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Circulating tumour DNA biomarkers in savolitinib-treated patients with non-small cell lung cancer harbouring MET exon 14 skipping alterations: a post hoc analysis of a pivotal phase 2 study

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机构： [1]HUTCHMED, Shanghai, China. [2]Peking University Cancer Hospital and Institute, Beijing, China. [3]Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China. [4]West China Hospital of Sichuan University, Chengdu, China. [5]Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China. [6]Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China. [7]The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [8]The Second Affiliated Hospital of Nanchang University, Nanchang, China. [9]The First Affiliated Hospital of Zhejiang University, Hangzhou, China. [10]Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China. [11]Jilin Cancer Hospital, Changchun, China. [12]The Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China. [13]Linyi Cancer Hospital, Linyi, China. [14]Cancer Hospital of Harbin Medical University, Harbin, China. [15]Liaoning Cancer Hospital, Shenyang, China. [16]Zhejiang Cancer Hospital, Hangzhou, China. [17]Xuzhou Central Hospital, Xuzhou, China. [18]Department of Medical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiaotong University, No. 241, Huaihai West Road, Shanghai 200030, China.

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Savolitinib, a selective MET inhibitor, showed efficacy in patients with non-small cell lung cancer (NSCLC), including pulmonary sarcomatoid carcinoma (PSC), harbouring MET exon 14 skipping alteration (METex14).To analyse post hoc, the association between circulating tumour DNA (ctDNA) biomarkers and clinical outcomes, including resistance, with savolitinib.A multicentre, single-arm, open-label phase 2 study.All enrolled patients with baseline plasma samples were included. Outcomes were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) by baseline METex14 and post-treatment clearance, coexisting gene alterations at baseline and disease progression.Among 66 patients with baseline ctDNA sequencing, 46 (70%) had detectable METex14. Frequent coexisting baseline gene alterations included TP53 and POT1 mutations. Patients with detectable baseline METex14 exhibited worse PFS [hazard ratio (HR), 1.77; 95% confidence interval (CI), 0.88-3.57; p = 0.108] and OS (HR, 3.26; 95% CI, 1.35-7.89; p = 0.006) than those without, despite showing a numerically higher ORR. Among 24 patients with baseline detectable METex14 and evaluable postbaseline samples, 13 achieved METex14 clearance post-treatment. Median time to first clearance was 1.3 months (range, 0.7-1.5). METex14 post-treatment clearance was associated with better ORR (92.3%; 95% CI, 64.0-99.8 versus 36.4%; 95% CI, 10.9-69.2; p = 0.0078), PFS (HR, 0.44; 95% CI, 0.2-1.3; p = 0.1225) and OS (HR, 0.31; 95% CI, 0.1-1.0; p = 0.0397) versus non-clearance. Among 22 patients with disease progression, 10 acquired pathway alterations (e.g. in RAS/RAF and PI3K/PTEN) alone or with secondary MET mutations (D1228H/N and Y1230C/H/S).ctDNA biomarkers may allow for longitudinal monitoring of clinical outcomes with savolitinib in patients with METex14-positive PSC and other NSCLC subtypes. Specifically, undetectable baseline METex14 or post-treatment clearance may predict favourable clinical outcomes, while secondary MET mutations and other acquired gene alterations may explain resistance to savolitinib.The trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.© The Author(s), 2022.

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出版当年[2022]版：

大类 | 2 区医学

小类 | 3 区肿瘤学

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大类 | 2 区医学

小类 | 3 区肿瘤学

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Q2 ONCOLOGY

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Q2 ONCOLOGY

影响因子： 4.3 最新[2023版] 4.9 最新五年平均 4.9 出版当年[2022版] 5.6 出版当年五年平均 5.485 出版前一年[2021版] 4.3 出版后一年[2023版]

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第一作者机构： [1]HUTCHMED, Shanghai, China.

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