Savolitinib combined with osimertinib is a potential novel therapy for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) harbouring MET amplification after progression on EGFR tyrosine kinase inhibitor (TKI) therapy. We aimed to evaluate the efficacy and safety of savolitinib–osimertinib versus standard of care platinum-based doublet chemotherapy in this patient population.
SACHI was a multicentre, randomised, active-controlled, open-label, phase 3 trial conducted across 68 Chinese hospitals. 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. 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. 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. Safety analysis was performed in all patients who received at least one dose of the study treatment. Interim analysis data cutoff was Aug 30, 2024. This study is registered with ClinicalTrials.gov (NCT05015608) and is complete.
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). 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. 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. All participants were Asian. 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 ratio 0·34 [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). 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).
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. This regimen offers a potential oral treatment option for this biomarker-selected population.
对于在接受表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）治疗后出现疾病进展且伴有MET扩增的EGFR突变阳性非小细胞肺癌（NSCLC）患者，赛沃替尼联合奥希替尼是一种潜在的新型疗法。我们旨在评估赛沃替尼-奥希替尼对比标准含铂双药化疗在该患者人群中的疗效和安全性。
SACHI是一项在中国68家医院开展的多中心、随机、活性对照、开放标签的3期试验。符合条件的局部晚期或转移性EGFR突变阳性NSCLC、且在EGFR TKI治疗失败后出现MET扩增的成年患者，以1:1的比例被随机分配至每日一次口服赛沃替尼-奥希替尼组或静脉化疗组（培美曲塞联合顺铂或卡铂），治疗均以21天为一个周期。通过交互式网络应答系统进行中心随机化，并根据是否存在脑转移、既往是否暴露于第三代EGFR TKI以及EGFR突变亚型进行分层，采用混合区组大小的随机化方法。主要终点是根据实体瘤疗效评价标准（RECIST）1.1版由研究者评估的无进展生存期（PFS），采用分层检验程序：首先在未接受过第三代EGFR TKI治疗的人群中进行，若结果为阳性，则在意向治疗（ITT）人群中进行。安全性分析在所有接受了至少一剂研究治疗的患者中进行。中期分析的数据截止日期为2024年8月30日。本研究已在ClinicalTrials.gov注册（NCT05015608），并已完成。
2021年10月15日至2024年8月30日期间，共纳入211例患者，其中106例被随机分配至赛沃替尼-奥希替尼组，105例被随机分配至化疗组；其中包括211例患者中的137例（65%）未接受过第三代EGFR TKI治疗（赛沃替尼-奥希替尼组69例；化疗组68例）。在赛沃替尼-奥希替尼组的106例患者中，中位年龄为59.4岁（IQR 54.3-65.8），62例（58%）为女性，44例（42%）为男性。在化疗组的105例患者中，中位年龄为61.9岁（IQR 56.3-69.1），55例（52%）为女性，50例（48%）为男性。所有参与者均为亚洲人。在未接受过第三代EGFR TKI治疗的人群（9.8个月 [95% CI 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）和ITT人群（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）中，与化疗相比，赛沃替尼-奥希替尼组的中位PFS均显著延长。在接受研究药物治疗的患者中，两组发生3级或以上治疗中出现的不良事件的患者比例相同（赛沃替尼-奥希替尼组106例患者中的60例[57%]；化疗组96例患者中的55例[57%]）。
对于在接受EGFR TKI治疗后出现疾病进展的EGFR突变阳性、MET扩增NSCLC患者，与化疗相比，赛沃替尼-奥希替尼联合疗法改善了PFS，同时保持了良好的耐受性。该方案为这一经生物标志物筛选的人群提供了一个潜在的口服治疗选择。
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