Savolitinib plus osimertinib versus chemotherapy for advanced, EGFR mutation-positive, MET-amplified non-small-cell lung cancer in China (SACHI): interim analysis of a multicentre, open-label, phase 3 randomised controlled trial.

We aimed to evaluate the efficacy and safety of savolitinib-osimertinib versus standard of care platinum-based doublet chemotherapy in this patient population.

我们旨在评估savolitinib-osimertinib与标准铂类双药化疗在这一患者群体中的疗效和安全性。

Methods

SACHI was a multicentre, randomised, active-controlled, open-label, phase 3 trial conducted across 68 Chinese hospitals.

SACHI 是一项在中国 68 家医院进行的多中心、随机、活性对照、开放标签的 3 期临床试验。

Eligible adults with locally advanced or metastatic EGFR mutation-positive NSCLC and MET amplification after EGFR TKI failure were randomly assigned (1:1) to once daily oral savolitinib-osimertinib or intravenous chemotherapy (pemetrexed plus either cisplatin or carboplatin), both in 21-day cycles.

符合条件的成年患者，患有局部晚期或转移性 EGFR 突变阳性 NSCLC 且在 EGFR TKI 治疗失败后出现 MET 扩增，被随机分配（1:1）至每日一次口服 savolitinib-osimertinib 或静脉化疗（培美曲塞联合顺铂或卡铂），均以 21 天为一个周期。

Central randomisation was implemented through an interactive web-response system with stratification based on the presence of brain metastases, previous exposure to third-generation EGFR TKIs, and EGFR mutation subtype, using a mixed block-size methodology.

通过交互式网络响应系统实施中央随机化，根据是否存在脑转移、之前是否接触过第三代EGFR TKIs以及EGFR突变亚型进行分层，采用混合块大小方法。

The primary endpoint, investigator-assessed progression-free survival(PFS) per Response Evaluation Criteria in Solid Tumours version 1.1, was tested using a hierarchical procedure: first in the third-generation EGFR TKI-naive population, and if positive, the intention-to-treat(ITT) population.

主要终点，即研究者评估的无进展生存期（PFS），根据实体瘤反应评估标准版本1.1进行评估，采用分层程序进行测试：首先在第三代EGFR TKI未经治疗的人群中进行，如果结果为阳性，则在意向治疗（ITT）人群中进行。

Safety analysis was performed in all patients who received at least one dose of the study treatment.

对所有至少接受一次研究治疗的患者进行了安全性分析。

Interim analysis data cutoff was Aug 30, 2024.

中期分析数据截止日期为2024年8月30日。

This study is registered with ClinicalTrials.gov (NCT05015608) and is complete.

该研究已在ClinicalTrials.gov注册（NCT05015608），研究已完成。

Results

Between Oct 15, 2021, and Aug 30, 2024, 211 patients were enrolled, 106 were randomly assigned to savolitinib-osimertinib and 105 were randomly assigned to chemotherapy, including 137 (65%) of 211 who were third-generation EGFR TKI-naive (69 in the savolitinib-osimertinib group; 68 in the chemotherapy group).

在2021年10月15日至2024年8月30日期间，共有211名患者入组，其中106名随机分配至savolitinib-osimertinib组，105名随机分配至化疗组，包括211名患者中的137名（占65%）为三代EGFR TKI初治患者（savolitinib-osimertinib组69名；化疗组68名）。

In 106 patients in the savolitinib-osimertinib group, the median age was 59·4 years (IQR 54·3-65·8), 62 (58%) were female, and 44 (42%) were male.

在接受萨沃替尼-奥希替尼治疗的106名患者中，中位年龄为59.4岁（四分位数间距54.3-65.8），女性占62人（58%），男性占44人（42%）。

In 105 patients in the chemotherapy group, the median age was 61·9 years (IQR 56·3-69·1), 55 (52%) were female, and 50 (48%) were male.

在接受化疗的105名患者中，中位年龄为61.9岁（四分位数间距56.3-69.1），女性占55人（52%），男性占50人（48%）。

All participants were Asian.

所有参与者均为亚洲人。

Median PFS was significantly prolonged with savolitinib-osimertinib versus chemotherapy in the third-generation EGFR TKI-naive (9·8 months [95% CI 6·9-12·5] vs 5·4 months [4·2-6·0]; hazard ratio0·34 [0·21-0·56]; p<0·0001) and ITT populations (8·2 months [6·9-11·2] vs 4·5 months [3·0-5·4]; 0·34 [0·23-0·49]; p<0·0001).

在第三代EGFR酪氨酸激酶抑制剂（TKI）未经治疗的患者中，与化疗相比，萨沃替尼-奥希替尼显著延长了中位无进展生存期（PFS）（9.8个月 [95% 置信区间 6.9-12.5] 对比 5.4个月 [4.2-6.0]；风险比0.34 [0.21-0.56]；p<0.0001），在意向治疗（ITT）人群中也观察到类似结果（8.2个月 [6.9-11.2] 对比 4.5个月 [3.0-5.4]；0.34 [0.23-0.49]；p<0.0001）。

Grade 3 or worse treatment-emergent adverse events occurred in the same proportion of patients in both groups who received the study drugs (60 [57%] of 106 patients in the savolitinib-osimertinib group and 55 [57%] of 96 patients in the chemotherapy group).

在接受研究药物治疗的两组患者中，3级或更严重的治疗相关不良事件的发生比例相同（106名患者中有60名[57%]在savolitinib-osimertinib组，96名患者中有55名[57%]在化疗组）。

interpretation

The savolitinib-osimertinib combination improved PFS versus chemotherapy in patients with EGFR mutation-positive, MET-amplified NSCLC that had progressed on EGFR TKI therapy, while maintaining a favourable tolerability profile.

在EGFR突变阳性、MET扩增的非小细胞肺癌患者中，对于那些在EGFR酪氨酸激酶抑制剂治疗后进展的患者，savolitinib-osimertinib联合疗法与化疗相比，改善了无进展生存期（PFS），同时保持了良好的耐受性。

This regimen offers a potential oral treatment option for this biomarker-selected population.

该方案为这一生物标志物筛选的人群提供了一种潜在的口服治疗选择。

funding

HUTCHMED and AstraZeneca.

和记黄埔医药与阿斯利康。