Background

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.

Methods

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.

Findings

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.

Interpretation

Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy.

Funding

Stand up to Cancer–Cancer Research UK and Bristol Myers Squibb.

中文翻译：

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Nivolumab 与安慰剂治疗复发性恶性间皮瘤（CONFIRM）：一项多中心、双盲、随机、3 期试验

背景

尚无 3 期试验显示在铂类化疗后进展的胸膜或腹膜恶性间皮瘤患者的生存率有所提高。本研究的目的是评估抗 PD-1 抗体 nivolumab 在这些患者中的疗效和安全性。

方法

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、3 期试验。东部肿瘤协作组体能状态为 0 或 1 的成年患者（年龄≥18 岁），组织学证实的胸膜或腹膜间皮瘤，既往接受过一线铂类化疗并有疾病进展的放射学证据，被随机分配被分配 (2:1) 接受 nivolumab 的固定剂量，每 2 周 240 mg，静脉内持续 30 分钟或安慰剂，直至疾病进展或最长 12 个月。随机序列是在交互式网络响应系统 (Alea) 中生成的；根据上皮样与非上皮样组织学对患者进行分层，并以 3 和 6 的随机块大小进行分配。参与者和治疗临床医生对分组分配不知情。共同主要终点是研究者评估的无进展生存期和总生存期，根据治疗政策估计值（相当于意向治疗原则）进行分析。根据组分配报告，所有被随机分配的患者都包括在安全人群中。该试验已在 Clinicaltrials.gov 注册，NCT03063450。

发现

在 2017 年 5 月 10 日至 2020 年 3 月 30 日期间，招募了 332 名患者，其中 221 名（67%）被随机分配到纳武利尤单抗组，111 名（33%）被分配到安慰剂组。中位随访时间为 11·6 个月（IQR 7·2–16·8）。纳武利尤单抗组的中位无进展生存期为 3·0 个月 (95% CI 2·8-4·1)，而安慰剂组为 1·8 个月 (1·4-2·6)（调整后的风险比 [HR ] 0·67 [95% CI 0·53–0·85；p=0·0012)。纳武利尤单抗组的中位总生存期为 10·2 个月 (95% CI 8·5–12·1)，而安慰剂组为 6·9 个月 (5·0–8·0)（调整后的 HR 0·69 [95 % CI 0·52–0·91]；p=0·0090)。最常报告的 3 级或更严重的治疗相关不良事件是腹泻（纳武单抗组 221 例中的 6 例 [3%] vs安慰剂组 111 人中有 2 人 [2%]）和输液相关反应（6 人 [3%]对无）。纳武利尤单抗组 90 例（41%）患者和安慰剂组 49 例（44%）患者发生严重不良事件。两组均无治疗相关死亡。

解释

Nivolumab 代表了一种可能对一线治疗取得进展的恶性间皮瘤患者有益的治疗方法。

资金

勇敢地面对英国癌症-癌症研究中心和百时美施贵宝。