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.

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 ( MET ex14).
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 MET ex14 and post-treatment clearance, coexisting gene alterations at baseline and disease progression.
Results: Among 66 patients with baseline ctDNA sequencing, 46 (70%) had detectable MET ex14. Frequent coexisting baseline gene alterations included TP53 and POT1 mutations. Patients with detectable baseline MET ex14 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 MET ex14 and evaluable postbaseline samples, 13 achieved MET ex14 clearance post-treatment. Median time to first clearance was 1.3 months (range, 0.7-1.5). MET ex14 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 MET ex14-positive PSC and other NSCLC subtypes. Specifically, undetectable baseline MET ex14 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.
Competing Interests: SL reports receiving research support from AstraZeneca, HUTCHMED, Bristol Myers Squibb, Hengrui Therapeutics, BeiGene, Roche and Hansoh; receiving speaker fees from AstraZeneca, Roche, Hansoh and Hengrui Therapeutics and being an advisor and consultant for AstraZeneca, Pfizer, Boehringer Ingelheim, HUTCHMED, Simcere, Zai Lab, GenomiCare, Yuhan Corporation, prIME Oncology, Menarini, InventisBio Co. Ltd and Roche. No disclosures were reported by the other authors.
(© The Author(s), 2022.)