摘要

PURPOSE:This randomized, double-blind, placebo-controlled, phase IIb study evaluated adding sorafenib to first-line modified FOLFOX6 (mFOLFOX6) for metastatic colorectal cancer (mCRC).
EXPERIMENTAL DESIGN:Patients were randomized to sorafenib (400 mg b.i.d.) or placebo, combined with mFOLFOX6 (oxaliplatin 85 mg/m(2); levo-leucovorin 200 mg/m(2); fluorouracil 400 mg/m(2) bolus and 2400 mg/m(2) continuous infusion) every 14 days. Primary endpoint was progression-free survival (PFS). Target sample was 120 events in 180 patients for >85% power (two-sided α = 0.20) to detect an HR = 0.65.
RESULTS:Of 198 patients randomized, median PFS for sorafenib plus mFOLFOX6 was 9.1 months versus 8.7 months for placebo plus mFOLFOX6 (HR = 0.88; 95% CI, 0.64-1.23; P = 0.46). There was no difference between treatment arms for overall survival. Subgroup analyses of PFS and overall survival showed no difference between treatment arms by KRAS or BRAF status (mutant and wild type). The most common grade 3/4 adverse events in the sorafenib and placebo arms were neutropenia (48% vs. 22%), peripheral neuropathy (16% vs. 21%), and grade 3 hand-foot skin reaction (20% vs. 0%). Treatment discontinuation because of adverse events was 9% and 6%, respectively. Generally, dose intensity (duration and cumulative doses) was lower in the sorafenib arm than in the placebo arm.
CONCLUSION:This study did not detect a PFS benefit with the addition of sorafenib to first-line mFOLFOX6 for mCRC. KRAS and BRAF status did not seem to impact treatment outcomes but the subgroups were small. These results do not support further development of sorafenib in combination with mFOLFOX6 in molecularly unselected patients with mCRC.

译文

目的: 这项随机、双盲、安慰剂对照的 IIb 期研究评估了在转移性结直肠癌 (mCRC) 的一线改良 FOLFOX6 (mFOLFOX6) 中添加索拉非尼。
实验设计: 患者被随机分配到索拉非尼 (400 mg b 我。 d.) 或安慰剂，与 mFOLFOX6 (奥沙利铂 85 mg/m (2); 左旋-亚叶酸钙 200 mg/m (2); 氟尿嘧啶 400 mg/m (2) 推注和 2400 mg/m (2) 持续输注) 相结合每 14 天。主要终点是无进展生存期 (PFS)。目标样本是 120 例患者中的 180 个事件，功率> 85% (双面 α = 0.20)，以检测 HR = 0.65。
结果: 在 198 名随机患者中，索拉非尼加 mFOLFOX6 的中位 PFS 为 9.1 个月，而安慰剂加 mFOLFOX6 的中位 PFS 为 8.7 个月 (HR = 0.88; 95% CI，0.64-1.23; P = 0.46)。治疗组之间的总生存率没有差异。PFS 和总生存期的亚组分析显示，KRAS 或 BRAF 状态 (突变型和野生型) 的治疗组之间没有差异。索拉非尼和安慰剂组中最常见的 3/4 级不良反应是中性粒细胞减少 (48% 对 22%)，周围神经病变 (16% 对 21%), 和 3 级手足皮肤反应 (20% 对 0%)。因不良事件中断治疗的比例分别为 9% 和 6%。通常，索拉非尼组的剂量强度 (持续时间和累积剂量) 低于安慰剂组。
结论: 本研究未检测到在 mCRC 一线 mFOLFOX6 中加入索拉非尼对 PFS 的益处。KRAS 和 BRAF 状态似乎不影响治疗结果，但亚组较小。这些结果不支持索拉非尼联合 mFOLFOX6 在分子上未选择的 mCRC 患者中的进一步发展。