Phase II, Double-Blinded, Randomized Study of Enzastaurin Plus Pemetrexed as Second-Line Therapy in Patients with Advanced Non-small Cell Lung Cancer
Phase II, Double-Blinded, Randomized Study of Enzastaurin Plus Pemetrexed as Second-Line Therapy in Patients with Advanced Non-small Cell Lung Cancer
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DOI：
10.1097/jto.0b013e3181cee24f
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发表时间：
2010-03-01
影响因子：
20.4
通讯作者：
von Pawel, Joachim
中科院分区：
文献类型：
--
作者：
Chiappori, Alberto;Bepler, Gerold;von Pawel, Joachim
前言：在一项双盲、随机、II期的研究中，我们观察了苯扎曲林联合培美曲塞作为二线治疗晚期(IIIA/B期或IV期)非小细胞肺癌患者的疗效。方法：患者在21天周期的第1天(周期第1天，第8天)加口服苯扎曲林(250 mg，每日2次；联合组)或安慰剂(培美曲塞组)静脉注射培美曲塞500 mg/m(2)。两组患者都接受了维生素B12、叶酸和地塞米松的补充。进行了一项中期分析，以确定是否需要进行III期研究。结果：中期分析显示，没有证据表明使用苯扎托林可以改善无进展生存率。在最终分析中(N=160，每组80例)，基线特征很好地平衡。两组的无进展生存期(3.0月，p=0.544)和总生存期(联合组9.6月，培美曲塞组7.4月，p=0.171)无显著差异。药物相关的严重不良事件包括合并上肢的脑血管意外、心悸和肾功能衰竭各1例，培美曲塞上肢的中性粒细胞减少症、血小板减少症和脂膜炎各1例。两组非血液系统药物相关的3/4级毒性反应相似。联合用药的3/4级血液学毒性较高，特别是白细胞减少(6.3%对0%)、中性粒细胞减少(15.2%对5.0%)和血小板减少(8.9%对1.3%)。在研究期间或停药30天内报告的26例死亡(联合组10例，培美曲塞组16例)中，没有一例与药物有关。结论：恩扎他林和培美曲塞联合治疗晚期非小细胞肺癌患者耐受性良好，但与培美曲塞和安慰剂作为二线治疗非小细胞肺癌患者相比并不能提高疗效。
Introduction: We examined the efficacy of enzastaurin plus pemetrexed as second-line therapy in patients with advanced (stage IIIA/B or IV) non-small cell lung cancer in a double-blinded, randomized, phase II study.Methods: Patients received pemetrexed 500 mg/m(2) intravenously on day 1 of 21-day cycles (day 8 in cycle 1) plus oral enzastaurin (250 mg two times per day; combination arm) or placebo (pemetrexed arm). Both arms received supplementation with vitamin B 12, folic acid, and dexamethasone. An interim analysis was conducted to determine whether efficacy would warrant a phase III study.Results: The interim analysis showed no evidence of improved progression-free survival with enzastaurin. At final analysis (N = 160, 80 in each arm), baseline characteristics were well balanced. There was no significant difference in progression-free survival (3.0 months, p = 0.544) or overall survival (9.6 months in combination arm and 7.4 months in pemetrexed arm, p = 0.171). Drug-related serious adverse events included cerebrovascular accident, palpitations, and renal failure (n = 1, each) in combination arm and neutropenic sepsis, thrombocytopenia, and panniculitis (n = 1, each) in pemetrexed arm. Nonhematologic drug-related grade 3/4 toxicities were similar in both arms. Grade 3/4 hematologic toxicities were higher with the combination, specifically leukopenia (6.3% versus 0%), neutropenia (15.2% versus 5.0%), and thrombocytopenia (8.9% versus 1.3%). Of the 26 deaths reported on-study or within 30 days of discontinuation (10 in combination arm and 16 in pemetrexed arm), none were drug related.Conclusion: The combination regimen of enzastaurin and pemetrexed is well tolerated but does not improve efficacy over pemetrexed and placebo as second-line treatment of unselected patients with advanced non-small cell lung cancer.