Efficacy and safety of limertinib versus gefitinib as first-line treatment for locally advanced or metastatic non-small-cell lung cancer with EGFR-sensitising mutation: a randomised, double-blind, double-dummy, phase 3 trial.

This study aimed to prospectively assess the efficacy and safety of limertinib versus gefitinib as a first-line treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR-sensitising mutation.

本研究旨在前瞻性评估Limertinib与吉非替尼作为一线治疗局部晚期或转移性非小细胞肺癌(NSCLC)伴有EGFR敏感突变的疗效和安全性。

Methods

This multicentre, randomised, double-blind, double-dummy, phase 3 trial was done at 56 hospitals in China.

这项多中心、随机、双盲、双模拟的III期临床试验在中国的56家医院进行。

Eligible patients were aged ≥18 years with locally advanced or metastatic NSCLC with EGFR-sensitising mutation (exon 19 deletion or exon 21 L858R mutation) detected in tumour tissue samples using the Cobas EGFR Mutation Test at a central laboratory.

符合条件的患者年龄≥18岁，患有局部晚期或转移性非小细胞肺癌（NSCLC），并且通过中央实验室使用Cobas EGFR突变测试在肿瘤组织样本中检测到EGFR敏感突变（外显子19缺失或外显子21 L858R突变）。

Patients were randomly assigned (1:1) to receive oral limertinib 80 mg twice a day and gefitinib-matching placebo 250 mg once a day or oral gefitinib 250 mg once a day plus limertinib-matching placebo 80 mg twice a day in 21-day cycles, until disease progression or other discontinuation criteria was met.

患者按1:1的比例随机分配，接受口服利美替尼80 mg每日两次和吉非替尼匹配安慰剂250 mg每日一次，或口服吉非替尼250 mg每日一次加利美替尼匹配安慰剂80 mg每日两次，21天为一个周期，直至疾病进展或其他停药标准达成。

Random assignment was stratified according to EGFR mutation type (exon 19 deletion or exon 21 L858R mutation) and CNS metastasis (yes or no) using permuted blocks (block size four) through an interactive web-based response system.

随机分配根据EGFR突变类型（外显子19缺失或外显子21 L858R突变）和中枢神经系统转移（是或否）进行分层，使用置换块（块大小为四）通过交互式网络响应系统进行。

The primary endpoint was independent central review (ICR)-assessed progression-free survival. All enrolled patients who received at least one dose of study treatment were included in the full analysis set for efficacy analysis.

主要终点是独立中心评估的无进展生存期。所有接受至少一次研究治疗的入组患者均被纳入全分析集进行疗效分析。

All enrolled patients who received at least one dose of study treatment and one safety assessment were included in the safety set.

所有接受至少一次研究治疗并进行至少一次安全性评估的入组患者均被纳入安全性集。

This study is registered with ClinicalTrials.gov, NCT04143607, and follow-up is ongoing.

本研究已在ClinicalTrials.gov注册，注册号为NCT04143607，随访正在进行中。

Results

Between June 30, 2021, and Sept 22, 2022, 337 patients were enrolled and 168 were randomly assigned to the limertinib group and 169 to the gefitinib group.

在2021年6月30日至2022年9月22日期间，共有337名患者被纳入研究，并有168名患者随机分配到limertinib组，169名患者分配到gefitinib组。

Patients' median age was 63 years (34-82). 214 (64%) of 337 patients were female and 123 (36%) were male.

患者的中位年龄为63岁（范围34-82岁）。337名患者中，214名（64%）为女性，123名（36%）为男性。

The median masked ICR-assessed progression-free survivalwas 20·7 months (95% CI 15·2-22·1) in the limertinib group and 9·7 months (95% CI 8·3-11·1) in the gefitinib group (hazard ratio[HR] 0·44 [95% CI 0·34-0·58]; p<0·0001).

在limertinib组中，盲法ICR评估的无进展生存期的中位数为20.7个月（95%置信区间15.2-22.1），而在gefitinib组中为9.7个月（95%置信区间8.3-11.1）（风险比[HR] 0.44 [95%置信区间0.34-0.58]；p<0.0001）。

Treatment-related adverse events of grade 3 or worse occurred in 42 (25%) of 168 patients in the limertinib group and 42 (25%) of 169 patients in the gefitinib group.

在接受利美替尼治疗的168名患者中，有42名（25%）发生了3级或更严重的治疗相关不良事件，而在接受吉非替尼治疗的169名患者中，也有42名（25%）发生了3级或更严重的治疗相关不良事件。

Treatment-related serious adverse events occurred in nine (5%) patients and 17 (10%) patients in each group, respectively.

在每个治疗组中，分别有9名（5%）和17名（10%）患者发生了治疗相关的严重不良事件。

Six (4%) patients in the limertinib group died due to adverse events, all of which were considered possibly unrelated to the study drug by investigators.

在利美替尼组中，有6名（4%）患者因不良事件死亡，调查人员认为这些死亡可能与研究药物无关。

In the gefitinib group, seven (4%) patients died due to adverse events, with three (2%) of those deaths judged as possibly related to the study drug by investigators.

在吉非替尼组中，有7名（4%）患者因不良事件死亡，其中3名（2%）的死亡被调查人员认为可能与研究药物有关。

Three treatment-related deaths in the gefitinib group were recorded (one case related to pneumonia and two with cause of death unknown).

记录到吉非替尼组中有三例与治疗相关的死亡病例（一例与肺炎相关，两例死因不明）。

interpretation

Limertinib showed superior efficacy compared with gefitinib and a manageable safety profile for locally advanced or metastatic NSCLC patients with EGFR-sensitising mutation and should be considered as another first-line treatment option for this patient population.

Limertinib 对比吉非替尼显示出更高的疗效，并且对于携带EGFR敏感突变的局部晚期或转移性非小细胞肺癌患者具有可管理的安全性特征，应考虑作为这一患者群体的另一种一线治疗选择。

funding

Jiangsu Aosaikang Pharmaceutical.

江苏奥赛康药业。

translation

For the Chinese translation of the abstract see Supplementary Materials section.

摘要的中文翻译请参见补充材料部分。