Table1_Value assessment of PD-1/PD-L1 inhibitors in the treatment of oesophageal and gastrointestinal cancers.DOCX

Background: Evidence of efficacy and safety of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) checkpoint inhibitors in oesophageal cancer (EC), gastric cancer (GC) and colorectal cancer (CRC) was inconsistent, obscuring their clinical application and decision-making. The aim of this study was to comprehensively evaluate the value of PD-1/PD-L1 inhibitors in EC, GC and CRC to select valuable PD-1/PD-L1 inhibitors, and to assess the association between the value and cost of PD-1/PD-L1 inhibitors.
Methods: A comprehensive search of trials of PD-1/PD-L1 inhibitors in EC, GC and CRC was performed in Chinese and English medical databases with a cut-off date of 1 July 2022. Two authors independently applied the ASCO-VF and ESMO-MCBS to assess the value of PD-1/PD-L1 inhibitors. A receiver operating characteristic (ROC) curve was generated to establish the predictive value of the ASCO-VF score to meet the threshold of the ESMO-MCBS grade. Spearman’s correlation was used to calculate the relationship between the cost and value of drugs.
Results: Twenty-three randomized controlled trials were identified: ten (43.48%) in EC, five (21.74%) in CRC, and eight (34.78%) in GC or gastroesophageal junction cancer (GEJC). For advanced diseases, ASCO-VF scores ranged from −12.5 to 69, with a mean score of 26.5 (95% CI 18.4–34.6). Six (42.9%) therapeutic regimens met the ESMO-MCBS benefit threshold grade. The area under the ROC curve was 1.0 (p = 0.002). ASCO-VF scores and incremental monthly cost were negatively correlated (Spearman’s ρ = −0.465, p = 0.034). ESMO-MCBS grades and incremental monthly cost were negatively correlated (Spearman’s ρ = −0.211, p = 0.489).
Conclusion: PD-1/PD-L1 inhibitors did not meet valuable threshold in GC/GEJC. Pembrolizumab met valuable threshold in advanced microsatellite instability–high CRC. The value of camrelizumab and toripalimab may be more worth paying in EC.

背景：目前针对程序性细胞死亡蛋白1（programmed cell death 1, PD-1）与程序性死亡配体1（programmed death ligand-1, PD-L1）免疫检查点抑制剂在食管癌（oesophageal cancer, EC）、胃癌（gastric cancer, GC）及结直肠癌（colorectal cancer, CRC）中的疗效与安全性证据尚不统一，这一现状阻碍了其临床应用与诊疗决策制定。本研究旨在全面评估PD-1/PD-L1抑制剂在EC、GC及CRC中的临床价值，以筛选具有临床价值的PD-1/PD-L1抑制剂，并探究此类抑制剂的价值与成本之间的关联。
方法：本研究以2022年7月1日为检索截止日期，在中英文医学数据库中全面检索针对EC、GC及CRC的PD-1/PD-L1抑制剂相关临床试验。由2名研究者独立采用美国临床肿瘤学会价值框架（American Society of Clinical Oncology Value Framework, ASCO-VF）与欧洲肿瘤内科学会临床获益量级量表（European Society for Medical Oncology-Magnitude of Clinical Benefit Scale, ESMO-MCBS）对PD-1/PD-L1抑制剂的临床价值进行评估。绘制受试者工作特征（receiver operating characteristic, ROC）曲线，以明确ASCO-VF评分对符合ESMO-MCBS获益阈值等级的预测效能。采用Spearman相关分析计算药物成本与价值之间的关联。
结果：本研究共纳入23项随机对照试验，其中食管癌相关试验10项（占比43.48%）、结直肠癌相关试验5项（占比21.74%）、胃癌或胃食管结合部癌（gastroesophageal junction cancer, GEJC）相关试验8项（占比34.78%）。针对晚期患者，ASCO-VF评分范围为-12.5至69，平均评分为26.5（95%置信区间：18.4~34.6）。共有6种（42.9%）治疗方案符合ESMO-MCBS获益阈值等级。ROC曲线下面积为1.0（p=0.002）。ASCO-VF评分与月均增量成本呈负相关（Spearman相关系数ρ=-0.465，p=0.034）；ESMO-MCBS等级与月均增量成本亦呈负相关（Spearman相关系数ρ=-0.211，p=0.489）。
结论：PD-1/PD-L1抑制剂在胃癌/胃食管结合部癌中未达到临床价值阈值。帕博利珠单抗（pembrolizumab）可使晚期微卫星高度不稳定（microsatellite instability-high, MSI-H）结直肠癌患者达到ESMO-MCBS获益阈值。卡瑞利珠单抗（camrelizumab）与特瑞普利单抗（toripalimab）在食管癌中的临床价值更值得临床投入。