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

Yongfeng Yu; Yongxin Ren; Jian Fang; Lejie Cao; Zongan Liang; Qisen Guo; Sen Han; Zimei Ji; Ye Wang; Yulan Sun; Yuan Chen; Xingya Li; Hua Xu; Jianying Zhou; Liyan Jiang; Ying Cheng; Zhigang Han; Jianhua Shi; Gongyan Chen; Rui Ma; Yun Fan; Sanyuan Sun; Longxian Jiao; Xiaoyun Jia; Linfang Wang; Puhan Lu; Qian Xu; Xian Luo; Weiguo Su; Shun Lu

doi:10.1177/17588359221133546

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

Ther Adv Med Oncol. 2022 Oct 31:14:17588359221133546. doi: 10.1177/17588359221133546. eCollection 2022.

Authors

Yongfeng Yu¹, Yongxin Ren², Jian Fang³, Lejie Cao⁴, Zongan Liang⁵, Qisen Guo⁶, Sen Han³, Zimei Ji⁴, Ye Wang⁵, Yulan Sun⁶, Yuan Chen⁷, Xingya Li⁸, Hua Xu⁹, Jianying Zhou¹⁰, Liyan Jiang¹, Ying Cheng¹¹, Zhigang Han¹², Jianhua Shi¹³, Gongyan Chen¹⁴, Rui Ma¹⁵, Yun Fan¹⁶, Sanyuan Sun¹⁷, Longxian Jiao², Xiaoyun Jia², Linfang Wang², Puhan Lu², Qian Xu², Xian Luo², Weiguo Su², Shun Lu¹⁸

Affiliations

¹ Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
² HUTCHMED, Shanghai, China.
³ Peking University Cancer Hospital and Institute, Beijing, China.
⁴ Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China.
⁵ West China Hospital of Sichuan University, Chengdu, China.
⁶ Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China.
⁷ Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
⁸ The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁹ The Second Affiliated Hospital of Nanchang University, Nanchang, China.
¹⁰ The First Affiliated Hospital of Zhejiang University, Hangzhou, 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.

Abstract

Background: 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).

Objective: To analyse post hoc, the association between circulating tumour DNA (ctDNA) biomarkers and clinical outcomes, including resistance, with savolitinib.

Design: A multicentre, single-arm, open-label phase 2 study.

Methods: 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.

Results: 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).

Conclusion: 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.

Registration: The trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.

Keywords: MET exon 14 skipping; circulating tumour DNA; non-small cell lung cancer; pulmonary sarcomatoid carcinoma; savolitinib.

Associated data

ClinicalTrials.gov/NCT02897479