Analysis of MET gene alterations in cfDNA samples from a phase II study of savolitinib in patients (pts) with MET-amplified gastroesophageal junction adenocarcinomas or gastric cancer (GEJ/GC)

BackgroundSavolitinib is a highly selective oral MET tyrosine kinase inhibitor and approved for treatment of NSCLC with METex14 alterations in China. In a phase II study (NCT04923932) in GEJ/GC pts with MET amplification (METamp), savolitinib demonstrated confirmed objective response rate (cORR) of 41.7% and 30% in savolitinib 600/400 mg QD and 300/200 mg BID cohort, respectively (Zhi Peng, et al. 2023 AACR, Poster CT152). Here we report the post-hoc analysis of MET gene alterations in cfDNA samples at baseline, upon savolitinib treatment and progression of disease (PD) and the associations of these findings with clinical outcome.MethodsPlasma samples were prospectively collected at pre-dose, C3D1 and PD. MET and other somatic gene alterations were detected by next generation sequencing (NGS) (Benrui Onco+, 337-gene panel, OrigiMed).ResultsAt cut-off date Jan 20 2023, 34 GEJ/GC pts with tumor tissue-detected METamp were enrolled, and 22 pts (65%) were identified METamp in their baseline cfDNA samples. In the 33 pts with both cfDNA NGS and tissue FISH results for METamp, higher cfDNA METamp detectable rate tended to correlate with higher MET FISH gene copy number (GCN): 68% in 28 pts with MET GCN≥10 versus 40% in 5 pts with 6≤MET GCN<10. Baseline cfDNA MET-amplified pts trended toward higher cORR (55%, 12/22) compared to non-amplified pts (8%, 1/12). Nine pts with baseline cfDNA METamp provided C3D1 cfDNA samples, of which 8 pts were detected METamp clearance at C3D1, and their cORR was 50% (4/8). Among the 14 pts who provided cfDNA at PD, secondary MET mutations were observed in 7 pts, and 2 of them also had concurrent mutations in other driver genes. Besides that, the secondary MET mutation was detected in 1 pt before clinical PD.ConclusionsOur findings suggest that METamp in baseline cfDNA was more frequently detected in pts with high MET GCN in tumor tissue, and it may be associated with higher ORR. Most pts with baseline cfDNA METamp experienced clearance of METamp early during savolitinib treatment. MET secondary mutations may be the most prominent acquired resistance mechanism. Given the small sample size limitation, further analysis with larger samples is needed.Clinical trial identificationNCT04923932.Legal entity responsible for the studyHutchmed Limited.FundingHutchmed Limited.DisclosureAll authors have declared no conflicts of interest.