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

 性状（由申请方提供）：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，通常作为非小细胞肺癌（NSCLC）的一线治疗药物，前提是患者具有EGFR的“激活”突变。然而，厄洛替尼并不是对所有有激活突变的NSCLC都有效。我们以前用示踪剂11 C-厄洛替尼的PET成像表明，只有EGFR激酶结构域的突变才能传递对厄洛替尼的敏感性。不幸的是，即使最初有效，EGFR TKI治疗最终也会失败 获得性耐药性的可能性目前，没有办法预测何时会出现阻力。当它发生时，我们不知道耐药机制是否在所有肿瘤部位都是等效的。通过PET，我们有能力成像厄洛替尼与突变EGFR肿瘤靶位点结合的程度。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策。我们的长期目标是进行临床试验，以确定（a）疾病表现时的11 C-厄洛替尼成像状态是否具有预后性，或其是否可用作厄洛替尼应答深度或持续时间的预测性生物标志物，以及（B）EGFR TKI耐药发作时11 C-厄洛替尼结合异质性的知识是否可改善患者结局。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11 C-厄洛替尼状态是否会改变患者的结局。本初步研究的目的是：（1）确定最能区分新诊断NSCLC中EGFR突变体与EGFR野生型肿瘤的特异性结合阈值;（2）确定获得性耐药时11 C-厄洛替尼特异性结合在患者间的变异性。如果可以在疾病表现时确定分离患者的阈值，并且可以通过该初步研究证实耐药患者之间的变异性，那么这两种措施将值得在随后的临床试验中更详细地评估其各自在改善患者结局方面的价值。我们还将继续探索目标。这些目标集中于（a）确定PET成像分析方法对误差的敏感性，（B）获得疾病表现时厄洛替尼结合的预测价值的初步数据，以及（c）评价11 C-厄洛替尼在EGFR突变型NSCLC和脑转移患者中的可用性。

 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.