Tiragolumab plus atezolizumab and chemotherapy as first-line treatment for patients with unresectable oesophageal squamous cell carcinoma (SKYSCRAPER-08): a randomised, double-blind, placebo-controlled, phase 3 trial.

We aimed to evaluate the efficacy and safety of adding tiragolumab and atezolizumab to chemotherapy as first-line treatment for unresectable or metastatic oesophageal squamous cell carcinoma.

我们的目标是评估将tiragolumab和atezolizumab加入化疗作为无法切除或转移性食管鳞状细胞癌一线治疗的疗效和安全性。

Methods

The SKYSCRAPER-08 randomised, double-blind, placebo-controlled, phase 3 trial was done at 67 centres in mainland China, South Korea, Thailand, Taiwan, and Hong Kong and enrolled adult patients (aged ≥18 years) with treatment-naive, unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma, with an Eastern Cooperative Oncology Group performance status of 0-1.

SKYSCRAPER-08 研究是一项随机、双盲、安慰剂对照的 III 期临床试验，研究在中国大陆、韩国、泰国、台湾和香港的 67 个中心进行，招募了年龄≥18岁的成年患者，这些患者均为未经治疗的、无法手术切除的局部晚期、无法手术切除的复发性或转移性食管鳞状细胞癌患者，且东部肿瘤协作组（ECOG）表现状态为 0-1。

Patients were randomly assigned (1:1) to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) and chemotherapy (paclitaxel [175 mg/m2] and cisplatin [60-80 mg/m2]) or placebo and chemotherapy through intravenous infusion for six 21-day cycles.

患者按 1:1 的比例随机分配，接受 tiragolumab（600 mg）联合 atezolizumab（1200 mg）和化疗（紫杉醇[175 mg/m2]和顺铂[60-80 mg/m2]）或安慰剂和化疗，通过静脉输注给药，为期六个21天的周期。

The primary outcomes were independent review facility-assessed progression-free survivaland overall survivalin the intention-to-treatpopulation (defined as all randomly assigned patients, regardless of whether they received any study treatment).

主要结果是独立审查机构评估的无进展生存期和总生存期，这是在意向治疗人群中进行的（定义为所有随机分配的患者，无论他们是否接受了任何研究治疗）。

This study was registered with ClinicalTrials.gov, NCT04540211, and is ongoing.

这项研究已在ClinicalTrials.gov上注册，编号为NCT04540211，并且正在进行中。

Results

Between Oct 30, 2020, and Nov 30, 2021, 461 patients were assigned to receive tiragolumab plus atezolizumab and chemotherapy (n=229) or placebo and chemotherapy (n=232); 406 (88%) were male and 55 (12%) female, and all patients were Asian.

在2020年10月30日至2021年11月30日期间，共有461名患者被分配接受tiragolumab联合atezolizumab和化疗(n=229)或安慰剂和化疗(n=232)；其中406名（88%）为男性，55名（12%）为女性，所有患者均为亚洲人。

Median survival follow-up was 12·6 months (IQR 6·8-18·0).

中位生存随访时间为12.6个月（四分位数间距6.8-18.0）。

Median independent review facility-assessed progression-free survival(cutoff June 15, 2022) in the tiragolumab plus atezolizumab and chemotherapy group was 6·2 months (95% CI 5·7-7·2) versus 5·4 months (95% CI 4·4-5·5) in the placebo and chemotherapy group (HR 0·56, 95% CI 0·45-0·70; p<0·0001).

独立审查机构评估的无进展生存期（截止日期为2022年6月15日）在tiragolumab联合atezolizumab和化疗组为6.2个月（95%置信区间5.7-7.2），而在安慰剂和化疗组为5.4个月（95%置信区间4.4-5.5）（HR 0.56，95%置信区间0.45-0.70；p<0.0001）。

Median overall survival(cutoff Feb 13, 2023) was 15·7 months (95% CI 13·3-20·4) and 11·1 months (95% CI 9·6-13·6; HR 0·70, 95% CI 0·55-0·88; p=0·0024).

总生存期的中位数（截止日期为2023年2月13日）为15.7个月（95%置信区间13.3-20.4）和11.1个月（95%置信区间9.6-13.6；HR 0.70，95%置信区间0.55-0.88；p=0.0024）。

The most common grade 3-4 adverse events in the tiragolumab plus atezolizumab and chemotherapy group versus the placebo and chemotherapy group were white blood cell count decrease (46 [20%] of 228 vs 35 [15%] of 227), neutrophil count decrease (78 [34%] vs 78 [34%]), and anaemia (19 [8%] vs 24 [11%]).

在tiragolumab联合atezolizumab和化疗组与安慰剂和化疗组中，最常见的3-4级不良事件是白细胞计数减少（228例中有46例[20%]对比227例中有35例[15%]）、中性粒细胞计数减少（78例[34%]对比78例[34%]）和贫血（19例[8%]对比24例[11%]）。

Serious adverse events occurred in 94 (41%) of 228 patients in the tiragolumab plus atezolizumab and chemotherapy group and 89 (39%) of 227 in the placebo and chemotherapy group; the most common serious adverse eventwas pneumonia (17 [7%] of 228 and 13 [6%] of 227).

在tiragolumab联合atezolizumab和化疗组的228名患者中有94例（41%）出现严重不良事件，而在安慰剂和化疗组的227名患者中有89例（39%）出现严重不良事件；最常见的严重不良事件是肺炎（228例中有17例[7%]，227例中有13例[6%]）。

Treatment-related deaths occurred in six patients (3%) in the tiragolumab plus atezolizumab and chemotherapy group (immune-mediated lung disease, pneumonitis, cardiac arrest, gastrointestinal haemorrhage, hepatic failure, and bacterial pneumonia) and two (1%) in the placebo and chemotherapy group (gastrointestinal infection and death of unknown cause).

在接受tiragolumab联合atezolizumab和化疗的组别中，有六名患者（3%）发生了与治疗相关的死亡（免疫介导的肺病、肺炎、心脏骤停、胃肠道出血、肝功能衰竭和细菌性肺炎），而在安慰剂和化疗组中，有两名患者（1%）发生了与治疗相关的死亡（胃肠道感染和不明原因的死亡）。

No new safety signals were identified.

没有发现新的安全信号。

interpretation

Independent review facility-assessed progression-free survivaland overall survivalwere significantly better in the tiragolumab plus atezolizumab and chemotherapy group compared with chemotherapy alone for unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma.

独立审查机构评估的无进展生存期和总生存期在tiragolumab联合atezolizumab和化疗组中显著优于仅接受化疗的不可切除的局部晚期、不可切除的复发性或转移性食管鳞状细胞癌患者。

These data support the rationale for exploring dual checkpoint inhibition added to chemotherapy for this group of patients with a high unmet need.

这些数据支持了为这一高未满足需求的患者群体探索将双重检查点抑制剂加入化疗的合理性。

funding

F Hoffmann-La Roche-Genentech.

F Hoffmann-La Roche-Genentech 公司