BACKGROUND Systemic second- and third-line therapies for malignant pleural mesothelioma (MPM) result in a median progression-free survival (mPFS) of <2 months and median overall survival (mOS) of 6-9 months. Lurbinectedin binds to the DNA of the regulatory region while inhibiting tumour-associated macrophage transcription. In early trials, encouraging outcomes occurred in patients (pts) with MPM treated with lurbinectedin. We aimed to generate lurbinectedin efficacy and safety data among pts with progressive MPM. PATIENTS AND METHODS Pts with progressing MPM treated with first-line platinum-pemetrexed chemotherapy with or without immunotherapy received lurbinectedin monotherapy. Treatment was given intravenously at 3.2 mg/m2 dose every 3 weeks until progression or unacceptable toxicity. Using Simon's two-stage design, the primary endpoint, progression-free survival (PFS) at 12 weeks (PFS12wks), was met if achieved by ≥21 pts (p0 ≤35% versus p1 ≥55%). RESULTS Forty-two pts from nine centres across Switzerland and Italy were recruited. Histology was epithelioid in 33 cases, sarcomatoid in 5, and biphasic in 4. Overall 10/42 (23.8%) underwent prior immunotherapy and 14/42 (33.3%) had progressed ≤6 months after first-line chemotherapy. At data cut-off PFS12wks was met by 22/42 pts (52.4%; 90% confidence interval (CI): 38.7% to 63.5%; P = 0.015) with an mPFS of 4.1 months and mOS of 11.1 months. The best response was complete and partial remission observed in one patient each and stable disease in 20 pts. The duration of disease control was 6.6 months (95% CI: 5.2-7.4). No significant difference in PFS12wks, mPFS, and mOS was recorded in epithelioid versus non-epithelioid cases and pts with prior immunotherapy versus those without. Similar mPFS but shorter mOS were observed among pts who progressed within ≤6 months after first-line chemotherapy. Lurbinectedin-related grade 3-4 toxicity was seen in 21 pts, mostly being neutropenia (23.8%) and fatigue (16.7%). CONCLUSIONS The primary efficacy endpoint was reached with acceptable toxicity. Lurbinectedin showed promising activity regardless of histology, prior immunotherapy, or outcome on prior treatment. CLINICALTRIALS. GOV IDENTIFIER NCT03213301.

中文翻译：

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Lurbinectin作为恶性胸膜间皮瘤的二线或三线姑息疗法：一项国际性，多中心，单组，II期临床试验（SAKK 17/16）。

背景技术恶性胸膜间皮瘤（MPM）的系统性二线和三线疗法导致中位无进展生存期（mPFS）<2个月和中位总体生存期（mOS）6-9个月。Lurbinectin与调节区的DNA结合，同时抑制肿瘤相关的巨噬细胞转录。在早期试验中，接受卢比克丁治疗的MPM患者（pts）发生令人鼓舞的结果。我们的目标是在进行性MPM的患者之间生成lurbinectin的疗效和安全性数据。患者和方法用一线铂培美曲塞化疗（有或没有免疫治疗）治疗的进展性MPM患者接受lurbinectin单药治疗。每3周以3.2 mg / m2的剂量静脉内给予治疗，直至进展或出现不可接受的毒性。使用Simon的两阶段设计，即主要终点，如果达到≥21分（p0≤35％vs p1≥55％），则达到12周无进展生存期（PFS）。结果招募了来自瑞士和意大利的9个中心的42分。组织学上皮样变化33例，肉瘤样变化5例，双相样变化4例。总共10/42（23.8％）接受了先前的免疫治疗，而14/42（33.3％）进行了一线化疗后≤6个月。截止数据时，PFS12wks满足22/42分（52.4％； 90％置信区间（CI）：38.7％至63.5％； P = 0.015），mPFS为4.1个月，mOS为11.1个月。最佳的反应是完全的，每位患者观察到部分缓解，并且在20分时病情稳定。疾病控制的持续时间为6.6个月（95％CI：5.2-7.4）。PFS12wks，mPFS，在上皮样病例和非上皮样病例中以及在先接受免疫治疗的患者与未进行过免疫治疗的患者中记录了mOS。一线化疗后≤6个月内进展的患者中，mPFS相似，但mOS较短。Lurbinectin相关的3-4级毒性反应出现在21分，主要是中性粒细胞减少症（23.8％）和疲劳（16.7％）。结论达到主要疗效终点并具有可接受的毒性。卢比替丁显示出有希望的活性，无论其组织学，先前的免疫治疗或先前治疗的结果如何。临床试验。GOV标识符NCT03213301。8％）和疲劳（16.7％）。结论达到主要疗效终点并具有可接受的毒性。无论组织学，先前的免疫疗法或先前的治疗结果如何，卢比克丁均显示出有希望的活性。临床试验。GOV标识符NCT03213301。8％）和疲劳（16.7％）。结论达到主要疗效终点并具有可接受的毒性。卢比替丁显示出有希望的活性，无论其组织学，先前的免疫治疗或先前治疗的结果如何。临床试验。GOV标识符NCT03213301。