背景： 所有惡性胸膜間皮瘤(MPM)患者最終在標準化療後複發。然而，在這種情況下沒有標準的治療方案。長春瑞濱顯示出有用的臨床活性，但尚未在一項隨機臨床試驗中進行正式評估，盡管它在世界範圍內廣泛使用。BRCA1 在 MPM 中調節紡錘體組裝檢查點，預測臨床前模型中長春瑞濱的敏感性[1,2]，提示 BRCA1 陰性患者可能是化療耐藥。
Background: All patients with malignant pleural mesothelioma (MPM) eventually relapse following standard chemotherapy. However, there is no standard treatment option in this setting. Vinorelbine, exhibits useful clinical activity but has not been formally evaluated in a randomised clinical trial, despite its widespread off-label use worldwide. BRCA1 regulates spindle assembly checkpoint in MPM and predicts vinorelbine sensitivity in preclinical models [1,2], suggesting that BRCA1 negative patients may be chemoresistant.
方法： VIM 是英國癌症研究中心(Cancer Research UK)資助的一項由研究人員發起的隨機對照 2 期多中心英國試驗，招募了一線化療後進展的 MPM 患者。將病人按 2：1 的比例隨機分配至長春瑞濱（60mg/m²,每周 Q21d 從第 2 周期升至 80mg / m²）+主動支持治療（ASC）與 ASC 對比，直到疾病進展，不可接受的毒性或撤回同意。主要結果是無進展生存期(PFS)，定義為從隨機化開始到任何進展(根據改良 RECIST 評估惡性胸膜間皮瘤療效的標準)或死亡的時間。該試驗在單側 20％顯著性水平上具有 90％的能力可檢測到 0.65 的危險比。次要終點是總生存期（OS），耐受性和安全性。
Methods: VIM, a Cancer Research UK funded, investigator-initiated randomised controlled phase 2 multi-centre UK trial, enrolled patients with MPM who had progressed after first-line chemotherapy. Pts were randomised 2:1 to either vinorelbine (60mg/m2 weekly Q21d escalating to 80mg/m2 from cycle 2) + active supportive care (ASC) versus ASC until disease progression, unacceptable toxicity or withdrawal of consent. The primary outcome was progression free survival (PFS) defined as the time from randomisation to any progression (based on Modified RECIST criteria for assessment of response in malignant pleural mesothelioma) or death. The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints were overall survival (OS), tolerability and safety.
結果： 從 2016 年 5 月至 2018 年 10 月，來自英國 10 個地點的 154 名患者被隨機分為長春瑞濱+ ASC (n=98)或 ASC (n=56)兩組。在意向治療分析中，129 個事件發生後，長春瑞濱+ASC 的中位無進展生存期為 4.2 個月(m)，而單純 ASC 的中位無生存期為 2.8 個月(風險比(HR)0.59;95% CI: 0.41 ~ 0.85;單側 p = 0.0017)。據報有 108 人死亡。長春瑞濱+ ASC 的中位 OS 為9.3 個月，而僅 ASC 的中位 OS 為 9.1 個月(HR = 0.79;95%可信區間:0.53 - 1.17;雙邊 p = 0.24)。之後將介紹毒性數據和亞組分析，包括 BRCA1 缺失的影響。
Results: Between May 2016 and Oct 2018, 154 patients were recruited from 10 UK sites and randomised to vinorelbine + ASC (n=98) or ASC alone (n=56). In the Intention-to-treat analysis, after 129 events, median PFS was 4.2 months (m) for vinorelbine + ASC compared to 2.8m for ASC alone (Hazard Ratio (HR) 0.59; 95% CI: 0.41 to 0.85; one-sided p = 0.0017). 108 deaths were reported. Median OS was 9.3m for vinorelbine + ASC compared to 9.1m for ASC alone (HR=0.79; 95% CI: 0.53 to 1.17; two-sided p = 0.24). Toxicity data and subgroup analyses including the impact of BRCA1 deficiency will be presented.
結論：試驗達到了主要終點。長春瑞濱在 MPM 複發患者中顯示出了有效的臨床療效，支持其核準標示外使用，作為 MPM 複發患者的治療選擇。
Conclusion: The trial met its primary endpoint. Vinorelbine demonstrates useful clinical efficacy in relapsed MPM, supporting its off-label use, as a treatment option for patients with relapsed MPM.
