肿瘤

口服长春瑞滨作为恶性胸膜间皮瘤患者二线治疗的随机 II 期临床试验

作者:会飞的大胖纸 来源:医学论坛网 日期:2021-06-30
导读

         背景: 所有恶性胸膜间皮瘤(MPM)患者最终在标准化疗后复发。然而,在这种情况下没有标准的治疗方案。长春瑞滨显示出有用的临床活性,但尚未在一项随机临床试验中进行正式评估,尽管它在世界范围内广泛使用。BRCA1 在 MPM 中调节纺锤体组装检查点,预测临床前模型中长春瑞滨的敏感性[1,2],提示 BRCA1 阴性患者可能是化疗耐药。 Background: All patients with m

关键字:  肿瘤 

背景: 所有恶性胸膜间皮瘤(MPM)患者最终在标准化疗后复发。然而,在这种情况下没有标准的治疗方案。长春瑞滨显示出有用的临床活性,但尚未在一项随机临床试验中进行正式评估,尽管它在世界范围内广泛使用。BRCA1 在 MPM 中调节纺锤体组装检查点,预测临床前模型中长春瑞滨的敏感性[1,2],提示 BRCA1 阴性患者可能是化疗耐药。

 

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 是英国癌症研究中心(Cancer Research UK)资助的一项由研究人员发起的随机对照 2 期多中心英国试验,招募了一线化疗后进展的 MPM 患者。将病人按 2:1 的比例随机分配至长春瑞滨(60mg/m²,每周 Q21d 从第 2 周期升至 80mg / m²)+主动支持治疗(ASC)与 ASC 对比,直到疾病进展,不可接受的毒性或撤回同意。主要结果是无进展生存期(PFS),定义为从随机化开始到任何进展(根据改良 RECIST 评估恶性胸膜间皮瘤疗效的标准)或死亡的时间。该试验在单侧 20%显著性水平上具有 90%的能力可检测到 0.65 的危险比。次要终点是总生存期(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.

 

结果: 从 2016 年 5 月至 2018 年 10 月,来自英国 10 个地点的 154 名患者被随机分为长春瑞滨+ ASC (n=98)或 ASC (n=56)两组。在意向治疗分析中,129 个事件发生后,长春瑞滨+ASC 的中位无进展生存期为 4.2 个月(m),而单纯 ASC 的中位无生存期为 2.8 个月(风险比(HR)0.59;95% CI: 0.41 ~ 0.85;单侧 p = 0.0017)。据报有 108 人死亡。长春瑞滨+ ASC 的中位 OS 为9.3 个月,而仅 ASC 的中位 OS 为 9.1 个月(HR = 0.79;95%可信区间:0.53 - 1.17;双边 p = 0.24)。之后将介绍毒性数据和亚组分析,包括 BRCA1 缺失的影响。

 

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.

 

结论:试验达到了主要终点。长春瑞滨在 MPM 复发患者中显示出了有效的临床疗效,支持其核准标示外使用,作为 MPM 复发患者的治疗选择。

 

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.

 

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