Kim Myung S, Xu Alexander, Haslam Alyson, Prasad Vinay
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Int J Cancer. 2022 Jun 1;150(11):1905-1910. doi: 10.1002/ijc.33968. Epub 2022 Feb 26.
PD-L1 expression is associated with differential response in cancers treated with checkpoint inhibitors. Clinical trials for Food and Drug Administration (FDA) approvals of programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors include limited subgroup analyses based on PD-L1 expression. We aimed to define the characteristics of PD-L1 defined subgroups of clinical trials leading to FDA approvals for new indications of PD-1/PD-L1 inhibitors. FDA approvals for PD-1/PD-L1 inhibitors from January 2014 to December 2020 were identified and the clinical trials leading to each drug approval were reviewed. We collected key variables from publicly available information on FDA website and peer-reviewed publications of clinical trials. We assessed regulatory characteristics (approval date, approved drug[s], cancer type, line of therapy and biomarker-restricted approval criteria) of each approval. Clinical trials leading to approvals were reviewed for trial design (RCT vs single arm study, primary endpoint) and PD-L1 defined subgroup design (no subgroup analysis, single threshold 2-group analysis, nested subgroups and adjacent subgroups). We then compared regulatory and trials characteristics (trial design, primary endpoint and biomarker approval criteria) between studies with nested and adjacent subgroups. There were 60 approvals for PD-1/PD-L1 inhibitors between January 2014 and December 2020. Twelve of 60 (20%) did not include any PD-L1 subgroups. Twenty-five of 60 (42%) approvals reported only two subgroups, 14 (23%) included adjacent subgroups and 9 (15%) had nested subgroups. Twenty-five of 60 trials (42%) are single arm studies. Comparison of characteristics between trials with nested subgroup design and adjacent subgroup design did not show differences. We conclude that approvals for new indications of PD-1/PD-L1 inhibitors are based on studies that do not include comprehensive reporting of outcomes by PD-L1 biomarker subgroups.
程序性死亡配体1（PD-L1）表达与接受检查点抑制剂治疗的癌症患者的不同反应相关。美国食品药品监督管理局（FDA）批准程序性死亡受体1（PD-1）/程序性死亡配体1（PD-L1）抑制剂的临床试验包括基于PD-L1表达的有限亚组分析。我们旨在确定导致FDA批准PD-1/PD-L1抑制剂新适应症的临床试验中，由PD-L1定义的亚组的特征。我们确定了2014年1月至2020年12月期间FDA批准的PD-1/PD-L1抑制剂，并审查了导致每种药物获批的临床试验。我们从FDA网站上公开可得的信息以及经过同行评审的临床试验出版物中收集了关键变量。我们评估了每次批准的监管特征（批准日期、获批药物、癌症类型、治疗线数和生物标志物限制批准标准）。对导致获批的临床试验进行审查，以了解试验设计（随机对照试验与单臂研究、主要终点）和PD-L1定义的亚组设计（无亚组分析、单阈值两组分析、嵌套亚组和相邻亚组）。然后，我们比较了有嵌套亚组和相邻亚组的研究之间的监管和试验特征（试验设计、主要终点和生物标志物批准标准）。2014年1月至2020年12月期间，PD-1/PD-L1抑制剂有60次获批。60次获批中有12次（20%）未包括任何PD-L1亚组。60次获批中有25次（42%）仅报告了两个亚组，14次（23%）包括相邻亚组，9次（15%）有嵌套亚组。60项试验中有25项（42%）是单臂研究。有嵌套亚组设计和相邻亚组设计的试验之间的特征比较未显示出差异。我们得出结论，PD-1/PD-L1抑制剂新适应症的获批是基于未全面报告PD-L1生物标志物亚组结果的研究。
