Metaxas Y, Früh M, Eboulet E I, Grosso F, Pless M, Zucali P A, Ceresoli G L, Mark M, Schneider M, Maconi A, Perrino M, Biaggi-Rudolf C, Froesch P, Schmid S, Waibel C, Appenzeller C, Rauch D, von Moos R
Department of Oncology/Haematology, Kantonsspital Graubünden, Chur, Switzerland.
Department of Medical Oncology and Haematology, Kantonsspital St. Gallen, St Gallen, Switzerland; University of Bern, Bern, Switzerland.
Ann Oncol. 2020 Apr;31(4):495-500. doi: 10.1016/j.annonc.2019.12.009. Epub 2020 Jan 16.
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.
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/m 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 (PFS), was met if achieved by ≥21 pts (p0 ≤35% versus p1 ≥55%).
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 PFS 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 PFS 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%).
The primary efficacy endpoint was reached with acceptable toxicity. Lurbinectedin showed promising activity regardless of histology, prior immunotherapy, or outcome on prior treatment. CLINICALTRIALS.
NCT03213301.
恶性胸膜间皮瘤（MPM）的全身二线及三线治疗的中位无进展生存期（mPFS）<2个月，中位总生存期（mOS）为6 - 9个月。鲁比卡丁可与调控区的DNA结合，同时抑制肿瘤相关巨噬细胞转录。在早期试验中，接受鲁比卡丁治疗的MPM患者取得了令人鼓舞的结果。我们旨在获取鲁比卡丁在进展期MPM患者中的疗效和安全性数据。
接受一线铂类培美曲塞化疗（联合或不联合免疫治疗）后病情进展的MPM患者接受鲁比卡丁单药治疗。每3周静脉注射一次，剂量为3.2mg/m²，直至病情进展或出现不可接受的毒性反应。采用西蒙两阶段设计，主要终点为12周时的无进展生存期（PFS），若≥21例患者达到该终点（p0≤35%，p1≥55%）则视为满足条件。
招募了来自瑞士和意大利9个中心的42例患者。组织学类型为上皮样33例，肉瘤样5例，双向性4例。总体而言，10/42（23.8%）的患者曾接受过免疫治疗，14/42（33.3%）的患者在一线化疗后≤6个月病情进展。在数据截止时，22/42例患者（52.4%；90%置信区间（CI）：38.7%至63.5%；P = 0.015）达到PFS，mPFS为4.1个月，mOS为11.1个月。最佳反应为1例患者完全缓解，1例患者部分缓解，20例患者病情稳定。疾病控制持续时间为6.6个月（95%CI：5.2 - 7.4）。上皮样与非上皮样病例以及曾接受免疫治疗与未接受免疫治疗的患者在PFS、mPFS和mOS方面无显著差异。在一线化疗后≤6个月内病情进展的患者中观察到类似的mPFS，但mOS较短。21例患者出现与鲁比卡丁相关的3 - 4级毒性反应，主要为中性粒细胞减少（23.8%）和疲劳（16.7%）。
在可接受的毒性情况下达到了主要疗效终点。无论组织学类型、既往免疫治疗情况或既往治疗结果如何，鲁比卡丁均显示出有前景的活性。临床试验。
NCT03213301
