Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Am J Clin Oncol. 2010 Dec;33(6):614-8. doi: 10.1097/COC.0b013e3181c4454d.
Sunitinib is an oral, multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors with proven clinical benefit in patients with metastatic renal cell carcinoma (RCC). This phase I/II study investigated sunitinib in combination with an epidermal growth factor receptor inhibitor, gefitinib, in patients with metastatic RCC.
In phase I, patients received sunitinib 37.5 or 50 mg in 6-week cycles (4 weeks on treatment, 2 off) plus gefitinib 250 mg, both once daily, to determine the sunitinib maximum tolerated dose (MTD). Pharmacokinetics was assessed for both drugs. In phase II, patients received sunitinib MTD plus gefitinib to evaluate the safety and antitumor activity of this combination.
Forty-two patients were enrolled: 11 in phase I, and 31 in phase II. In phase I, 2 dose-limiting toxicities were observed with sunitinib 50 mg (grade 2 left ventricular ejection fraction decline and grade 3 fatigue), and 37.5 mg was declared the MTD. Thirteen patients treated at the MTD achieved a partial response (objective response rate: 37%; 95% confidence interval, 22-55) and 12 (34%) had stable disease. Median progression-free survival was 11 months (95% confidence interval, 6-17). The most commonly reported grade 3/4 treatment-related adverse event was diarrhea (14%), the only grade 3/4 adverse event to occur in >2 patients. Pharmacokinetic analyses did not indicate any drug-drug interactions.
In metastatic RCC, sunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapy with an acceptable safety profile. Dosing, pharmacokinetic profile, and safety support study of sunitinib plus an epidermal growth factor receptor inhibitor in other tumor types.
舒尼替尼是一种口服的、多靶点的酪氨酸激酶抑制剂，可抑制血管内皮生长因子和血小板衍生生长因子受体，已被证明对转移性肾细胞癌（RCC）患者具有临床益处。本Ⅰ/Ⅱ期研究探讨了舒尼替尼联合表皮生长因子受体抑制剂吉非替尼治疗转移性 RCC 患者的疗效。
在Ⅰ期研究中，患者接受舒尼替尼 37.5 或 50mg 治疗，每 6 周为一个周期（4 周治疗，2 周停药），同时每日一次给予吉非替尼 250mg，以确定舒尼替尼的最大耐受剂量（MTD）。评估了两种药物的药代动力学。在Ⅱ期研究中，患者接受舒尼替尼 MTD 联合吉非替尼治疗，以评估该联合方案的安全性和抗肿瘤活性。
共纳入 42 例患者：Ⅰ期 11 例，Ⅱ期 31 例。Ⅰ期研究中，舒尼替尼 50mg 组观察到 2 例剂量限制毒性（2 级左心室射血分数下降和 3 级疲劳），37.5mg 被确定为 MTD。13 例接受 MTD 治疗的患者获得部分缓解（客观缓解率：37%；95%置信区间，22-55），12 例（34%）病情稳定。中位无进展生存期为 11 个月（95%置信区间，6-17）。最常见的 3/4 级治疗相关不良事件是腹泻（14%），只有 2 例以上患者发生 3/4 级不良事件。药代动力学分析未显示任何药物相互作用。
在转移性 RCC 中，舒尼替尼联合吉非替尼的疗效与舒尼替尼单药治疗相当，且安全性可接受。舒尼替尼联合表皮生长因子受体抑制剂在其他肿瘤类型中的研究需要进一步确定剂量、药代动力学特征和安全性。
