Biomarkers of Response to Immuno-chemotherapy & oliGometastatic Hypofractionated radioTherapy (BRIGHT) for Lung Cancer: Synergy of PET/CT Imaging and Peripheral Blood Assays

摘要 转移性非小细胞肺癌（NSCLC）患者的管理需要导航 日益多样化的治疗景观。虽然抗程序化免疫检查点抑制剂（ICI） 细胞死亡1（PD 1）及其配体PDL 1与化疗（chemoICI）联合治疗是 转移性NSCLC，并在一些患者中改善了生存期，但大多数受治疗相关性 严重的经济负担，几乎没有临床益处。放射治疗可以延长 转移性疾病（寡转移性）部位有限或疾病进展部位有限的患者 （寡进展），但对于哪些患者和病变将受益，尚未达成共识 辐射。通过早期反应评估进行患者选择和治疗适应性是一个未满足的要求。 需要增加化疗，免疫治疗和放射治疗的有效组合， 转移性NSCLC并改善结局。生物标志物对我们理解复杂反应至关重要 化学ICI和辐射的模式。在开始化疗ICI的新诊断转移性NSCLC患者中， 治疗标准，我们建议通过结合正电子发射来评估和监测治疗反应， 肉眼可见疾病负荷的断层扫描（PET）成像和隐匿性肿瘤的循环免疫学生物标志物 通过以下目标支持精确治疗的全身疾病负担：（1）构建临床PET 对风险分层的化学ICI反应模式的成像和循环免疫生物标志物特征 （a）早期广泛进展，（B）寡进展，和（c）反应性疾病;（2）构建 临床PET成像和循环免疫生物标志物标记的寡渐进放射治疗 反应模式，以识别受益于消融辐射的患者和病变;以及（3） 临床PET成像和全球循环免疫生物标志物与生存结局。 将在化学ICI之前进行氟脱氧葡萄糖（FDG）PET扫描和外周血抽取，3 化疗后12周，化疗后12周。对于发生进展性疾病的患者，我们将 在放射治疗前和放射治疗后1个月采集FDG PET扫描和外周血。我们将开发 联合定量PET成像和化学ICI的循环免疫生物标志物特征， 将患者分为以下组的放射反应：（i）预测发展为 需要积极的二线全身治疗的快速广泛进展性疾病，（ii）中度风险 预计发生寡进展性疾病的患者，需要对高风险病变进行巩固放射治疗 目标，（iii）预测对一线治疗具有持久长期反应的低风险患者。成功 该项目的完成将支持启动生物标志物反应适应性化学ICI的临床试验 转移性非小细胞肺癌患者的放射治疗，以改善癌症控制 和生存。

ABSTRACT Management of patients with metastatic non-small cell lung cancer (NSCLC) requires navigation of an increasingly diverse therapeutic landscape. Although immune checkpoint inhibitors (ICI) of anti-programmed cell death 1 (PD1) and its ligand PDL1, in combination with chemotherapy (chemoICI), are standard of care for metastatic NSCLC and have improved survival in some patients, the majority are subject to treatment-related toxicity at significant financial burden with little clinical benefit. Radiation therapy can prolong survival in patients with limited sites of metastatic disease (oligometastatic), or limited sites of progressive disease (oligoprogression) on systemic therapy, but no consensus exists on which patients and lesions would benefit from irradiation. Patient selection and treatment adaptation through early response assessment is an unmet need to increase the effective combination of chemotherapy, immunotherapy, and radiation therapy in metastatic NSCLC and improve outcomes. Biomarkers are critical to our understanding of complex response patterns to chemoICI and radiation. In patients with newly diagnosed metastatic NSCLC starting chemoICI per standard of care, we propose to assess and monitor treatment response by combining positron emission tomography (PET) imaging of macroscopic disease burden and circulating immunologic biomarkers of occult systemic disease burden in support of precision therapy through the following aims: (1) construct clinical PET imaging and circulating immunologic biomarker signatures of chemoICI response patterns to risk stratify patients into (a) early widespread progression, (b) oligoprogression, and (c) responsive disease; (2) construct clinical PET imaging and circulating immunologic biomarker signatures of oligoprogressive radiation therapy response patterns to identify patients and lesions that benefit from ablative radiation; and (3) correlate localized clinical PET imaging and global circulating immunologic biomarkers with survival outcomes. Fluorodeoxyglucose (FDG) PET scans and peripheral blood draws will be performed prior to chemoICI, 3 weeks into chemoICI, and 12 weeks into chemoICI. For patients who develop oligoprogressive disease, we will acquire FDG PET scans and peripheral blood prior to and 1-month post radiation therapy. We will develop combined quantitative PET imaging and circulating immunologic biomarker signatures of chemoICI and radiation response that stratify patients into the following groups: (i) high-risk patients predicted to develop rapid widespread progressive disease who require aggressive second-line systemic therapy, (ii) moderate-risk patients predicted to develop oligoprogressive disease who require consolidation radiation to high-risk lesion targets, (iii) low-risk patients predicted to have durable long-term response to first-line therapy. Successful completion of this project will support the launch of a clinical trial on biomarker response-adaptive chemoICI and radiation therapy in patients with metastatic non-small cell lung cancer, in order to improve cancer control and survival.