A Phase Ib, Dose-Finding Study of Erlotinib in Combination With a Fixed Dose of Pertuzumab in Patients With Advanced Non Small-Cell Lung Cancer
A Phase Ib, Dose-Finding Study of Erlotinib in Combination With a Fixed Dose of Pertuzumab in Patients With Advanced Non Small-Cell Lung Cancer
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DOI：
10.1016/j.cllc.2012.03.004
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发表时间：
2012-11-01
影响因子：
3.6
通讯作者：
Galdermans, Danny
中科院分区：
文献类型：
--
作者：
Felip, Enriqueta;Ranson, Malcolm;Galdermans, Danny
帕妥珠单抗是一种人表皮生长因子受体2二聚体抑制剂，已在非小细胞肺癌中显示出药效学活性。在一项1b期研究中，15例化疗失败的IIIb/IV期非小细胞肺癌患者接受了厄洛替尼，随后接受了厄洛替尼和帕妥珠单抗的联合治疗。这种组合有令人鼓舞的疗效，并没有影响erlotinib.Background的药代动力学：帕妥珠单抗，二聚体抑制剂的人表皮生长因子受体2（HER 2），已被证明具有药效学活性，与稳定的疾病在非小细胞肺癌。联合厄洛替尼和帕妥珠单抗可增强抗肿瘤活性。本研究旨在确定厄洛替尼和帕妥珠单抗联合给药的推荐剂量;评估安全性、初步疗效和药代动力学;并分析生物标志物。患者和方法：招募了15例化疗失败的IIIb/IV期非小细胞肺癌患者。患者接受厄洛替尼（第-8天至-1天），然后接受联合治疗（21天为1个周期，共6个周期）。帕妥珠单抗以840 mg静脉内给药，然后每三周一次420 mg，厄洛替尼每日给药（100或150 mg）。结果：未观察到剂量限制性毒性。不良事件通常为1/2级，可管理。客观缓解率为20%（3/15例患者; 2例缓解者为突变型HER 1，1例缓解者为野生型HER 1），中位总无进展生存期为9.3周。高HER 1、HER 2和HER 3信使RNA表达与无进展生存期增加相关。联合治疗不影响厄洛替尼的药代动力学;然而，帕妥珠单抗的平均暴露量（最大浓度，231 mg/L; 0 - 21天浓度-时间曲线下面积，1780 mg*d/L）略高于既往研究。结论：联合治疗在体能状态良好的患者中耐受性良好，疗效令人鼓舞。负荷剂量帕妥珠单抗840 mg，随后420 mg，每3周一次，加每日厄洛替尼150 mg似乎是该联合治疗的最合适方案。
Pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, has demonstrated pharmacodynamic activity in non-small-cell lung cancer. In a phase 1b study, 15 patients with stage IIIb/IV non-small-cell lung cancer who had failed chemotherapy received erlotinib followed by combination therapy that comprised erlotinib and pertuzumab. This combination had encouraging efficacy and did not affect the pharmacokinetics of erlotinib.Background: Pertuzumab, a dimerization inhibitor of human epidermal growth factor receptor 2 (HER2), has demonstrated pharmacodynamic activity, with stable disease in non-small-cell lung cancer. Combining erlotinib and pertuzumab may enhance antitumor activity. This study aimed to establish the recommended dosing of the erlotinib and pertuzumab combination; assess safety, preliminary efficacy, and pharmacokinetics; and analyze biomarkers. Patients and Methods: Fifteen patients with stage IIIb/IV non-small-cell lung cancer who failed chemotherapy were recruited. The patients received erlotinib (days -8 to -1), then combination therapy (21-day cycles for 6 cycles). Pertuzumab was given intravenous at 840 mg, then 420 mg once every three weeks, with erlotinib given daily (100 or 150 mg). Results: No dose-limiting toxicities were observed. Adverse events were generally grade 1/2 and manageable. The objective response rate was 20% (3/15 patients; 2 responders had mutant HER1, 1 responder had wild-type HER1), median overall progression-free survival was 9.3 weeks. High HER1, HER2, and HER3 messenger RNA expression correlated with increased progression-free survival. Combination therapy did not affect erlotinib's pharmacokinetics; however, pertuzumab mean exposures (maximum concentration, 231 mg/L; area under the concentration-time curve from 0 to 21 days, 1780 mg*d/L) were slightly higher than in previous studies. Conclusions: Combination therapy was well tolerated in patients with good performance status, with encouraging efficacy. A loading dose of pertuzumab 840 mg followed by 420 mg once every three weeks plus daily erlotinib 150 mg appears to be the most appropriate regimen for this combination.