Department of Thoracic Oncology and Biostatistics, Clinical Trials and Clinical Pharmacology Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612-9497, USA.
J Clin Oncol. 2010 Mar 10;28(8):1387-94. doi: 10.1200/JCO.2009.25.4029. Epub 2010 Feb 8.
Src family kinase (SFK) proteins are frequently activated in cancer and can coordinate tumor cell growth, survival, invasion, and angiogenesis. Given the importance of SFK signaling in cancer, known cooperation between SFK and epidermal growth factor receptor (EGFR) signaling, and efficacy of EGFR inhibitors, we performed a phase I trial combining dasatinib, an SFK and multikinase inhibitor, with erlotinib, an EGFR inhibitor, in patients with advanced non-small-cell lung cancer.
Patients received erlotinib for 1 week before addition of dasatinib; pharmacokinetics were performed after weeks 1 and 2. Four cohorts were examined, including twice-daily and daily dasatinib dosing. Responses were assessed after 8 weeks. Plasma levels of angiogenic markers (vascular endothelial growth factor [VEGF], interleukin-8, and basic fibroblast growth factor [bFGF]) were determined before and during treatment.
Thirty-four patients were enrolled. The average duration of treatment was 73 days. The main adverse events include GI (diarrhea, anorexia, and nausea), skin rash, cytopenias, pleural effusions, and fatigue. No effect of escalating doses of dasatinib was observed on erlotinib pharmacokinetics. Two partial responses and one bone response were observed, and the disease control rate was 63%. Reductions in plasma VEGF and bFGF were observed, and reductions in VEGF correlated with disease control.
The combination of erlotinib and dasatinib is tolerable, with adverse effects consistent with the two agents. Disease control and inhibition of plasma angiogenesis markers were observed. Personalized strategies for deployment of SFK should receive further attention.
Src 家族激酶 (SFK) 蛋白在癌症中经常被激活，能够协调肿瘤细胞的生长、存活、侵袭和血管生成。鉴于 SFK 信号在癌症中的重要性、SFK 与表皮生长因子受体 (EGFR) 信号之间的已知合作关系以及 EGFR 抑制剂的疗效，我们在晚期非小细胞肺癌患者中进行了一项 I 期试验，将 SFK 和多激酶抑制剂 dasatinib 与 EGFR 抑制剂 erlotinib 联合使用。
患者在加用 dasatinib 前先接受 erlotinib 治疗 1 周；在第 1 和第 2 周后进行药代动力学检查。检查了四个队列，包括每日两次和每日 dasatinib 剂量。在 8 周后评估反应。在治疗前和治疗期间测定血管生成标志物（血管内皮生长因子 [VEGF]、白细胞介素-8 和碱性成纤维细胞生长因子 [bFGF]）的血浆水平。
共纳入 34 例患者。平均治疗时间为 73 天。主要不良事件包括胃肠道（腹泻、厌食和恶心）、皮疹、血细胞减少、胸腔积液和疲劳。未观察到 dasatinib 剂量递增对 erlotinib 药代动力学的影响。观察到 2 例部分缓解和 1 例骨反应，疾病控制率为 63%。观察到血浆 VEGF 和 bFGF 减少，VEGF 减少与疾病控制相关。
厄洛替尼和 dasatinib 的联合使用是可耐受的，不良反应与两种药物一致。观察到疾病控制和抑制血浆血管生成标志物。应进一步关注 SFK 的个体化应用策略。
