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

• Published in: Therapeutic advances in medical oncology Vol. 14; p. 17588359221133546
• Main Authors: Yu, Yongfeng, Ren, Yongxin, Fang, Jian, Cao, Lejie, Liang, Zongan, Guo, Qisen, Han, Sen, Ji, Zimei, Wang, Ye, Sun, Yulan, Chen, Yuan, Li, Xingya, Xu, Hua, Zhou, Jianying, Jiang, Liyan, Cheng, Ying, Han, Zhigang, Shi, Jianhua, Chen, Gongyan, Ma, Rui, Fan, Yun, Sun, Sanyuan, Jiao, Longxian, Jia, Xiaoyun, Wang, Linfang, Lu, Puhan, Xu, Qian, Luo, Xian, Su, Weiguo, Lu, Shun
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 2022; Sage Publications Ltd
• Subjects: 1-Phosphatidylinositol 3-kinase; Biomarkers; Clinical outcomes; Lung cancer; Lung carcinoma; Mutation; Non-small cell lung carcinoma; Original Research; p53 Protein; Patients; PTEN protein; Raf protein; Small cell lung carcinoma; Tumors; non-small cell lung cancer; savolitinib; pulmonary sarcomatoid carcinoma; circulating tumour DNA; MET exon 14 skipping
• ISSN: 1758-8359; 1758-8340; 1758-8359
• DOI: 10.1177/17588359221133546

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.