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| 项目名称 | 一项在接受完全切除术后经含铂辅助化疗的 IIB 期、IIIA 期或选择性 IIIB 期 PD-L1 阳性非小细胞肺癌受试者中比较 TIRAGOLUMAB 联合阿替利珠单抗与安慰剂联合阿替利珠单抗的 III 期、随机、双盲研究 | | | | | | | | 5片（按方案如需中心实验室检测EGFR/ALK的需另加5片） | | | | | | | | | | |
Background: Tiragolumab (tira) + atezolizumab (atezo) has shown encouraging survival outcomes in pts with metastatic NSCLC, primarily in pts with PD-L1-high tumors (tumor proportion score [TPS] ≥50%). SKYSCRAPER-01 (NCT04294810) is a phase III, double-blind, placebo-controlled, randomized trial investigating the efficacy and safety of first-line tira + atezo in pts with PD-L1-high NSCLC.
Methods: Eligible pts (previously untreated; PD-L1-high, locally advanced unresectable/metastatic NSCLC; EGFR/ALK wildtype) were randomized 1:1 to receive tira 600 mg IV + atezo 1200 mg IV or pbo + atezo 1200 mg IV every 3 weeks until disease progression, loss of clinical benefit, or unacceptable toxicity. Primary endpoints: investigator-assessed progression-free survival (INV-PFS) and overall survival (OS) in the primary analysis set (PAS; TPS ≥50%; 22C3 assay). Secondary endpoints: INV-objective response rate (INV-ORR) and INV-duration of response (INV-DOR) in the PAS; OS in the secondary analysis set (SAS; tumor cell [TC] ≥50%; SP263 assay).
Results: A total of 534 pts were randomized (tira + atezo, n=266; pbo + atezo, n=268). Pt characteristics were balanced between treatment arms. At the final PFS analysis (data cut-off 12 Mar 2022; median follow-up 9.9 months), median INV-PFS was 7.0 months with tira + atezo and 5.6 months with pbo + atezo (HR 0.78; 95% CI 0.63, 0.97; p=0.02; PAS). At the final OS analysis (data cut-off 24 Sep 2024; median follow-up 17.9 months), median OS was 23.1 months with tira + atezo and 16.9 months with pbo + atezo (HR 0.87; 95% CI 0.71, 1.08; p=0.22; PAS; Table). Tira + atezo demonstrated an acceptable safety profile, consistent with previous observations.
Conclusion: The primary endpoints of INV-PFS and OS were not met in the SKYSCRAPER-01 study. Numerical improvements in both PFS and OS with tira + atezo versus pbo + atezo suggest potential antitumor activity of TIGIT targeting in NSCLC.
| PAS (TPS ≥50% per 22C3 assay) | Tira + atezo
(n=262) | Pbo + atezo
(n=259) | | Median PFS, months (95% CI)*† | 7.0 (5.6, 9.8) | 5.6 (4.4, 7.0) | | HR (95% CI); p-value | 0.78 (0.63, 0.97); p=0.02 | | Median OS, months (95% CI)*† | 23.1 (17.7, 28.8) | 16.9 (14.6, 23.1) | | HR (95% CI); p-value | 0.87 (0.71, 1.08); p=0.22 | | ORR, %* | 45.8 | 35.1 | | Median DOR, months (95% CI)* | 18.0 (13.6, 24.4) | 14.6 (9.7, 18.6) | | SAS (TC ≥50% per SP263 assay) | Tira + atezo
(n=211) | Pbo + atezo
(n=209) | | Median OS, months (95% CI)* | 24.6 (17.9, 32.0) | 20.6 (16.6, 29.3) | | HR (95% CI) | 0.93 (0.73, 1.18) | | Safety evaluable set‡ | Tira + atezo
(n=267) | Pbo + atezo
(n=263) | | Any grade AEs, % | 95.9 | 91.3 | | Grade 3-4 AEs, % | 41.2 | 33.8 | | Grade 5 AEs, % | 10.9 | 9.9 | | Treatment-related grade 5 AEs, % | 1.5 | 0.8 | | AEs leading to treatment withdrawal, % | 16.1 | 6.5 | | Any grade AESIs, % | 70.0 | 50.6 | | *PFS analysis: data cut-off 12 Mar 2022 (PFS final analysis/first OS interim analysis); OS ORR, and DOR analysis: data cut-off 24 Sep 2024 (OS final analysis). PFS, ORR and DOR were assessed by the investigator. †Primary endpoints. ‡All randomized patients who received ≥1 dose of study treatment. AE, adverse event; atezo, atezolizumab; AESIs, adverse events of special interest; CI, confidence interval; DOR, duration of response; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PAS, primary analysis set; pbo, placebo; PFS, progression-free survival; SAS, secondary analysis set; TC, tumor cell; tira, tiragolumab; TPS, tumor proportion score. |
来自2021年的资料
基于CITYSCAPE试验2期中观察到的有前景的疗效和安全性数据，tiragolumab（一款新型免疫检查点抑制剂,为抗TIGIT单克隆抗体）和阿替利珠单抗的组合被授予突破性疗法认定。
美国食品及药物管理局授予了新型癌症免疫治疗tiragolumab突破性疗法认定（BTD），该药与阿替利珠单抗组成组合，用于PD-L1高表达且无EGFR或ALK肿瘤细胞基因组异常的转移性非小细胞肺癌患者的一线治疗。
tiragolumab是首个获此殊荣的抗TIGIT单克隆抗体，基于全球双盲随机2期CITYSCAPE试验(NCT03563716)的数据，被授予BTD。
该试验对比研究PD-L1阳性局部晚期不可切除或转移性非小细胞肺癌患者的一线治疗使用tiragolumab和阿替利珠单抗组合与阿替利珠单抗和安慰剂组合的差异。
入组的患者被1比1随机分配，要么被给予600毫克tiragolumab（静脉注射）加上1200毫克阿替利珠单抗（静脉注射），要么被给予安慰剂加上阿替利珠单抗，每三周一次直至疾病进展或失去临床获益。
该研究的双主要观察终点为总缓解率（ORR）和无进展生存期（PFS）。关键次要观察终点包括安全性和总生存期。
到目前为止，基于2020年美国临床肿瘤学会(ASCO)虚拟科学项目上提交的试验结果，tiragolumab组合药物已经证明了有前途的有效性和安全性。
到了2019年6月30日（主要分析日期），ORRtiragolumab组31.3%(95%CI, 19.5%-43.2%)，安慰剂组16.2%(95%CI, 6.7%-25.7%)，优势比2.57(95% CI, 1.07-6.14)。而且，中位PFStiragolumab组5.4个月(95%CI, 4.2-not evaluable)，安慰剂组3.6个月(95%CI, 2.7-4.4)，危害比0.57(95% CI, 0.37-0.90)。
在安全性方面，治疗相关不良事件(trae)在tiragolumab组和安慰剂组中分别占80.6%和72.0%;3级及以上的病例分别为14.9%和19.1%。另外，导致停药的AEs分别为7.5%和10.3%。
在新的截止日期2019年12月2日，研究人员发现，新增6个月后续护理后（中位后续护理为10.9个月），ORR和中位PFS的改善情况在tiragolumab组中继续保持，与安慰组对比。tiragolumab组，ORR为37.3%(95% CI, 25.0%-49.6%)，中位PFS为5.6个月(95%CI, 4.2-10.4)，安慰剂组，ORR为20.6%(95% CI,10.2%-30.9%) ，中位PFS为3.9months (95% CI, 2.7-4.5)。安全档案也保持可耐受。
值得注意的是，一项对PD-L1高表达（肿瘤细胞阳性比例分数≥50%）患者展开的探索性分析显示出有临床意义的ORR，与阿替利珠单抗和安慰剂组对比(66% vs 24%)，中位PFS尚未到达，与安慰剂组的4.11个月对比 (HR,0.30; 95% CI, 0.15-0.61)。
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