A Randomized, Open-Label Phase II Trial of Volasertib as Monotherapy and in Combination With Standard-Dose Pemetrexed Compared With Pemetrexed Monotherapy in Second-Line Treatment for Non-Small-Cell Lung Cancer
A Randomized, Open-Label Phase II Trial of Volasertib as Monotherapy and in Combination With Standard-Dose Pemetrexed Compared With Pemetrexed Monotherapy in Second-Line Treatment for Non-Small-Cell Lung Cancer
复制标题
DOI：
10.1016/j.cllc.2015.05.010
复制
发表时间：
2015-11-01
影响因子：
3.6
通讯作者：
Chu, Quincy
中科院分区：
文献类型：
--
作者：
Ellis, Peter M.;Leighl, Natasha B.;Chu, Quincy
二线治疗方案，提高晚期非小细胞肺癌（NSCLC）患者的生存率是必要的。这项随机、II期试验（n = 143）研究了volasertib单药治疗或与培美曲塞联合治疗与培美曲塞单药治疗在既往铂类药物化疗后疾病进展的NSCLC患者中的比较。Volasertib与培美曲塞的联合治疗与培美曲塞单药治疗相比没有改善疗效。简介：Volasertib是一种有效的、选择性的细胞周期激酶抑制剂，通过靶向Polo样激酶诱导有丝分裂阻滞和细胞凋亡。在这项研究中，我们比较了volasertib、volasertib联合培美曲塞和培美曲塞单药治疗一线铂类化疗后疾病进展的晚期非小细胞肺癌（NSCLC）患者。患者和方法：使用导入期（n = 12）来确定volasertib是否可以全剂量与培美曲塞500 mg/m2联合使用。后续患者随机分配至volasertib组（n = 37）、volasertib+培美曲塞组（n = 47）、或培美曲塞组（n = 47），每21天在第1天给药一次。主要终点为无进展生存期（PFS）;次要终点包括客观缓解率和药代动力学。结果：随机化阶段选择Volasertib 300 mg。volasertib单药治疗的招募因缺乏疗效而提前停止。培美曲塞组的中位PFS为5.3个月，volasertib+培美曲塞组为3.3个月（风险比[HR]，1.141; 95%置信区间[CI]，0.73-1.771），volasertib组为1.4个月（HR，2.045; 95% CI，1.27-3.292）。培美曲塞组的ORR为10.6%，volasertib组为21.3%，volasertib组为8.1%。最常见的所有级别相关不良事件（培美曲塞/volasertib+培美曲塞/volasertib）为：疲劳（28 [61%]/27 [59%]/11 [31%]），恶心（21 [46%]/19 [41%]/0 [0%]），食欲减退（14 [31%]/13 [28%]/2 [6%]），中性粒细胞减少症（4 [9%]/8 [17%]/9 [25%]）、皮疹（9 [20%]/8 [17%]/2 [6%]）、呕吐（6 [13%]/13 [28%]/0 [0%]）和腹泻（8 [17%]/11 [24%]/0 [0%]）。药代动力学分析显示volasertib和培美曲塞之间无药物相互作用。结论：对于晚期或转移性NSCLC的二线治疗，与培美曲塞单药相比，volasertib联合标准培美曲塞未显著增加毒性，也未改善疗效。
Second-line therapy options that improve survival for patients with advanced non-small-cell lung cancer (NSCLC) are needed. This randomized, phase II trial (n = 143) investigated volasertib monotherapy or in combination with pemetrexed compared with pemetrexed monotherapy in patients with NSCLC whose disease had progressed after previous platinum-based chemotherapy. The combination of volasertib with pemetrexed did not improve efficacy compared with pemetrexed monotherapy.Introduction: Volasertib is a potent, selective, cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. In this study we compared volasertib, volasertib with pemetrexed, and pemetrexed alone in patients with advanced non-small-cell lung cancer (NSCLC) whose disease progressed after first-line platinum-based chemotherapy. Patients and Methods: A run-in phase (n = 12) was used to determine whether volasertib could be combined in full dose with pemetrexed 500 mg/m(2). Subsequent patients were randomized to volasertib (n = 37), volasertib with pemetrexed (n = 47), orpemetrexed(n = 47) administered on day1 every 21days. Theprimary endpointwasprogression-free survival (PFS); secondary end points included objective response rate and pharmacokinetics. Results: Volasertib 300 mg was chosen for the randomized phase. Recruitment to single-agent volasertib was stopped early because of lack of efficacy. Median PFS was 5.3 months with pemetrexed compared with 3.3 months with volasertib with pemetrexed (hazard ratio [HR], 1.141; 95% confidence interval [CI], 0.73-1.771) and 1.4monthswith volasertib (HR, 2.045; 95% CI, 1.27-3.292). ORRs were 10.6% with pemetrexed, 21.3% for volasertib with pemetrexed, and 8.1% with volasertib. The most common all-grade related adverse events (pemetrexed/volasertib with pemetrexed/volasertib) were: fatigue (28 [61%]/27 [59%]/11 [31%]), nausea (21 [46%]/19 [41%]/0 [0%]), decreased apetite (14 [31%]/13 [28%]/2 [6%]), neutropenia (4 [9%]/8 [17%]/9 [25%]), rash (9 [20%]/8 [17%]/2 [6%]), vomiting (6 [13%]/13 [28%]/0 [0%]), and diarrhea (8 [17%]/11 [24%]/0 [0%]). Pharmacokinetics analyses showed no drug-drug interactions between volasertib and pemetrexed. Conclusion: For treatment in the second-line for advanced or metastatic NSCLC, the combination of volasertib with standard pemetrexed did not increase toxicity significantly but also did not improve efficacy compared with single-agent pemetrexed.