Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030-4009, USA.
Lancet Oncol. 2010 Jul;11(7):619-26. doi: 10.1016/S1470-2045(10)70132-7.
Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC).
Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB-IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m(2) intravenously every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov, number NCT00312377.
1391 patients received vandetanib plus docetaxel (n=694 [197 women]) or placebo plus docetaxel (n=697 [224 women]). Vandetanib plus docetaxel led to a significant improvement in PFS versus placebo plus docetaxel (hazard ratio [HR] 0.79, 97.58% CI 0.70-0.90; p<0.0001); median PFS was 4.0 months in the vandetanib group versus 3.2 months in placebo group. A similar improvement in PFS with vandetanib plus docetaxel versus placebo plus docetaxel was seen in women (HR 0.79, 0.62-1.00, p=0.024); median PFS was 4.6 months in the vandetanib group versus 4.2 months in the placebo group. Among grade 3 or higher adverse events, rash (63/689 [9%] vs 7/690 [1%]), neutropenia (199/689 [29%] vs 164/690 [24%]), leukopenia (99/689 [14%] vs 77/690 [11%]), and febrile neutropenia (61/689 [9%] vs 48/690 [7%]) were more common with vandetanib plus docetaxel than with placebo plus docetaxel. The most common serious adverse event was febrile neutropenia (46/689 [7%] in the vandetanib group vs 38/690 [6%] in the placebo group).
The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy.
凡德他尼是一种每日一次的口服血管内皮生长因子受体（VEGFR）、表皮生长因子受体（EGFR）和转染重排（RET）酪氨酸激酶抑制剂。在一项针对先前治疗过的非小细胞肺癌（NSCLC）患者的随机 2 期研究中，与单独使用多西他赛相比，凡德他尼 100mg 联合多西他赛显著改善了无进展生存期（PFS），包括女性患者的 PFS 更长。这些结果支持了在这项更大规模的、明确的 3 期试验（ZODIAC）中对联合用药的研究。
在 2006 年 5 月至 2008 年 4 月期间，在一线化疗后进展的局部晚期或转移性（IIIb-IV 期）NSCLC 患者通过第三方交互式语音系统随机 1:1 分配，接受凡德他尼（100mg/天）联合多西他赛（75mg/m2 静脉注射，每 21 天一次；最多 6 个周期）或安慰剂联合多西他赛。主要目的是比较两组在意向治疗人群中的 PFS。女性是一个主要分析人群。该研究已经完成，并在 ClinicalTrials.gov 注册，编号为 NCT00312377。
共有 1391 名患者接受了凡德他尼联合多西他赛（n=694[197 名女性]）或安慰剂联合多西他赛（n=697[224 名女性]）治疗。与安慰剂联合多西他赛相比，凡德他尼联合多西他赛显著改善了 PFS（风险比[HR]0.79，97.58%CI0.70-0.90；p<0.0001）；凡德他尼组的中位 PFS 为 4.0 个月，安慰剂组为 3.2 个月。在女性中，凡德他尼联合多西他赛与安慰剂联合多西他赛相比，PFS 也有类似的改善（HR0.79，0.62-1.00，p=0.024）；凡德他尼组的中位 PFS 为 4.6 个月，安慰剂组为 4.2 个月。在 3 级或更高的不良事件中，皮疹（63/689[9%]vs7/690[1%]）、中性粒细胞减少症（199/689[29%]vs164/690[24%]）、白细胞减少症（99/689[14%]vs77/690[11%]）和发热性中性粒细胞减少症（61/689[9%]vs48/690[7%]）在凡德他尼联合多西他赛组比安慰剂联合多西他赛组更常见。最常见的严重不良事件是发热性中性粒细胞减少症（凡德他尼组 46/689[7%]vs安慰剂组 38/690[6%]）。
凡德他尼联合多西他赛可显著改善一线治疗后进展的晚期 NSCLC 患者的 PFS。
