西地尼布联合 mFOLFOX6 对比贝伐珠单抗联合 mFOLFOX6 一线治疗晚期结直肠癌的双盲、随机 III 期研究（HORIZON III）。

Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III).

机构信息

Department of Internal Medicine IV, Hematology & Oncology, University Clinic Halle (Saale), Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany.

出版信息

J Clin Oncol. 2012 Oct 10;30(29):3588-95. doi: 10.1200/JCO.2012.42.5355. Epub 2012 Sep 10.

DOI:10.1200/JCO.2012.42.5355

PMID:22965961

Abstract

PURPOSE

To compare the efficacy of cediranib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor [VEGFR TKI]) with that of bevacizumab (anti-VEGF-A monoclonal antibody) in combination with chemotherapy as first-line treatment for advanced metastatic colorectal cancer (mCRC).

PATIENTS AND METHODS

HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer] had an adaptive phase II/III design. Patients randomly assigned 1:1:1 received mFOLFOX6 [oxaliplatin 85 mg/m(2) and leucovorin 400 mg/m(2) intravenously followed by fluorouracil 400 mg/m(2) intravenously on day 1 and then continuous infusion of 2,400 mg/m(2) over the next 46 hours every 2 weeks] with cediranib (20 or 30 mg per day) or bevacizumab (5 mg/kg every 14 days). An independent end-of-phase II analysis concluded that mFOLFOX6/cediranib 20 mg met predefined criteria for continuation; subsequent patients received mFOLFOX6/cediranib 20 mg or mFOLFOX6/bevacizumab (randomly assigned 1:1). The primary objective was to compare progression-free survival (PFS).

RESULTS

In all, 1,422 patients received mFOLFOX6/cediranib 20 mg (n = 709) or mFOLFOX6/bevacizumab (n = 713). Primary analysis revealed no significant difference between arms for PFS (hazard ratio [HR], 1.10; 95% CI, 0.97 to 1.25; P = .119), overall survival (OS; HR, 0.95; 95% CI, 0.82 to 1.10; P = .541), or overall response rate (46.3% v 47.3%). Median PFS and OS were 9.9 and 22.8 months for mFOLFOX6/cediranib and 10.3 and 21.3 months for mFOLFOX6/bevacizumab. The PFS upper 95% CI was outside the predefined noninferiority limit (HR < 1.2). Common adverse events with more than 5% incidence in the cediranib arm included diarrhea, neutropenia, and hypertension. Cediranib-treated patients completed fewer chemotherapy cycles than bevacizumab-treated patients (median 10 v 12 cycles). Patient-reported outcomes (PROs) were significantly less favorable in cediranib-treated versus bevacizumab-treated patients (P < .001).

CONCLUSION

Cediranib activity, in terms of PFS and OS, was comparable to that of bevacizumab when added to mFOLFOX6; however, the predefined boundary for PFS noninferiority was not met. The cediranib safety profile was consistent with previous studies but led to less favorable PROs compared with bevacizumab. Investigation of oral TKIs in CRC continues.

摘要

目的

比较西地尼布（血管内皮生长因子受体酪氨酸激酶抑制剂[VEGFR TKI]）联合化疗与贝伐单抗（抗 VEGF-A 单克隆抗体）作为晚期转移性结直肠癌（mCRC）一线治疗的疗效。

方法

HORIZON III[西地尼布联合 FOLFOX6 对比贝伐单抗联合 FOLFOX6 治疗未经治疗的转移性结直肠癌患者]采用适应性 II/III 期设计。患者随机按 1:1:1 接受 mFOLFOX6[奥沙利铂 85mg/m²和亚叶酸钙 400mg/m²静脉推注，然后氟尿嘧啶 400mg/m²静脉推注，第 1 天，然后连续输注 2400mg/m²，每 2 周 46 小时]联合西地尼布（每天 20 或 30mg）或贝伐单抗（每 14 天 5mg/kg）。独立的 II 期终点分析得出结论，mFOLFOX6/西地尼布 20mg 符合继续治疗的预设标准；随后的患者接受 mFOLFOX6/西地尼布 20mg 或 mFOLFOX6/贝伐单抗（随机分配 1:1）。主要目的是比较无进展生存期（PFS）。

结果

共有 1422 例患者接受 mFOLFOX6/西地尼布 20mg（n=709）或 mFOLFOX6/贝伐单抗（n=713）治疗。主要分析显示，两组 PFS 无显著差异（风险比[HR]，1.10；95%CI，0.97 至 1.25；P=0.119）、总生存期（OS；HR，0.95；95%CI，0.82 至 1.10；P=0.541）或总缓解率（46.3%比 47.3%）。mFOLFOX6/西地尼布和 mFOLFOX6/贝伐单抗的中位 PFS 和 OS 分别为 9.9 和 22.8 个月和 10.3 和 21.3 个月。PFS 上限 95%CI 超出了预设的非劣效性界限（HR<1.2）。西地尼布组发生率超过 5%的常见不良反应包括腹泻、中性粒细胞减少和高血压。接受西地尼布治疗的患者完成的化疗周期数少于接受贝伐单抗治疗的患者（中位数 10 与 12 个周期）。与接受贝伐单抗治疗的患者相比，接受西地尼布治疗的患者的患者报告结局（PROs）明显较差（P<0.001）。