Shanghai Chest Hospital, Respiratory Medicine Department, Shanghai Jiao Tong University, Shanghai, China.
Piedmont Cancer Institute, Atlanta, GA, USA.
Lancet Respir Med. 2024 Oct;12(10):775-786. doi: 10.1016/S2213-2600(24)00178-4. Epub 2024 Sep 9.
There is an unmet need for second-line and third-line treatments that are effective and tolerable for advanced or metastatic non-small-cell lung cancer (NSCLC) with no driver mutations.
In this phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial, we enrolled patients from 58 medical centres in Australia, China, and the USA. Eligible patients were adults with epidermal growth factor receptor (EGFR) wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned (1:1) using an independent stratified randomisation schedule with a block size of four to receive intravenous docetaxel 75 mg/m on day 1 and either plinabulin (30 mg/m) or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Safety was analysed in all patients who had received at least one dose of study drug or placebo. This trial is registered with ClinicalTrials.gov (NCT02504489) and is now closed.
Between Nov 30, 2015, and Jan 6, 2021, 919 patients were screened for inclusion. 360 patients were excluded, and 559 were enrolled and randomly assigned to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). 406 (73%) of 559 patients were male, 153 (27%) were female, and 488 (87%) were Asian. Median OS was 10·5 months (95% CI 9·34-11·87) in the plinabulin group compared with 9·4 months (8·38-10·68) in the control group (stratified HR 0·82, 95% CI 0·68-0·99; p=0·0399). Mean OS was 15·08 months (13·42-16·74) in the plinabulin group compared with 12·77 months (11·45-14·10) in the placebo group using restricted mean survival time analysis (difference 2·31 months, 95% CI 0·18-4·44; p=0·0332). Treatment-emergent adverse events occurred in 273 (>99%) of 274 patients in the plinabulin group and 276 (99%) of 278 patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the plinabulin group than in the placebo group, with the most frequent being diarrhoea (24 [9%] of 274 patients vs three [1%] of 278) and vomiting (six [2%] vs one [<1%]), as did transient grade 3 hypertension (50 [18%] vs eight [3%]). Treatment-emergent death was reported in 12 patients (4%) in the plinabulin group and ten patients (4%) in the placebo group.
Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population.
BeyondSpring Pharmaceuticals.
对于没有驱动突变的晚期或转移性非小细胞肺癌（NSCLC）患者，需要有效的二线和三线治疗方法，而目前这方面的治疗选择有限。
在这项国际、多中心、单盲、平行组、随机对照 3 期临床试验中，我们从澳大利亚、中国和美国的 58 个医学中心招募了患者。符合条件的患者为表皮生长因子受体（EGFR）野生型 NSCLC 患者，这些患者在接受一线含铂化疗后进展。患者按照 1:1 的比例随机分组（使用独立分层随机分组方案，分组大小为 4），接受静脉注射多西他赛 75mg/m2，第 1 天和第 8 天分别接受plinabulin（30mg/m2）或安慰剂，每 21 天为一个周期，直至疾病进展、不可接受的毒性作用、退出或死亡。主要终点是在意向治疗（ITT）人群中的总生存期（OS）。对至少接受过一次研究药物或安慰剂治疗的所有患者进行了安全性分析。这项试验在 ClinicalTrials.gov （NCT02504489）上注册，现已关闭。
在 2015 年 11 月 30 日至 2021 年 1 月 6 日期间，有 919 名患者接受了入组筛选。360 名患者被排除，559 名患者入组并随机分配接受多西他赛和 plinabulin（n=278）或多西他赛和安慰剂（n=281）治疗。559 名患者中，406 名（73%）为男性，153 名（27%）为女性，488 名（87%）为亚洲人。plinabulin 组的中位 OS 为 10.5 个月（95%CI 9.34-11.87），对照组为 9.4 个月（8.38-10.68）（分层 HR 0.82，95%CI 0.68-0.99；p=0.0399）。plinabulin 组的平均 OS 为 15.08 个月（13.42-16.74），安慰剂组为 12.77 个月（11.45-14.10）（采用限制平均生存时间分析，差异为 2.31 个月，95%CI 0.18-4.44；p=0.0332）。plinabulin 组 274 例患者（99%）和安慰剂组 278 例患者（99%）中发生了治疗出现的不良事件。plinabulin 组比安慰剂组更常发生 3 级或 4 级胃肠道疾病，最常见的是腹泻（274 例患者中有 24 例[9%]，278 例患者中有 3 例[1%]）和呕吐（274 例患者中有 6 例[2%]，278 例患者中有 1 例[<1%]），以及短暂的 3 级高血压（274 例患者中有 50 例[18%]，278 例患者中有 8 例[3%]）。plinabulin 组有 12 例（4%）患者和安慰剂组有 10 例（4%）患者报告了治疗出现的死亡。
plinabulin 加多西他赛显著改善了晚期或转移性 EGFR 野生型 NSCLC 患者的 OS，可以作为该人群的一种新的治疗选择。
百时美施贵宝公司。
