Thoracic Oncology Unit, Fondazione IRCSS Istituto Nazionale dei Tumori, Milano, Italy.
Department of Oncology, Lausanne University Hospital, and Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.
Cochrane Database Syst Rev. 2021 Apr 30;4(4):CD013257. doi: 10.1002/14651858.CD013257.pub3.
BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have changed the first-line treatment of people with advanced non-small cell lung cancer (NSCLC). Single-agent pembrolizumab (a PD-1 inhibitor) is currently the standard of care as monotherapy in patients with PD-L1 expression ≥ 50%, either alone or in combination with chemotherapy when PD-L1 expression is less than 50%. Atezolizumab (PD-L1 inhibitor) has also been approved in combination with chemotherapy and bevacizumab (an anti-angiogenic antibody) in first-line NSCLC regardless of PD-L1 expression. The combination of first-line PD-1/PD-L1 inhibitors with anti-CTLA-4 antibodies has also been shown to improve survival compared to platinum-based chemotherapy in advanced NSCLC, particularly in people with high tumour mutational burden (TMB). The association of ipilimumab (an anti CTLA4) and nivolumab (PD-1 inhibitor) has been approved by the US Food and Drug Administration (FDA) in all patients with PD-L1 expression ≥1%. Although these antibodies are currently used in clinical practice, some questions remain unanswered, such as the best-treatment strategy, the role of different biomarkers for treatment selection and the effectiveness of immunotherapy according to specific clinical characteristics. OBJECTIVES: To determine the effectiveness and safety of first-line immune checkpoint inhibitors (ICIs), as monotherapy or in combination, compared to platinum-based chemotherapy, with or without bevacizumab for people with advanced NSCLC, according to the level of PD-L1 expression. SEARCH METHODS: We performed an electronic search of the main databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase) from inception until 31 December 2020 and conferences meetings from 2015 onwards. SELECTION CRITERIA: We included randomised controlled trials (RCTs) reporting on the efficacy or safety of first-line ICI treatment for adults with advanced NSCLC who had not previously received any anticancer treatment. We included trials comparing single- or double-ICI treatment to standard first-line therapy (platinum-based chemotherapy +/- bevacizumab). All data come from 'international multicentre studies involving adults, age 18 or over, with histologically-confirmed stage IV NSCLC. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the search results and a fourth review author resolved any disagreements. Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were overall objective response rate (ORR) by RECIST v 1.1, grade 3 to 5 treatment-related adverse events (AEs) (CTCAE v 5.0) and health-related quality of life (HRQoL). We performed meta-analyses where appropriate using the random-effects model for hazard ratios (HRs) or risk ratios (RRs), with 95% confidence intervals (95% CIs), and used the I² statistic to investigate heterogeneity. MAIN RESULTS: Main results We identified 15 trials for inclusion, seven completed and eight ongoing trials. We obtained data for 5893 participants from seven trials comparing first-line single- (six trials) or double- (two trials) agent ICI with platinum-based chemotherapy, one trial comparing both first-line single- and double-agent ICsI with platinum-based chemotherapy. All trials were at low risk of selection and detection bias, some were classified at high risk of performance, attrition or other source of bias. The overall certainty of evidence according to GRADE ranged from moderate-to-low because of risk of bias, inconsistency, or imprecision. The majority of the included trials reported their outcomes by PD-L1 expressions, with PD-L1 ≥ 50 being considered the most clinically useful cut-off level for decision makers. Also, iIn order to avoid overlaps between various PDL-1 expressions we prioritised the review outcomes according to PD-L1 ≥ 50. Single-agent ICI In the PD-L1 expression ≥ 50% group single-agent ICI probably improved OS compared to platinum-based chemotherapy (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.60 to 0.76, 6 RCTs, 2111 participants, moderate-certainty evidence). In this group, single-agent ICI also may improve PFS (HR: 0.68, 95% CI 0.52 to 0.88, 5 RCTs, 1886 participants, low-certainty evidence) and ORR (risk ratio (RR):1.40, 95% CI 1.12 to 1.75, 4 RCTs, 1672 participants, low-certainty evidence). HRQoL data were available for only one study including only people with PD-L1 expression ≥ 50%, which suggested that single-agent ICI may improve HRQoL at 15 weeks compared to platinum-based chemotherapy (RR: 1.51, 95% CI 1.08 to 2.10, 1 RCT, 297 participants, low-certainty evidence). In the included studies, treatment-related AEs were not reported according to PD-L1 expression levels. Grade 3-4 AEs may be less frequent with single-agent ICI compared to platinum-based chemotherapy (RR: 0.41, 95% CI 0.33 to 0.50, I² = 62%, 5 RCTs, 3346 participants, low-certainty evidence). More information about efficacy of single-agent ICI compared to platinum-based chemotherapy according to the level of PD-L1 expression and to TMB status or specific clinical characteristics is available in the full text. Double-agent ICI Double-ICI treatment probably prolonged OS compared to platinum-based chemotherapy in people with PD-L1 expression ≥50% (HR: 0.72, 95% CI 0.59 to 0.89 2 RCTs, 612 participants, moderate-certainty evidence). Trials did not report data on HRQoL, PFS and ORR according to PD-L1 groups. Treatment related AEs were not reported according to PD-L1 expression levels. The frequency of grade 3-4 AEs may not differ between double-ICI treatment and platinum-based chemotherapy (RR: 0.78, 95% CI 0.55 to 1.09, I² = 81%, 2 RCTs, 1869 participants, low-certainty evidence). More information about efficacy of double-agent ICI according to the level of PD-L1 expression and to TMB status is available in the full text. AUTHORS' CONCLUSIONS: Authors' conclusions The evidence in this review suggests that single-agent ICI in people with NSCLC and PD-L1 ≥50% probably leads to a higher overall survival rate and may lead to a higher progression-free survival and overall response rate when compared to platinum-based chemotherapy and may also lead to a lower rate of adverse events and higher HRQoL. Combined ICI in people with NSCLC and PD-L1 ≥50% also probably leads to a higher overall survival rate when compared to platinum-based chemotherapy, but its effect on progression-free survival, overall response rate and HRQoL is unknown due to a lack of data. The rate of adverse events may not differ between groups. This review used to be a living review. It is transitioned out of living mode because current research is exploring ICI in association with chemotherapy or other immunotherapeutic drugs versus ICI as single agent rather than platinum based chemotherapy.
背景：针对 PD-1/PD-L1 轴的免疫检查点抑制剂 (ICIs) 改变了晚期非小细胞肺癌 (NSCLC) 患者的一线治疗方法。单药 pembrolizumab（一种 PD-1 抑制剂）目前是 PD-L1 表达≥50%的患者的标准治疗方法，无论是单独使用还是与 PD-L1 表达低于 50%时联合化疗使用。atezolizumab（PD-L1 抑制剂）也已在一线 NSCLC 中与化疗和贝伐珠单抗（一种抗血管生成抗体）联合批准，无论 PD-L1 表达如何。与基于铂类的化疗相比，一线 PD-1/PD-L1 抑制剂联合抗 CTLA-4 抗体也已显示出改善晚期 NSCLC 患者的生存，特别是在高肿瘤突变负担 (TMB) 的患者中。Ipilimumab（一种抗 CTLA4）和 nivolumab（PD-1 抑制剂）的联合已被美国食品和药物管理局 (FDA) 批准用于所有 PD-L1 表达≥1%的患者。尽管这些抗体目前已在临床实践中使用，但仍存在一些尚未解决的问题，例如最佳治疗策略、不同生物标志物对治疗选择的作用以及根据特定临床特征免疫治疗的有效性。
目的：确定一线免疫检查点抑制剂 (ICIs) 作为单药或联合治疗与基于铂类的化疗相比，在 PD-L1 表达水平下，对晚期 NSCLC 患者的有效性和安全性。
检索方法：我们对主要数据库（Cochrane 对照试验中心注册库、MEDLINE、Embase）进行了电子检索，检索时间截至 2020 年 12 月 31 日，并对会议进行了检索。
入选标准：我们纳入了随机对照试验 (RCTs)，这些试验报告了未经任何抗癌治疗的晚期 NSCLC 成人患者一线 ICI 治疗的疗效或安全性。我们纳入了比较单药或双药 ICI 治疗与标准一线治疗（基于铂类的化疗 +/- 贝伐珠单抗）的试验。所有数据均来自“国际多中心研究，涉及年龄在 18 岁或以上、组织学证实为 IV 期 NSCLC 的成年人”。
数据收集和分析：三位综述作者独立评估了检索结果，第四位综述作者解决了任何分歧。主要结局是总生存期 (OS) 和无进展生存期 (PFS)；次要结局是根据 RECIST v1.1 评估的总客观缓解率 (ORR)、治疗相关不良事件 (CTCAE v5.0) 等级 3 至 5 级和健康相关生活质量 (HRQoL)。我们适当地进行了 meta 分析，使用随机效应模型计算危险比 (HR) 或风险比 (RR)，置信区间 (95%CI) 为 95%，使用 I² 统计量来评估异质性。
主要结果：我们确定了 15 项试验纳入本研究，其中 7 项已完成，8 项正在进行中。我们从 7 项比较一线单药（6 项试验）或双药（2 项试验）ICI 与基于铂类的化疗的试验中获得了 5893 名参与者的数据，1 项试验比较了一线单药和双药 ICI 与基于铂类的化疗。所有试验均处于低选择和检测偏倚的风险，一些试验被归类为高绩效、失配或其他来源的偏倚的风险。根据 GRADE，整体证据确定性为中度至低，因为存在选择偏倚、不一致性或不精确性。大多数纳入的试验根据 PD-L1 表达报告了他们的结果，PD-L1≥50 被认为是决策者最有用的临界值。此外，为了避免各种 PDL-1 表达之间的重叠，我们根据 PD-L1≥50 优先审查结果。
单药 ICI：在 PD-L1 表达≥50%的组中，与基于铂类的化疗相比，单药 ICI 可能改善 OS（HR：0.68，95%置信区间 [CI]：0.60 至 0.76，6 项 RCT，2111 名参与者，中等确定性证据）。在该组中，单药 ICI 也可能改善 PFS（HR：0.68，95%CI：0.52 至 0.88，5 项 RCT，1886 名参与者，低确定性证据）和 ORR（RR：1.40，95%CI：1.12 至 1.75，4 项 RCT，1672 名参与者，低确定性证据）。仅有的一项包括 PD-L1 表达≥50%的研究报告了 HRQoL 数据，该研究表明与基于铂类的化疗相比，单药 ICI 可能在 15 周时改善 HRQoL（RR：1.51，95%CI：1.08 至 2.10，1 项 RCT，297 名参与者，低确定性证据）。在纳入的研究中，未根据 PD-L1 表达水平报告治疗相关的不良事件。与基于铂类的化疗相比，单药 ICI 可能导致治疗相关的不良事件频率较低（RR：0.41，95%CI：0.33 至 0.50，I²=62%，5 项 RCT，3346 名参与者，低确定性证据）。更多关于单药 ICI 与基于铂类的化疗相比的疗效，以及与 TMB 状态或特定临床特征相关的信息，详见全文。
双药 ICI：与基于铂类的化疗相比，双药 ICI 治疗可能延长 PD-L1 表达≥50%的患者的 OS（HR：0.72，95%CI：0.59 至 0.89，2 项 RCT，612 名参与者，中等确定性证据）。试验未报告根据 PD-L1 组的数据报告 HRQoL、PFS 和 ORR。未根据 PD-L1 表达水平报告治疗相关的不良事件。双药 ICI 治疗组与基于铂类的化疗组相比，治疗相关的不良事件频率可能没有差异（RR：0.78，95%CI：0.55 至 1.09，I²=81%，2 项 RCT，1869 名参与者，低确定性证据）。更多关于双药 ICI 根据 PD-L1 表达和 TMB 状态的疗效信息，详见全文。
作者结论：作者的结论是，与基于铂类的化疗相比，在 PD-L1 表达≥50%的 NSCLC 患者中，单药 ICI 可能导致更高的总生存率，并可能导致更高的无进展生存率和总反应率，与铂类化疗相比，单药 ICI 可能导致治疗相关的不良事件频率较低，生活质量较高。在 PD-L1 表达≥50%的 NSCLC 患者中，联合 ICI 也可能导致更高的总生存率，但由于缺乏数据，其对无进展生存期、总反应率和 HRQoL 的影响尚不清楚。与对照组相比，两组的不良反应发生率可能没有差异。本综述曾是一项正在进行的综述。由于目前的研究正在探索 ICI 与化疗或其他免疫治疗药物联合使用，而不是 ICI 作为单一药物与基于铂类的化疗相比，因此它已转变为非进行性综述。
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