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)患者的治疗需要导航 日益多样化的治疗景观。尽管抗程序性免疫检查点抑制物(ICI) 细胞死亡1(PD1)及其配体PDL1结合化疗(Chemici)是治疗的标准方案 转移性非小细胞肺癌并已改善了部分患者的存活率，大多数患者都接受了相关的治疗 毒性大，经济负担大，临床获益不大。放射治疗可以延长小鼠的生存时间 转移性疾病(少转移)或进展性疾病有限部位的患者 (寡进展)全身治疗，但对于哪些患者和皮损将受益还没有达成共识 不受辐射影响。通过早期反应评估进行患者选择和治疗适应是一项尚未满足的任务 需要增加化疗、免疫治疗和放射治疗的有效组合 转移性非小细胞肺癌和改善预后。生物标志物是我们理解复杂反应的关键 化疗和放射治疗的模式。在新诊断的转移性非小细胞肺癌患者中， 护理标准，我们建议通过结合正电子发射来评估和监测治疗反应。 隐匿性疾病宏观疾病负担和循环免疫生物标志物的体层摄影(PET)成像 通过以下目标支持精准治疗的系统性疾病负担：(1)构建临床PET 化疗ICI反应模式的影像和循环免疫生物标记物特征对风险分层的影响 患者分为(A)早期广泛性进展，(B)少进展，(C)反应性疾病；(2)构建 寡聚进展性放射治疗的临床PET影像和循环免疫生物标记物特征 识别受益于消融性放射治疗的患者和皮损的反应模式；以及(3)局部相关 临床PET成像和全球循环免疫生物标记物与生存结果的关系。 化疗前将进行氟脱氧葡萄糖(FDG)PET扫描和外周血抽血，3 化疗后数周，化疗后12周。对于患有少进性疾病的患者，我们将 在放射治疗前和治疗后1个月获取FDG PET扫描和外周血。我们将发展 联合定量PET成像和循环免疫标记物标记的化学和免疫缺陷 将患者分成以下几组的放射反应：(I)高危患者 迅速蔓延的进展性疾病，需要积极的二线系统治疗，(2)中等风险 预计会发展为少进展性疾病的患者，需要对高危病变进行巩固放射治疗 目标：(3)预测对一线治疗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记物反应-适应性化学ICI的临床试验 和放射治疗在转移性非小细胞肺癌患者中的应用，以提高癌症控制 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.