英国 24 家医院进行的多中心、安慰剂对照、双盲、平行组、随机、三期临床试验。纳入年龄≥18 岁、东部肿瘤协作组体能状态 0 或 1 分、组织学证实的胸膜或腹膜恶性间皮瘤、接受过一线基于铂类的化疗且影像学证实疾病进展的患者，以 2:1 的比例随机分配接受每 2 周静脉输注 240 mg 纳武利尤单抗（30 分钟内）或安慰剂，直至疾病进展或最多 12 个月。随机序列由交互式网络应答系统（Alea）生成；根据上皮样与非上皮样组织学进行分层，并以 3 和 6 的随机块大小进行分组。患者和治疗医生对分组情况均设盲。主要研究终点为研究者评估的无进展生存期和总生存期，根据治疗意向评估（相当于意向治疗原则）进行分析。所有随机分配的患者均纳入安全性人群，并按分组情况进行报告。该试验在 ClinicalTrials.gov 上注册，编号为 NCT03063450。
2017 年 5 月 10 日至 2020 年 3 月 30 日期间，共纳入 332 例患者，其中 221 例（67%）被随机分配至纳武利尤单抗组，111 例（33%）被分配至安慰剂组）。中位随访时间为 11.6 个月（IQR 7.2-16.8）。纳武利尤单抗组无进展生存期的中位数为 3.0 个月（95%CI 2.8-4.1），安慰剂组为 1.8 个月（1.4-2.6）（调整后的 HR 0.67 [95%CI 0.53-0.85；p=0.0012）。纳武利尤单抗组总生存期的中位数为 10.2 个月（95%CI 8.5-12.1），安慰剂组为 6.9 个月（5.0-8.0）（调整后的 HR 0.69 [95%CI 0.52-0.91；p=0.0090）。最常见的 3 级或更高级别的治疗相关不良事件为腹泻（纳武利尤单抗组 6 例[3%]，安慰剂组 2 例[2%]）和输注相关反应（纳武利尤单抗组 6 例[3%]，安慰剂组无）。纳武利尤单抗组 90 例（41%）和安慰剂组 49 例（44%）患者发生严重不良事件。两组均无治疗相关死亡。
纳武利尤单抗可能对接受过一线治疗后进展的恶性间皮瘤患者有益。
Stand up to Cancer-Cancer Research UK 和 Bristol Myers Squibb。
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