Background

There is a preclinical rationale for inhibiting angiogenesis in mesothelioma. We aimed to assess the efficacy and safety of the anti-VEGFR-2 antibody ramucirumab combined with gemcitabine in patients with pretreated malignant pleural mesothelioma.

Methods

RAMES was a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial done at 26 hospitals in Italy. Eligible patients were aged 18 years or older, had Eastern Cooperative Oncology Group performance status 0–2, and histologically proven malignant pleural mesothelioma progressing during or after first-line treatment with pemetrexed plus platinum. Patients were randomly assigned (1:1) to receive intravenous gemcitabine 1000 mg/m² on days 1 and 8 every 3 weeks plus either intravenous placebo (gemcitabine plus placebo group) or ramucirumab 10 mg/kg (gemcitabine plus ramucirumab group) on day 1 every 3 weeks, until tumour progression or unacceptable toxicity. Central randomisation was done according to a minimisation algorithm method, associated with a random element using the following stratification factors: ECOG performance status, age, histology, and first-line time-to-progression. The primary endpoint was overall survival, measured from the date of randomisation to the date of death from any cause. Efficacy analyses were assessed in all patients who had been correctly randomised and received their allocated treatment, and safety analyses were assessed in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03560973, and with EudraCT, 2016-001132-36.

Findings

Between Dec 22, 2016, and July 30, 2018, of 165 patients enrolled 161 were correctly assigned and received either gemcitabine plus placebo (n=81) or gemcitabine plus ramucirumab (n=80). At database lock (March 8, 2020), with a median follow-up of 21·9 months (IQR 17·7–28·5), overall survival was longer in the ramucirumab group (HR 0·71, 70% CI 0·59–0·85; p=0·028). Median overall survival was 13·8 months (70% CI 12·7–14·4) in the gemcitabine plus ramucirumab group and 7·5 months (6·9–8·9) in the gemcitabine plus placebo group. Grade 3–4 treatment-related adverse events were reported in 35 (44%) of 80 patients in the gemcitabine plus ramucirumab group and 24 (30%) of 81 in the gemcitabine plus placebo group. The most common treatment-related grade 3–4 adverse events were neutropenia (16 [20%] for gemcitabine plus ramucirumab vs ten [12%] for gemcitabine plus placebo) and hypertension (five [6%] vs none). Treatment-related serious adverse events were reported in five (6%) in the gemcitabine plus ramucirumab group and in four (5%) patients in the gemcitabine plus placebo group; the most common was thromboembolism (three [4%] for gemcitabine plus ramucirumab vs two [2%] for gemcitabine plus placebo). There were no treatment-related deaths.

Interpretation

Ramucirumab plus gemcitabine significantly improved overall survival after first-line standard chemotherapy, with a favourable safety profile. This combination could be a new option in this setting.

Funding

Eli Lilly Italy.

Translation

For the Italian translation of the abstract see Supplementary Materials section.

中文翻译：

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吉西他滨联合或不联合雷莫芦单抗作为恶性胸膜间皮瘤 (RAMES) 的二线治疗：一项随机、双盲、安慰剂对照 2 期试验

 背景

抑制间皮瘤血管生成有其临床前依据。我们的目的是评估抗 VEGFR-2 抗体雷莫芦单抗联合吉西他滨治疗经治恶性胸膜间皮瘤患者的疗效和安全性。

 方法

RAMES 是一项多中心、随机、双盲、安慰剂对照的 2 期试验，在意大利 26 家医院进行。符合资格的患者年龄为 18 岁或以上，东部肿瘤合作组表现状态为 0-2，并且组织学证明恶性胸膜间皮瘤在培美曲塞加铂类一线治疗期间或之后进展。患者被随机分配 (1:1) 接受静脉注射吉西他滨 1000 mg/m ²第 1 天和第 8 天每 3 周加静脉注射安慰剂（吉西他滨加安慰剂组）或雷莫芦单抗 10 mg/kg（吉西他滨加雷莫芦单抗组）每 3 周 1 次，直至肿瘤进展或出现不可接受的毒性。中心随机化是根据最小化算法方法进行的，与使用以下分层因素的随机元素相关：ECOG 表现状态、年龄、组织学和一线进展时间。主要终点是总生存期，从随机分组日期到任何原因死亡日期进行测量。对所有已正确随机分组并接受指定治疗的患者进行疗效分析，并对所有接受至少一剂指定治疗的患者进行安全性分析。该试验已在 ClinicalTrials.gov（NCT03560973）和 EudraCT（2016-001132-36）注册。

 发现

2016年12月22日至2018年7月30日期间，入组的165名患者中有161人被正确分配并接受吉西他滨加安慰剂（n = 81）或吉西他滨加雷莫芦单抗（n = 80）治疗。截至数据库锁定（2020 年 3 月 8 日），中位随访时间为 21·9 个月（IQR 17·7–28·5），雷莫芦单抗组的总生存期更长（HR 0·71，70% CI 0） ·59–0·85；p=0·028)。吉西他滨加雷莫芦单抗组的中位总生存期为 13·8 个月 (70% CI 12·7–14·4)，吉西他滨加安慰剂组的中位总生存期为 7·5 个月 (6·9–8·9)。吉西他滨联合雷莫芦单抗组 80 名患者中有 35 名患者（44%）报告了 3-4 级治疗相关不良事件，吉西他滨联合安慰剂组 81 名患者中有 24 名患者（30%）报告了 3-4 级治疗相关不良事件。最常见的治疗相关 3-4 级不良事件是中性粒细胞减少症（吉西他滨加雷莫芦单抗组为 16 例 [20%]，吉西他滨加安慰剂组为10 例 [12%]）和高血压（5 例 [6%]例为无）。吉西他滨联合雷莫芦单抗组有 5 名 (6%) 患者报告了治疗相关的严重不良事件，吉西他滨联合安慰剂组有 4 名 (5%) 患者报告了治疗相关的严重不良事件；最常见的是血栓栓塞（吉西他滨加雷莫芦单抗组为 3 例 [4%]，吉西他滨加安慰剂组为 2 例 [2%]）。没有出现与治疗相关的死亡。

 解释

雷莫芦单抗联合吉西他滨显着改善了一线标准化疗后的总生存期，且安全性良好。这种组合可能是这种情况下的一个新选择。

 资金

 礼来公司意大利。

 翻译

有关摘要的意大利语翻译，请参阅补充材料部分。