First-line serplulimab plus chemotherapy with or without HLX04 versus chemotherapy in locally advanced or metastatic non-squamous non-small-cell lung cancer (ASTRUM-002): a randomised, double-blind, multicentre phase 3 trial.

We evaluated serplulimab (an anti-PD-1 antibody) plus HLX04 (a bevacizumab biosimilar) and chemotherapy in non-squamous NSCLC.

我们评估了抗PD-1抗体serplulimab联合HLX04（一种贝伐珠单抗生物类似药）以及化疗在非鳞状NSCLC中的疗效。

Methods

ASTRUM-002 is a randomised, double-blind, multicentre, phase 3 trial with a three-arm design.

ASTRUM-002是一项随机、双盲、多中心的3期临床试验，采用三臂设计。

Patients (aged ≥18 years and ≤75 years) with locally advanced or metastatic non-squamous NSCLC without EGFR sensitising mutations or ALK/ROS1 rearrangements and previous systemic therapy were randomly assigned (1:1:1; stratified by PD-L1 expression, smoking history, and brain metastasis) to receive serplulimab (4·5 mg/kg intravenously) plus HLX04 (15 mg/kg intravenously) and chemotherapy (pemetrexed and carboplatin; group A), serplulimab plus chemotherapy plus HLX04 placebo (group B), or chemotherapy plus serplulimab placebo plus HLX04 placebo (group C).

年龄在≥18岁且≤75岁的患者，患有局部晚期或转移性非鳞状NSCLC，没有EGFR敏感突变或ALK/ROS1重排，并且之前接受过系统治疗，被随机分配（1:1:1；按PD-L1表达、吸烟史和脑转移进行分层）接受serplulimab（4.5 mg/kg静脉注射）加HLX04（15 mg/kg静脉注射）和化疗（培美曲塞和卡铂；A组），serplulimab加化疗加HLX04安慰剂（B组），或化疗加serplulimab安慰剂加HLX04安慰剂（C组）。

The primary endpoint was the blinded independent central review assessed progression-free survivalper the Response Evaluation Criteria in Solid Tumors version 1.1, assessed in the intention-to-treatpopulation.

主要终点是根据实体瘤疗效评价标准1.1版，通过盲法独立中央审查评估的无进展生存期，在意向治疗人群中进行评估。

This study is registered with ClinicalTrials.gov, NCT03952403, and is complete.

该研究已在ClinicalTrials.gov上注册，编号为NCT03952403，并已完成。

Results

Between Nov 25, 2019, and June 15, 2022, 642 patients were enrolled across 72 hospitals in China; six in the safety run-in phase and the remaining 636 patients were randomised to group A (212 patients), B (214), or C (210). 465 (73%) were male, 171 (27%) were female, and 599 (94%) were of Han ethnicity.

2019年11月25日至2022年6月15日，中国72家医院共纳入642名患者；其中6名患者进入安全启动阶段，其余636名患者随机分为A组（212名患者）、B组（214名）和C组（210名）。465名（73%）为男性，171名（27%）为女性，599名（94%）为汉族。

By the data cutoff date of June 15, 2023, the median follow-up duration was 23·4 months (95% CI 21·6-24·9) in group A, 23·1 (21·4-25·6) in group B, and 23·0 (20·7-25·6) in group C.

截至2023年6月15日数据截止日期，A组的中位随访时间为23.4个月（95%置信区间21.6-24.9），B组为23.1个月（21.4-25.6），C组为23.0个月（20.7-25.6）。

Median progression-free survivalwas 12·6 months (95% CI 8·7-14·0; 123 events) in group A, 11·0 months (95% CI 8·4-12·7; 130 events) in group B, and 5·6 months (95% CI 4·8-6·8; 156 events) in group C.

A组的中位无进展生存期为12.6个月（95%置信区间8.7-14.0；123个事件），B组为11.0个月（95%置信区间8.4-12.7；130个事件），C组为5.6个月（95%置信区间4.8-6.8；156个事件）。

A significant reduction was seen in risk of progressive disease or death for patients in group B compared with group C (hazard ratio[HR] 0·55, 95% CI 0·43-0·69; p<0·0001).

与C组相比，B组患者的疾病进展或死亡风险显著降低（风险比[HR] 0.55，95%置信区间0.43-0.69；p<0.0001）。

No significant improvement in progression-free survivalwas seen for group A compared with group B (HR 0·86, 0·67-1·11; p=0·25).

与B组相比，A组无显著的无进展生存期改善（风险比0·86，95%置信区间0·67-1·11；p=0·25）。

Treatment-related serious adverse events occurred in 82 (39%) patients in group A, 79 (37%) in group B, and 51 (24%) in group C.

治疗相关的严重不良事件在A组的82名（39%）患者、B组的79名（37%）患者和C组的51名（24%）患者中发生。

Grade 3 or worse treatment-related adverse events occurred in 149 (71%) patients in group A, 142 (66%) in group B, and 119 (57%) in group C.

在A组中，有149名（71%）患者出现了3级或更严重的治疗相关不良事件，在B组中有142名（66%），在C组中有119名（57%）。

Treatment-related adverse events leading to death occurred in ten (5%) patients in group A, five (2%) in group B, and seven (3%) in group C.

在A组中，有十名（5%）患者因治疗相关不良事件导致死亡，在B组中有五名（2%），在C组中有七名（3%）。

interpretation

The addition of serplulimab to chemotherapy led to significantly longer progression-free survivalin patients with locally advanced or metastatic non-squamous NSCLC compared with chemotherapy alone and represents an alternative first-line treatment option for this patient population.

将赛普利单抗加入化疗中，使得局部晚期或转移性非鳞状NSCLC患者的无进展生存期显著延长，与单纯化疗相比，为这一患者群体提供了另一种一线治疗选择。

HLX04 plus serplulimab and chemotherapy did not confer further statistical benefit compared with serplulimab plus chemotherapy.

HLX04联合赛普利单抗和化疗并未带来进一步的统计学益处，与仅使用赛普利单抗加化疗相比。

funding

Shanghai Henlius Biotech.

上海复宏汉霖生物技术有限公司