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.

 描述（由适用提供）：Erlotinib是与表皮生长因子受体（EGFR）结合的酪氨酸激酶抑制剂（TKI）。 Erlotinib是一种非常有效的治疗剂，通常被处方为非小细胞肺癌（NSCLC）的一线治疗，前提是患者具有EGFR的“激活”突变。但是，erlotinib在所有NSCLC中都没有有效，并且具有激活突变。我们先前使用示踪剂11C-羟基洛替尼向PET成像展示了，EGFR的激酶结构域的突变传达了对Erlotinib的敏感性。不幸的是，即使最初有效，EGFR TKI的治疗最终让位 获得耐药性。目前，无法预测何时会发生阻力。当这样做时，我们不知道在所有肿瘤部位的抗性机制是否等效。使用PET，我们有能力成像具有突变体EGFR的肿瘤中厄洛替尼与其靶位点结合的程度。了解患者的厄洛替尼结合状态可能对医生预测治疗成功和做出治疗决策很有用。 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.本研究的短期目标旨在为未来的临床试验奠定基础，以测试是否了解11C-羟基洛丁替尼的状态会改变患者的预后。本试验研究的目标是：（1）确定在新诊断的NSCLC中最能区分EGFR突变体与EGFR野生型肿瘤的特定结合阈值； （2）确定在获得性抗性时11C-羟基洛替尼特异性结合的患者之间的变异性。如果在疾病表现中可以鉴定出对单独患者的阈值，并且该试验研究可以证实各种抵抗患者的变异性，那么在随后的临床试验中，这两种措施都应在改善患者预后的随后临床试验中进行更详细的评估。我们还将追求探索目标。这些目的是（a）确定PET成像分析方法对误差的敏感性，（b）获得有关疾病呈现时厄洛替尼结合的预测价值的初步数据，以及（c）评估EGFR Mutant NSCLC和大脑转移酶的患者中11C-氯洛氏菌的可用性。