Sati Neha, Boyne Devon J, Cheung Winson Y, Cash Sarah B, Arora Paul
Department of Biology, McMaster University, Hamilton, Ontario, Canada.
Cytel Inc, Toronto, Ontario, Canada.
JAMA Netw Open. 2021 Jan 4;4(1):e2034201. doi: 10.1001/jamanetworkopen.2020.34201.
Programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors are immune checkpoint inhibitors widely used in the treatment of metastatic clear cell renal cell carcinoma (ccRCC) and other cancers. There is a lack of understanding regarding which factors are associated with therapeutic response.
To conduct a systematic literature review of trials reporting on factors associated with differential response to PD-1/PD-L1 inhibitors among patients diagnosed with metastatic ccRCC and quantitatively synthesize the magnitude to which each factor modified the response to PD-1/PD-L1 inhibitors.
The MEDLINE and Cochrane Register of Trials databases were searched for studies published in English from 2006 onward. Searches were last run on September 3, 2019.
This systematic review and meta-analysis assessed 662 phase 2/3 randomized clinical trials that provided subgroup analyses of any baseline characteristics regarding the treatment response to PD-1/PD-L1 inhibitors, alone or as part of a combination therapy, with respect to overall survival (OS) or progression-free survival (PFS) among patients with metastatic ccRCC.
A novel quantitative approach was used to synthesize subgroup findings across trials. The ratio of the subgroup-specific hazard ratios (HRs) from each study were pooled using a random-effects meta-analysis whereby ratios of 1.00 would indicate that the subgroup-specific HRs were equal in magnitude.
Main outcomes were OS and PFS.
From an initial 662 reports, 7 trials were considered eligible for inclusion. Meta-analyses suggested the treatment response to PD-1/PD-L1 inhibitors in patients with metastatic ccRCC was significantly associated with age (OS: ratio of HR for age ≥75 years to HR for age <65 years, 1.51; 95% CI, 1.01-2.26), PD-L1 expression (PFS: ratio of HR for PD-L1 < 1% to HR for PD-L1 ≥ 10%, 2.21; 95% CI, 1.14-4.27; ratio of HR for PD-L1 < 1% to HR for PD-L1 ≥ 1%, 1.36; 95% CI, 1.10-1.68), Memorial Sloan Kettering Cancer Center risk score (PFS: ratio of HR for immediate risk score to HR for poor risk score, 1.62; 95% CI, 1.14-2.29; ratio of HR for favorable risk score to HR for poor risk score, 1.53; 95% CI, 1.00-2.34; ratio of HR for favorable risk score to HR for intermediate risk score, 0.96; 95% CI, 0.70-1.30), and sarcomatoid tumor presence (PFS: ratio of HR for no sarcomatoid differentiation to HR for sarcomatoid differentiation, 1.54; 95% CI, 1.07-2.21).
This analysis suggests that older age, low levels of PD-L1 expression, and the absence of sarcomatoid tumor differentiation are associated with a diminished response to anti-PD-1/PD-L1 immunotherapies with respect to survival outcomes among patients with metastatic ccRCC.
程序性细胞死亡蛋白1/程序性细胞死亡配体1（PD-1/PD-L1）抑制剂是广泛用于治疗转移性透明细胞肾细胞癌（ccRCC）和其他癌症的免疫检查点抑制剂。目前对于哪些因素与治疗反应相关尚缺乏了解。
对报告转移性ccRCC患者中与PD-1/PD-L1抑制剂不同反应相关因素的试验进行系统文献综述，并定量综合每个因素对PD-1/PD-L1抑制剂反应的影响程度。
检索MEDLINE和Cochrane试验注册数据库，以获取2006年起发表的英文研究。检索最后一次运行于2019年9月3日。
本系统综述和荟萃分析评估了662项2/3期随机临床试验，这些试验提供了关于单独或作为联合治疗一部分的PD-1/PD-L1抑制剂治疗反应的任何基线特征的亚组分析，涉及转移性ccRCC患者的总生存期（OS）或无进展生存期（PFS）。
采用一种新的定量方法综合各试验的亚组研究结果。使用随机效应荟萃分析汇总每项研究中亚组特异性风险比（HRs）的比值，其中比值为1.00表示亚组特异性HRs在大小上相等。
主要结局为OS和PFS。
从最初的662份报告中，7项试验被认为符合纳入标准。荟萃分析表明，转移性ccRCC患者对PD-1/PD-L1抑制剂的治疗反应与年龄（OS：年龄≥75岁的HR与年龄<65岁的HR之比，1.51；95%CI，1.01-2.26）、PD-L1表达（PFS：PD-L1<1%的HR与PD-L1≥10%的HR之比，2.21；95%CI，1.14-4.27；PD-L1<1%的HR与PD-L1≥1%的HR之比，1.36；95%CI，1.10-1.68）、纪念斯隆凯特琳癌症中心风险评分（PFS：即刻风险评分的HR与不良风险评分的HR之比，1.62；95%CI，1.14-2.29；有利风险评分的HR与不良风险评分的HR之比，1.53；95%CI，1.00-2.34；有利风险评分的HR与中等风险评分的HR之比，0.96；95%CI，0.70-1.30）以及肉瘤样肿瘤的存在（PFS：无肉瘤样分化的HR与肉瘤样分化的HR之比，1.54；95%CI，1.07-2.）显著相关。
该分析表明，年龄较大、PD-L1表达水平较低以及无肉瘤样肿瘤分化与转移性ccRCC患者生存结局方面对抗PD-1/PD-L1免疫疗法的反应减弱相关。
