Background: Approved TKIs primarily inhibit either the KIT ATP binding pocket (exon 13/14) or a subset of activation loop mutations (exon 17/18) and do not demonstrate activity across both regions known to cause imatinib resistance in GIST. This leaves significant liabilities in inhibitory coverage of known KIT resistance mutations. DCC-2618 is a potent kinase switch control inhibitor active across a broad range of mutations which emerge on treatment with approved TKIs. Methods: This is a dose-escalation study of oral DCC-2618 (QD or BID q28 days) followed by an expansion cohort in pre-treated TKI resistant GIST. During the escalation phase, FDG-PET scans were performed at baseline and after 3 wks of therapy; CT scans every 2 cycles. Next generation sequencing (NGS) of plasma cell-free (cf) DNA was performed throughout the study to quantify KIT, PDGFRa and other molecular alterations. Concordance of mutational status between plasma cfDNA and tumor tissue was assessed. Results: 33/42 pts enrolled had KIT (30) or PDGFRa-(3) driven GIST and received daily doses ranging from 40-400 mg. Mean prior lines of therapy was 4.8. The dose selected for expansion was 150 mg QD. Safety for all 42 pts was as follows: grade (G) 3/4 adverse effects (regardless of attribution, occurring in > 1 pt) included anemia (15), asymptomatic lipase increase () (7), hypertension (4), creatine phosphokinase (CPK) (2), lower GI hemorrhage (2). Two of the G3/4 lipase at 100 mg BID and 200 mg BID and one CPK at 150 mg QD were DLTs. Of 19 pts with KIT mutant GIST assessed by FDG PET, 15 (79%) had a partial metabolic response per EORTC criteria. 2 out of 23 evaluable patients showed RECIST partial responses (PRs) and 6 out of 11 evaluable patients at doses of

No abstract

No abstract

No abstract

No abstract