替雷利珠单抗联合阿替利珠单抗对比安慰剂联合阿替利珠单抗作为 PD-L1 选择的非小细胞肺癌一线治疗（CITYSCAPE）：一项随机、双盲、II 期研究的主要和随访分析。
Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study.
机构信息
Yonsei Cancer Centre, Yonsei University College of Medicine, Seoul, South Korea.
Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain.
出版信息
Lancet Oncol. 2022 Jun;23(6):781-792. doi: 10.1016/S1470-2045(22)00226-1. Epub 2022 May 13.
BACKGROUND
Targeted inhibition of the PD-L1-PD-1 pathway might be further amplified through combination of PD-1 or PD-L1 inhibitors with novel anti-TIGIT inhibitory immune checkpoint agents, such as tiragolumab. In the CITYSCAPE trial, we aimed to assess the preliminary efficacy and safety of tiragolumab plus atezolizumab (anti-PD-L1) therapy as first-line treatment for non-small-cell lung cancer (NSCLC).
METHODS
CITYSCAPE is a phase 2, randomised, double-blind, placebo-controlled trial. Patients with chemotherapy-naive, PD-L1-positive (defined as a tumour proportion score of ≥1% by 22C3 immunohistochemistry pharmDx assay; Dako, Agilent Technologies, Santa Clara, CA, USA) recurrent or metastatic NSCLC with measurable disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and no EGFR or ALK alterations were enrolled from 41 clinics in Europe, Asia, and the USA. Patients were randomly assigned (1:1), via an interactive voice or web-based response system, to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) or placebo plus atezolizumab intravenously once every 3 weeks. Investigators and patients were masked to treatment assignment. The co-primary endpoints were investigator-assessed objective response rate and progression-free survival as per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population, analysed after approximately 80 progression-free survival events had been observed in the primary population. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03563716, and is ongoing.
FINDINGS
Patients were enrolled between Aug 10, 2018, and March 20, 2019. At data cutoff for the primary analysis (June 30, 2019), 135 of 275 patients assessed for eligibility were randomly assigned to receive tiragolumab plus atezolizumab (67 [50%]) or placebo plus atezolizumab (68 [50%]). In this primary analysis, after a median follow-up of 5·9 months (4·6-7·6, in the intention-to-treat population, 21 patients (31·3% [95% CI 19·5-43·2]) in the tiragolumab plus atezolizumab group versus 11 patients (16·2% [6·7-25·7]) in the placebo plus atezolizumab group had an objective response (p=0·031). Median progression-free survival was 5·4 months (95% CI 4·2-not estimable) in the tiragolumab plus atezolizumab group versus 3·6 months (2·7-4·4) in the placebo plus atezolizumab group (stratified hazard ratio 0·57 [95% CI 0·37-0·90], p=0·015). 14 (21%) patients receiving tiragolumab plus atezolizumab and 12 (18%) patients receiving placebo plus atezolizumab had serious treatment-related adverse events. The most frequently reported grade 3 or worse treatment-related adverse event was lipase increase (in six [9%] patients in the tiragolumab plus atezolizumab group vs two [3%] in the placebo plus atezolizumab group). Two treatment-related deaths (of pyrexia and infection) occurred in the tiragolumab plus atezolizumab group.
INTERPRETATION
Tiragolumab plus atezolizumab showed a clinically meaningful improvement in objective response rate and progression-free survival compared with placebo plus atezolizumab in patients with chemotherapy-naive, PD-L1-positive, recurrent or metastatic NSCLC. Tiragolumab plus atezolizumab was well tolerated, with a safety profile generally similar to that of atezolizumab alone. These findings demonstrate that tiragolumab plus atezolizumab is a promising immunotherapy combination for the treatment of previously untreated, locally advanced unresectable or metastatic NSCLC.
FUNDING
F Hoffmann-La Roche and Genentech.
背景
通过将 PD-1 或 PD-L1 抑制剂与新型抗 TIGIT 抑制性免疫检查点药物（如 tiragolumab）联合使用，可能会进一步放大对 PD-L1-PD-1 通路的靶向抑制作用。在 CITYSCAPE 试验中，我们旨在评估 tiragolumab 联合 atezolizumab（抗 PD-L1）作为 PD-L1 阳性（由 22C3 免疫组化 pharmDx 检测法定义为肿瘤比例评分≥1%；Dako，Agilent Technologies，Santa Clara，CA，USA）复发性或转移性非小细胞肺癌（NSCLC）患者的一线治疗的初步疗效和安全性。
方法
CITYSCAPE 是一项 2 期、随机、双盲、安慰剂对照试验。来自欧洲、亚洲和美国的 41 家诊所共招募了 41 家诊所的患者，这些患者为化疗初治、PD-L1 阳性（由 22C3 免疫组化 pharmDx 检测法定义为肿瘤比例评分≥1%；Dako，Agilent Technologies，Santa Clara，CA，USA）的复发性或转移性 NSCLC 患者，有可测量的疾病，东部肿瘤协作组表现状态为 0 或 1，无 EGFR 或 ALK 改变。患者通过交互式语音或基于网络的应答系统，以 1:1 的比例随机分配（1:1），接受 tiragolumab（600mg）联合 atezolizumab（1200mg）或安慰剂联合 atezolizumab 静脉注射，每 3 周一次。研究者和患者对治疗分配进行了盲法评估。主要终点是研究者评估的客观缓解率和无进展生存期，按照实体瘤反应评估标准 1.1 版（在意向治疗人群中）进行分析，在主要人群中观察到大约 80 例无进展生存期事件后进行分析。所有接受至少一剂研究药物的患者均进行了安全性评估。该试验在 ClinicalTrials.gov 注册，NCT03563716，正在进行中。
结果
患者于 2018 年 8 月 10 日至 2019 年 3 月 20 日入选。在主要分析数据截止日期（2019 年 6 月 30 日）时，在符合条件的 275 名患者中，有 135 名患者被随机分配接受 tiragolumab 联合 atezolizumab（67[50%]）或安慰剂联合 atezolizumab（68[50%]）。在这项主要分析中，中位随访 5.9 个月（4.6-7.6，在意向治疗人群中），在 tiragolumab 联合 atezolizumab 组中有 21 例（31.3%[95%CI 19.5-43.2%]）患者有客观缓解，而在安慰剂联合 atezolizumab 组中有 11 例（16.2%[6.7-25.7%]）患者有客观缓解（p=0.031）。在 tiragolumab 联合 atezolizumab 组中，中位无进展生存期为 5.4 个月（95%CI 4.2-不可估计），而在安慰剂联合 atezolizumab 组中为 3.6 个月（2.7-4.4）（分层风险比 0.57[95%CI 0.37-0.90]，p=0.015）。14 名（21%）接受 tiragolumab 联合 atezolizumab 治疗的患者和 12 名（18%）接受安慰剂联合 atezolizumab 治疗的患者发生严重的治疗相关不良事件。最常报告的 3 级或更高级别的治疗相关不良事件是脂肪酶升高（在 tiragolumab 联合 atezolizumab 组中为 6 例[9%]，在安慰剂联合 atezolizumab 组中为 2 例[3%]）。tiragolumab 联合 atezolizumab 组有 2 例（3%）治疗相关死亡（发热和感染）。
解释
与安慰剂联合 atezolizumab 相比，tiragolumab 联合 atezolizumab 可显著提高客观缓解率和无进展生存期，在化疗初治、PD-L1 阳性、复发性或转移性 NSCLC 患者中。tiragolumab 联合 atezolizumab 耐受性良好，安全性与单独使用 atezolizumab 大致相似。这些发现表明，tiragolumab 联合 atezolizumab 是一种有前途的免疫治疗联合用药，用于治疗未经治疗的局部晚期不可切除或转移性 NSCLC。
资金来源
F Hoffmann-La Roche 和 Genentech。
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