Validation of Quantitative 11C-Erlotinib PET for Imaging EGFR-Mutant Lung Cancer

定量 11C-厄洛替尼 PET 对 EGFR 突变肺癌成像的验证

• 批准号: 9070650
• 负责人: Joseph N. Contessa
• 金额: $ 25.77万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-19 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070650
• 关键词: 2-tyrosine; Animal Model; Binding; Biological Markers; Blood - brain barrier anatomy; Cancer Patient; Clinical; Clinical Trials; Data; Data Analyses; Dependence; Diagnosis; Disease; Disease Progression; Drug Interactions; Drug effect disorder; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Foundations; Future; Goals; Health; Heterogeneity; Image; Image Analysis; Kinetics; Knowledge; Lung; Malignant neoplasm of lung; Measures; Metastatic malignant neoplasm to brain; Methodology; Methods; Modeling; Molecular Target; Muscle; Mutation; Neoplasm Metastasis; Newly Diagnosed; Non-Small-Cell Lung Carcinoma; Oncologist; Patient-Focused Outcomes; Patients; Phosphotransferases; Physicians; Pilot Projects; Positron-Emission Tomography; Predictive Value; Reporting; Research; Research Design; Resistance; Site; Testing; Therapeutic Agents; Tracer; Tyrosine Kinase Inhibitor; Validation; Work; acquired drug resistance; antitumor drug; base; chemotherapy; clinical decision-making; comparative; design; drug efficacy; effective therapy; experience; improved; individual patient; mutant; novel; outcome forecast; patient population; pre-clinical; predictive marker; prognostic; radiotracer; resistance mechanism; response; small molecule inhibitor; soft tissue; success; targeted treatment; therapy outcome; therapy resistant; tool; treatment strategy; tumor

 DESCRIPTION (provided by applicant): Erlotinib is a tyrosine kinase inhibitor (TKI) that binds to the epidermal growth factor receptor (EGFR). Erlotinib is an extremely effective therapeutic agent and is commonly prescribed as a first-line therapy for non-small cell lung cancer (NSCLC) provided that patients have an "activating" mutation of EGFR. However, erlotinib is not effective in all NSCLC with activating mutations. We have shown previously with PET imaging using the tracer 11C-erlotinib that only mutations of the kinase domain of EGFR convey sensitivity to erlotinib. Unfortunately even if initially effective, treatment with EGFR TKIs eventually gives way to acquired drug resistance. At present, there is no way to predict when resistance will occur. When it does, we do not know if the mechanism of resistance is equivalent at all tumor sites. With PET, we have the power to image the degree of erlotinib binding to its target site in tumors with mutant EGFR. Knowing the erlotinib-binding status of patients could be useful to physicians for predicting treatment success and for making treatment decisions. Our long term goals are to conduct a clinical trial to determine (a) if 11C-erlotinib imaging status at disease presentation i prognostic or if it can be used as a predictive biomarker for the depth or duration of response to erlotinib, and (b) if knowledge of the heterogeneity of 11C-erlotinib binding at the onset of EGFR TKI resistance can improve patient outcomes. The short term goals of the present study are designed to lay the foundation for a future clinical trial to test if knowing 11C-erlotinib status changes patient outcomes. The goals of the present pilot study are, (1) to determine the specific binding threshold that best differentiates EGFR mutant from EGFR wild-type tumors in newly diagnosed NSCLC; and (2) to determine the variability across patients in 11C- erlotinib specific binding at acquired resistance. If a threshold to separate patients can be identified at disease presentation, and variability across patients at resistance can be confirmed by this pilot study, then both measures will deserve to be evaluated in greater detail in a subsequent clinical trial for their respective values in improving patient outcomes. We will also pursue exploratory aims. These aims focus on (a) determining the sensitivity of the PET imaging analysis methods to error, (b) gaining preliminary data on the predictive value of erlotinib binding at disease presentation, and (c) evaluating the availability of 11C-erlotinib in patients with EGFR mutant NSCLC and brain metastases.

 说明(申请人提供)：厄洛替尼是一种酪氨酸激酶抑制剂(TKI)，可与表皮生长因子受体(EGFR)结合。厄洛替尼是一种非常有效的治疗药物，通常被用作非小细胞肺癌(NSCLC)的一线治疗药物，前提是患者的EGFR基因发生了“激活”突变。然而，厄洛替尼并不是对所有有激活突变的非小细胞肺癌都有效。我们之前已经使用示踪剂11C-erlotinib进行了PET成像，表明只有EGFR的激酶域的突变才能传递对erlotinib的敏感性。不幸的是，即使最初有效，EGFR TKIs的治疗最终也会失败 与获得性抗药性有关。目前还无法预测何时会出现阻力。当它发生时，我们不知道是否所有肿瘤部位的耐药机制都是相同的。通过正电子发射计算机断层扫描，我们有能力在带有突变的EGFR的肿瘤中成像厄洛替尼与其目标位置的结合程度。了解患者的厄洛替尼结合状态可能有助于医生预测治疗成功和做出治疗决定。我们的长期目标是进行一项临床试验，以确定(A)11C-erlotinib显像状态是否可以预测预后，或者它是否可以作为对erlotinib反应的深度或持续时间的预测生物标志物，以及(B)了解11C-erlotinib在EGFR TKI耐药开始时结合的异质性是否可以改善患者的预后。本研究的短期目标旨在为未来的临床试验奠定基础，以测试了解11C-erlotinib状态是否会改变患者的预后。目前这项先导性研究的目标是：(1)确定在新诊断的NSCLC中最能区分EGFR突变和EGFR野生型肿瘤的特异性结合阈值；(2)确定获得性耐药时11C-erlotinib特异性结合的患者之间的变异性。如果可以在疾病表现时确定区分患者的阈值，并且可以通过这项先导性研究证实抵抗患者之间的可变性，那么这两种方法都值得在随后的临床试验中更详细地评估它们在改善患者预后方面的各自价值。我们还将追求探索性目标。这些目标集中在(A)确定PET成像分析方法对错误的敏感性，(B)获得关于erlotinib结合在疾病表现时的预测价值的初步数据，以及(C)评估11C-erlotinib在EGFR突变的NSCLC和脑转移患者中的可用性。