University of Chicago Comprehensive Cancer Center, Chicago, IL 60637, USA.
Lancet Oncol. 2011 Mar;12(3):256-62. doi: 10.1016/S1470-2045(11)70004-3.
Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial.
In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m(2) intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146.
Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]).
The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease.
Pfizer.
阿昔替尼是一种强效、选择性的血管内皮生长因子（VEGF）受体 1、2 和 3 的抑制剂。一项吉西他滨联合或不联合阿昔替尼治疗晚期胰腺癌的随机 2 期试验表明，阿昔替尼治疗组的总生存期延长。基于这些结果，我们旨在评估吉西他滨联合阿昔替尼治疗在 3 期试验中的总体生存效果。
在这项双盲、安慰剂对照、3 期研究中，符合条件的患者患有转移性或局部晚期胰腺腺癌，无未控制的高血压或静脉血栓形成，东部合作肿瘤学组表现状态 0 或 1。根据疾病程度（转移性与局部晚期），患者被随机分配（1:1）接受吉西他滨 1000mg/m²静脉注射，每 28 天一次，第 1、8 和 15 天，联合阿昔替尼或安慰剂。阿昔替尼或安慰剂与食物一起口服，起始剂量为 5mg，每日两次，如果耐受良好，可以滴定至 10mg，每日两次。采用中央随机化程序按分层随机分配患者至各治疗组。患者、研究者和试验赞助商对治疗分配均不知情。主要终点为总生存期。所有疗效分析均针对有数据可用于分析的所有接受治疗的患者进行；安全性和治疗管理以及依从性评估基于接受的治疗。这项研究在 ClinicalTrials.gov 注册，编号为 NCT00471146。
2007 年 7 月 27 日至 2008 年 10 月 31 日期间，共有 632 名患者入组并被分配至治疗组（阿昔替尼组 316 名，安慰剂组 316 名）。在 2009 年 1 月的中期分析中，独立数据监测委员会得出结论，无效边界已被跨越。吉西他滨联合阿昔替尼组的中位总生存期为 8.5 个月（95%CI 6.9-9.5）（n=314，两名患者的数据缺失），吉西他滨联合安慰剂组为 8.3 个月（6.9-10.3）（n=316；风险比 1.014，95%CI 0.786-1.309；单侧 p=0.5436）。吉西他滨联合阿昔替尼组和吉西他滨联合安慰剂组最常见的 3 级或更高级别的不良事件分别为高血压（20 [7%]和 5 [2%]事件）、腹痛（20 [7%]和 17 [6%]）、疲劳（27 [9%]和 21 [7%]）和厌食（19 [6%]和 11 [4%]）。
阿昔替尼联合吉西他滨不能改善晚期胰腺癌患者的总生存期。这些结果进一步证明，针对 VEGF 信号的靶向治疗在这种疾病中是无效的策略。
辉瑞公司。
