背景:自酪氨酸激酶抑制剂获得批准以来,血管生成抑制剂和免疫检查点抑制剂,晚期肾细胞癌(RCC)的治疗格局发生了根本性变化。今天,不同药物类别的联合疗法在复杂的一线治疗中占有重要地位.由于大量的药物可用,有必要找出最有效的治疗方法,同时考虑其副作用和对生活质量(QoL)的影响。
目的:评估和比较一线治疗成人晚期肾癌的益处和危害,并产生临床相关的疗法排名。次要目标是通过进行持续的更新搜索来保持证据的流通,使用活的系统审查方法,并纳入来自临床研究报告(CSR)的数据。
方法:我们搜索了CENTRAL,MEDLINE,Embase,会议程序和相关审判登记册,直至2022年2月9日。我们搜索了几个数据平台来识别CSR。
方法:我们纳入了随机对照试验(RCT),评估至少一种靶向治疗或免疫疗法用于晚期RCC成人一线治疗。我们排除了仅评估白介素-2与干扰素-α的试验以及辅助治疗设置的试验。我们还排除了先前接受过全身抗癌治疗的成年人的试验,如果超过10%的参与者先前接受过治疗,或者未治疗参与者的数据不能单独提取.
方法:所有必要的审查步骤(即筛选和研究选择,数据提取,偏倚风险和确定性评估)由至少两名综述作者独立进行.我们的结果是总生存期(OS),QoL,严重不良事件(SAE),无进展生存期(PFS),不良事件(AE),因AE而停止研究治疗的参与者人数,以及开始第一次后续治疗的时间。在可能的情况下,对不同的风险组进行了分析(有利的,中间,差)根据国际转移性肾细胞癌数据库协会评分(IMDC)或纪念斯隆·凯特琳癌症中心(MSKCC)标准。我们的主要比较物是舒尼替尼(SUN)。低于1.0的风险比(HR)或风险比(RR)有利于实验臂。
结果:我们包括36个RCT和15,177名参与者(男性11,061名,女性4116名)。在大多数试验和结果中,偏倚风险主要被认为是“高”或“某些担忧”。这主要是由于缺乏有关随机化过程的信息,结果评估者的致盲,以及结果测量和分析的方法。此外,研究方案和统计分析计划很少可用.在这里,我们展示了我们的主要结果操作系统的结果,QoL,和SAEs,对于所有联合进行当代治疗的风险组:pembrolizumab+axitinib(PEM+AXI),阿维鲁单抗+阿西替尼(AVE+AXI),纳武单抗+卡博替尼(NIV+CAB),乐伐替尼+派姆单抗(LEN+PEM),nivolumab+ipilimumab(NIV+IPI),CAB,和帕唑帕尼(PAZ)。每个风险组的结果和我们次要结局的结果报告在总结的结果表和本综述的全文中。其他治疗和比较的证据也可以在全文中找到。各风险组的总生存率(OS),PEM+AXI(HR0.73,95%置信区间(CI)0.50至1.07,中等确定性)和NIV+IPI(HR0.69,95%CI0.69至1.00,中等确定性)可能会改善OS,相比太阳,分别。LEN+PEM可能会提高OS(HR0.66,95%CI0.42至1.03,低确定性),与太阳相比。PAZ和SUN之间的OS差异可能很小或没有差异(HR0.91,95%CI0.64至1.32,中等确定性),与SUN相比,我们不确定CAB是否提高了OS(HR0.84,95%CI0.43至1.64,非常低的确定性)。当用SUN治疗时,中位生存期为28个月。LEN+PEM的生存期可能会提高到43个月,并可能改善到:使用NIV+IPI的41个月,39个月与PEM+AXI,与PAZ合作31个月。我们不确定CAB的生存期是否提高到34个月。AVE+AXI和NIV+CAB的比较数据不可用。生活质量(QoL)一个RCT使用FACIT-F测量QoL(得分范围为0至52;得分越高意味着QoL越好),并报告平均后得分高9.00分(低9.86至高27.86,非常低的确定性)与PAZ比与太阳。PEM+AXI的对比数据不可用,AVE+AXI,NIV+CAB,LEN+PEM,NIV+IPI,还有CAB.不同风险组的严重不良事件(SAE),与SUN相比,PEM+AXI可能略微增加SAE的风险(RR1.29,95%CI0.90至1.85,中等确定性)。LEN+PEM(RR1.52,95%CI1.06至2.19,中度确定性)和NIV+IPI(RR1.40,95%CI1.00至1.97,中度确定性)可能会增加SAE的风险,相比太阳,分别。PAZ和SUN之间的SAE风险差异可能很小或没有差异(RR0.99,95%CI0.75至1.31,中度确定性)。与SUN相比,我们不确定CAB是否降低或增加SAE的风险(RR0.92,95%CI0.60至1.43,确定性非常低)。当用SUN治疗时,人们经历SAE的平均风险为40%。LEN+PEM的风险可能增加到:61%,57%的NIV+IPI,52%与PEM+AXI。PAZ可能保持在40%。我们不确定CAB的风险是否降低到37%。AVE+AXI和NIV+CAB的比较数据不可用。
结论:关于主要治疗方法的发现仅来自一项试验的直接证据,因此,应谨慎解释结果。需要更多的试验来比较这些干预措施和组合,而不仅仅是太阳。此外,评估免疫疗法和靶向疗法对不同亚组的影响至关重要,研究应侧重于评估和报告相关亚组数据.本综述中的证据主要适用于晚期透明细胞RCC。
Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma (RCC) has changed fundamentally. Today, combined therapies from different drug categories have a firm place in a complex first-line therapy. Due to the large number of drugs available, it is necessary to identify the most effective therapies, whilst considering their side effects and impact on quality of life (QoL).
To evaluate and compare the benefits and harms of first-line therapies for adults with advanced RCC, and to produce a clinically relevant ranking of therapies. Secondary objectives were to maintain the currency of the evidence by conducting continuous update searches, using a living systematic review approach, and to incorporate data from clinical study reports (CSRs).
We searched CENTRAL, MEDLINE, Embase, conference proceedings and relevant trial registries up until 9 February 2022. We searched several data platforms to identify CSRs.
We included randomised controlled trials (RCTs) evaluating at least one targeted therapy or immunotherapy for first-line treatment of adults with advanced RCC. We excluded trials evaluating only interleukin-2 versus interferon-alpha as well as trials with an adjuvant treatment setting. We also excluded trials with adults who received prior systemic anticancer therapy if more than 10% of participants were previously treated, or if data for untreated participants were not separately extractable.
All necessary
review steps (i.e. screening and study selection, data extraction, risk of bias and certainty assessments) were conducted independently by at least two
review authors. Our outcomes were overall survival (OS), QoL, serious adverse events (SAEs), progression-free survival (PFS), adverse events (AEs), the number of participants who discontinued study treatment due to an AE, and the time to initiation of first subsequent therapy. Where possible, analyses were conducted for the different risk groups (favourable, intermediate, poor) according to the International Metastatic Renal-Cell Carcinoma Database Consortium Score (IMDC) or the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Our main comparator was sunitinib (SUN). A hazard ratio (HR) or risk ratio (RR) lower than 1.0 is in favour of the experimental arm.
We included 36 RCTs and 15,177 participants (11,061 males and 4116 females). Risk of bias was predominantly judged as being \'high\' or \'some concerns\' across most trials and outcomes. This was mainly due to a lack of information about the randomisation process, the blinding of outcome assessors, and methods for outcome measurements and analyses. Additionally, study protocols and statistical analysis plans were rarely available. Here we present the results for our primary outcomes OS, QoL, and SAEs, and for all risk groups combined for contemporary treatments: pembrolizumab +
axitinib (PEM+AXI), avelumab +
axitinib (AVE+AXI), nivolumab + cabozantinib (NIV+CAB), lenvatinib + pembrolizumab (LEN+PEM), nivolumab + ipilimumab (NIV+IPI), CAB, and pazopanib (PAZ). Results per risk group and results for our secondary outcomes are reported in the summary of findings tables and in the full text of this review. The evidence on other treatments and comparisons can also be found in the full text. Overall survival (OS) Across risk groups, PEM+AXI (HR 0.73, 95% confidence interval (CI) 0.50 to 1.07, moderate certainty) and NIV+IPI (HR 0.69, 95% CI 0.69 to 1.00, moderate certainty) probably improve OS, compared to SUN, respectively. LEN+PEM may improve OS (HR 0.66, 95% CI 0.42 to 1.03, low certainty), compared to SUN. There is probably little or no difference in OS between PAZ and SUN (HR 0.91, 95% CI 0.64 to 1.32, moderate certainty), and we are uncertain whether CAB improves OS when compared to SUN (HR 0.84, 95% CI 0.43 to 1.64, very low certainty). The median survival is 28 months when treated with SUN. Survival may improve to 43 months with LEN+PEM, and probably improves to: 41 months with NIV+IPI, 39 months with PEM+AXI, and 31 months with PAZ. We are uncertain whether survival improves to 34 months with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. Quality of life (QoL) One RCT measured QoL using FACIT-F (score range 0 to 52; higher scores mean better QoL) and reported that the mean post-score was 9.00 points higher (9.86 lower to 27.86 higher, very low certainty) with PAZ than with SUN. Comparison data were not available for PEM+AXI, AVE+AXI, NIV+CAB, LEN+PEM, NIV+IPI, and CAB. Serious adverse events (SAEs) Across risk groups, PEM+AXI probably increases slightly the risk for SAEs (RR 1.29, 95% CI 0.90 to 1.85, moderate certainty) compared to SUN. LEN+PEM (RR 1.52, 95% CI 1.06 to 2.19, moderate certainty) and NIV+IPI (RR 1.40, 95% CI 1.00 to 1.97, moderate certainty) probably increase the risk for SAEs, compared to SUN, respectively. There is probably little or no difference in the risk for SAEs between PAZ and SUN (RR 0.99, 95% CI 0.75 to 1.31, moderate certainty). We are uncertain whether CAB reduces or increases the risk for SAEs (RR 0.92, 95% CI 0.60 to 1.43, very low certainty) when compared to SUN. People have a mean risk of 40% for experiencing SAEs when treated with SUN. The risk increases probably to: 61% with LEN+PEM, 57% with NIV+IPI, and 52% with PEM+AXI. It probably remains at 40% with PAZ. We are uncertain whether the risk reduces to 37% with CAB. Comparison data were not available for AVE+AXI and NIV+CAB.
Findings concerning the main treatments of interest comes from direct evidence of one trial only, thus results should be interpreted with caution. More trials are needed where these interventions and combinations are compared head-to-head, rather than just to SUN. Moreover, assessing the effect of immunotherapies and targeted therapies on different subgroups is essential and studies should focus on assessing and reporting relevant subgroup data. The evidence in this
review mostly applies to advanced clear cell RCC.