Aumolertinib with or without chemotherapy in EGFR-mutated advanced non-small-cell lung cancer (AENEAS2): an open-label, multicentre, randomised, controlled, phase 3 trial.

Given the previously established clinical efficacy and adverse eventprofile of aumolertinib, we aimed to evaluate the efficacy and adverse eventprofile of aumolertinib in combination with platinum-based chemotherapy versus aumolertinib monotherapy as first-line treatment for patients with locally advanced or metastatic NSCLC patients with EGFR-sensitive mutations.

鉴于奥莫利替尼先前已确立的临床疗效和不良事件特征，我们旨在评估奥莫利替尼联合基于铂的化疗与奥莫利替尼单药治疗作为局部晚期或转移性NSCLC患者（携带EGFR敏感突变）一线治疗的疗效和不良事件特征。

Methods

The open-label, multicentre, randomised, controlled, phase 3 AENEAS2 trial was done across 60 hospitals in China.

公开标签、多中心、随机、对照的第三阶段AENEAS2试验在中国的60家医院进行。

Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1; treatment-naive; histologically or cytologically confirmed locally advanced or metastatic NSCLC harbouring EGFR-sensitive mutations (ex19del/L858R with or without other EGFR mutations) were eligible.

年龄至少18岁的患者，东部肿瘤协作组表现状态（ECOG PS）为0-1；未接受过治疗；经组织学或细胞学证实的局部晚期或转移性非小细胞肺癌（NSCLC），携带EGFR敏感突变（ex19del/L858R，无论是否伴有其他EGFR突变）的患者符合入选条件。

Brain metastases were allowed if neurologically stable.

如果神经系统稳定，允许有脑转移。

Previous EGFR-TKI therapy was an exclusion criterion.

之前的EGFR-TKI治疗是排除标准。

Patients were randomly assigned (1:1) with block randomisation (block size of 6), stratified by EGFR mutation type and baseline brain metastasis, to receive aumolertinib monotherapy (110 mg orally once a day) or combination therapy (aumolertinib 110 mg orally once a day plus pemetrexed 500 mg/m2 intravenously with cisplatin [75 mg/m2] or carboplatin [area under the plasma concentration-time curve 5] intravenously on day 1 of 21-day cycles for 4-6 cycles), followed by maintenance therapy (aumolertinib 110 mg orally once a day and pemetrexed 500 mg/m2 intravenously once every 3 weeks).

患者按1:1的比例随机分配（随机区组大小为6），按EGFR突变类型和基线脑转移进行分层，接受aumolertinib单药治疗（每日口服110 mg）或联合治疗（每日口服aumolertinib 110 mg加静脉注射pemetrexed 500 mg/m2，以及顺铂[75 mg/m2]或卡铂[血浆浓度-时间曲线下面积5]静脉注射，每21天为一个周期，共4-6个周期），随后进行维持治疗（每日口服aumolertinib 110 mg和每3周静脉注射pemetrexed 500 mg/m2一次）。

The primary endpoint was progression-free survivalassessed by blinded independent central review (BICR; RECIST version 1.1).

主要终点是通过盲法独立中心评审（BICR；RECIST版本1.1）评估的无进展生存期。

Efficacy was analysed in the full-analysis set, which included all randomly assigned patients, and safety was analysed in patients who received at least one dose of the actual trial treatment.

疗效分析包括了所有随机分配的患者，即全分析集，而安全性分析则包括了至少接受了一次实际试验治疗的患者。

The trial is registered at ClinicalTrials.gov, NCT04923906, and is ongoing, but closed to enrolment.

该试验已在ClinicalTrials.gov注册，注册号为NCT04923906，目前仍在进行中，但已停止招募新患者。

Results

Between Aug 4, 2021, to June 18, 2024, of 1011 patients assessed for eligibility, 624 randomly assigned patients (median age 59·0 years [IQR 52·0-66·0]; 337 [54%] were female, 287 [46%] were male) were randomly assigned. 310 (50%) patients received combination therapy and 314 (50%) received monotherapy.

2021年8月4日至2024年6月18日期间，共有1011名患者被评估以确定其是否符合入组资格，其中624名患者（中位年龄59.0岁 [四分位数间距52.0-66.0]；337名 [54%] 为女性，287名 [46%] 为男性）被随机分配。310名（50%）患者接受了联合治疗，另外314名（50%）患者接受了单一治疗。

As of the data cutoff date (June 18, 2024), the median follow-up was 23·4 months (IQR 20·5-26·5), In the full-analysis set, median BICR-assessed progression-free survivalwas 28·9 months (95% CI 26.3, NA) in the combination therapy versus 18·9 months (17·8-21·1) in the monotherapy (hazard ratio[HR] 0·47, 95% CI 0·37-0·60; log-rank p<0·0001).

截至数据截止日期（2024年6月18日），中位随访时间为23.4个月（四分位数间距20.5-26.5）。在全分析集中，BICR评估的中位无进展生存期在联合治疗组为28.9个月（95%置信区间26.3, NA），而在单一治疗组为18.9个月（17.8-21.1）（风险比[HR] 0.47, 95%置信区间0.37-0.60；对数秩检验p<0.0001）。

The most common grade 3-4 adverse events (occurring in at least 20% in any group) were neutrophil count decreased (168 [55%] of 304 in the combination group versus four [1%] of 316 in monotherapy group), white blood cell count decreased (103 [34%] vs one [<1%]), and platelet count decreased (62 [20%] vs two [1%]).

最常见的3-4级不良事件（在任何组中发生率至少为20%）是中性粒细胞计数减少（组合组304人中有168人[55%]，单药治疗组316人中有4人[1%]），白细胞计数减少（103人[34%]对比1人[<1%]），以及血小板计数减少（62人[20%]对比2人[1%]）。

Serious adverse events occurred in 109 (36%) patients in the combination group and 53 (17%) in the monotherapy group, the most common of which were platelet count decreased (22 [7%] vs 0), neutrophil count decreased (17 [6%] vs 0), white blood cell count decreased (13 [4%] vs 0), and anaemia (ten [3%] vs two [1%]).

严重不良事件在组合组的109名（36%）患者和单药治疗组的53名（17%）患者中发生，其中最常见的包括血小板计数减少（22人[7%]对比0人），中性粒细胞计数减少（17人[6%]对比0人），白细胞计数减少（13人[4%]对比0人），以及贫血（10人[3%]对比2人[1%]）。

Treatment-related deaths occurred in one (<1%) patient in the combination group (encephalopathy) and two (1%) in the monotherapy group (pulmonary embolism and respiratory failure with circulatory collapse).

联合治疗组中有一名（<1%）患者因治疗相关死亡（脑病），单药治疗组中有两名（1%）患者因治疗相关死亡（肺栓塞和循环衰竭导致的呼吸衰竭）。

interpretation

Aumolertinib in combination with chemotherapy significantly improved progression-free survival. Although this regimen was associated with increased toxicity, the side-effects were managed with dose adjustment and supportive treatment aligned with clinical practice.

Aumolertinib与化疗联合使用显著改善了无进展生存期。尽管这种方案与增加的毒性相关，但通过剂量调整和与临床实践相符的支持性治疗，副作用得到了管理。

Long-term follow-up is required to assess overall survival. The AENEAS2 study provides evidence to guide clinical practice regarding EGFR-TKIs and their combination use in treating patients with advanced EGFR-mutated NSCLC.

需要长期随访以评估总生存。AENEAS2 研究提供了证据，指导临床实践关于 EGFR-TKIs 及其联合使用在治疗晚期 EGFR 突变 NSCLC 患者中的应用。

funding

Jiangsu Hansoh Pharmaceutical Group, and the Collaborative Innovation Center for Clinical and Translational Science by Ministry of Education & Shanghai.

江苏豪森药业集团，以及由教育部和上海合办的临床与转化医学协同创新中心。

translations

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。