DataSheet_1_Sequential PET/CT and pathological biomarker crosstalk predict response to PD-1 blockers alone or combined with sunitinib in propensity score-matched cohorts of cancer of unknown primary treatment.docx

IntroductionThe efficacy of immune checkpoint inhibitors (ICIs), including toripalimab and pembrolizumab, has not been confirmed in the treatment of cancer of unknown primary (CUP), which has a very poor prognosis. Combined with anti-angiogenic therapies, ICIs are hypothesized to be effective in prolonging overall survival. The study aims to give evidence on the treatment effects of sunitinib combined with ICIs, find pathological biomarkers associated with changes in volumetric 18F FDG PET/CT parameters, and investigate inner associations among these markers associated with response on PET/CT.
MethodsThe study recruited patients receiving combined treatment (ICIs + sunitinib), compared the effects of combined treatment with those of separate treatment and age-matched negative controls, and analyzed propensity score-matched (PSM) pairs. Markers associated with survival were identified, and their inner associations were tested using structural equation modeling.
ResultsA total of 292 patients were enrolled in the final analysis, with 53 patients receiving combined treatment. Survival analysis demonstrated significantly prolonged survival in either combined or separate treatment, with the combined arm showing better response when PSM-paired using pre-treatment whole-body PET/CT parameters. The angiogenic markers KDR and VEGF mediate the PD-1 blockade impact on volumetric value changes in positive and negative manners.
ConclusionThe anti-angiogenic agent sunitinib may potentiate PD-1 blockade by diminishing angiogenesis or its downstream effects. The combined separate treatment increased the survival of CUP patients, and the responses could be evaluated using volumetric PET/CT parameters.

引言：免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）包括特瑞普利单抗与帕博利珠单抗，其在原发灶不明癌（cancer of unknown primary, CUP）治疗中的疗效尚未得到证实，而该类癌症预后极差。有假说认为，将ICIs与抗血管生成治疗联合应用，可有效延长患者总生存期。本研究旨在为舒尼替尼联合ICIs的治疗效果提供循证依据，筛选与18F-氟代脱氧葡萄糖正电子发射断层显像/计算机断层扫描（18F-FDG PET/CT）体积参数变化相关的病理生物标志物，并探究这些与PET/CT应答相关的标志物之间的内在关联。
方法：本研究纳入接受联合治疗（ICIs+舒尼替尼）的患者，将联合治疗方案与单一治疗方案及年龄匹配的阴性对照组进行疗效对比，并对倾向得分匹配（propensity score-matched, PSM）队列进行配对分析。筛选与生存相关的标志物，并采用结构方程模型检验这些标志物之间的内在关联。
结果：最终共有292例患者纳入最终分析，其中53例接受联合治疗。生存分析显示，联合治疗组与单一治疗组患者的生存期均显著延长；经基于治疗前全身PET/CT参数的倾向得分匹配配对后，联合治疗组的应答效果更优。血管生成标志物激酶插入域受体（kinase insert domain receptor, KDR）与血管内皮生长因子（vascular endothelial growth factor, VEGF）可分别以正向与负向方式介导PD-1阻断治疗对体积参数变化的影响。
结论：抗血管生成药物舒尼替尼可能通过抑制血管生成或其下游通路效应，增强PD-1阻断治疗的疗效。联合治疗与单一治疗方案均可提升原发灶不明癌患者的生存预后，且其治疗应答可通过PET/CT体积参数进行评估。