A Phase I/II Study Combining Erlotinib and Dasatinib for Non‐Small Cell Lung Cancer. (28th August 2014)

• Record Type: Journal Article
• Authors: Gold, Kathryn A.; Lee, J. Jack; Harun, Nusrat; Tang, Ximing; Price, Justina; Kawedia, Jitesh D.; Tran, Hai T.; Erasmus, Jeremy J.; Blumenschein, George R.; William, William N.; Wistuba, Ignacio I.; Johnson, Faye M.
• Is Part Of: Oncologist. Volume 19:Number 10(2014)
• Page Start: 1040
• Page End: 1041
• Publication Date: 2014-08-28
• Subjects: Oncology -- Periodicals; Tumors -- Periodicals; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Oncology; Tumors; Neoplasms; Electronic journals; Periodicals; Periodicals; 616.994
• DOI: 10.1634/theoncologist.2014-0228
• Languages: English
• ISSNs: 1083-7159

Abstract

Abstract : Background: EGFR and Src are frequently activated in non‐small cell lung cancer (NSCLC). In preclinical models, combining EGFR and Src inhibition has additive synergistic effects. We conducted a phase I/II trial of the combination of Src inhibitor dasatinib with EGFR inhibitor erlotinib to determine the maximum tolerated dose (MTD), pharmacokinetic drug interactions, biomarkers, and efficacy in NSCLC. Methods: The phase I 3+3 dose‐escalation study enrolled patients with solid tumors to determine the MTD. The phase II trial enrolled patients with advanced NSCLC who had undergone no previous treatments to determine progression‐free survival (PFS) and response. Pharmacokinetic and tissue biomarker analyses were performed. Results: MTD was 150 mg of erlotinib and 70 mg of dasatinib daily based on 12 patients treated in the phase I portion. No responses were observed in phase I. The 35 NSCLC patients treated in phase II had an overall disease control rate of 59% at 6 weeks. Five patients (15%) had partial responses; all had activating EGFR mutations. Median PFS was 3.3 months. Epithelial‐mesenchymal transition markers did not correlate with outcomes. Conclusion: The combination of erlotinib and dasatinib is safe and feasible in NSCLC. The results of this study do not support use of this combination in molecularly unselected NSCLC. Abstract : 摘要 背景 . 非小细胞肺癌（NSCLC）中表皮生长因子受体（EGFR）和Src常被激活。在临床前模型中，联合EGFR和Src抑制剂具有加成协同效应。我们开展了一项I/II期临床试验，旨在确定Src抑制剂达沙替尼联合EGFR抑制剂厄洛替尼用于治疗NSCLC患者的最大耐受剂量（MTD）、药物间药动学相互作用、生物标记物和有效性。 方法 . I期阶段为3+3剂量递增研究，纳入实体肿瘤患者以确定MTD。II期试验纳入既往未接受治疗的进展期NSCLC患者，以确定无进展生存（PFS）和缓解情况。研究还进行了药动学和组织生物标记物分析。 结果 . 依据I期试验中12例患者的数据，厄洛替尼MTD为150 mg/d，达沙替尼为70 mg/d在I期试验中未观察到缓解。II期试验中接受治疗的35例NSCLC患者6周时总疾病控制率为59%。5例患者（15%）为部分缓解，均存在 EGFR 激活突变。中位PFS为3.3个月。上皮‐间质细胞转化标记物与转归无相关性。 结论 . 使用厄洛替尼与达沙替尼联合方案治疗NSCLC是安全和可行的。本研究结果不支持这一联合方案用于未经分子选择的NSCLC。 The Oncologist 2014;19: 1040‐1041