BACKGROUND: Most gastrointestinal stromal tumors (GIST) driven by KIT or 
platelet-derived growth factor receptor A (PDGFRA) mutations develop resistance 
to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a 
two-part, single-arm, dose escalation and expansion study designed to evaluate 
safety and antineoplastic activity of avapritinib, a selective, potent inhibitor 
of KIT and PDGFRA, in patients with unresectable or metastatic GIST.
MATERIALS AND METHODS: Eligible patients were 18 years or older with 
histologically or cytologically confirmed unresectable GIST and Eastern 
Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 
300 mg or 400 mg once daily. Primary endpoints were safety in patients who 
initiated avapritinib at 300 mg or 400 mg once daily and overall response rate 
(ORR) in patients in the safety population with three or more previous lines of 
TKI therapy.
RESULTS: As of November 16, 2018, in the safety population (n = 204), the most 
common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia 
(102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 
(8%) patients discontinued due to treatment-related AEs, most frequently 
confusion, encephalopathy, and fatigue. ORR in response-evaluable patients with 
GIST harboring KIT or non-D842V PDGFRA mutations and with at least three prior 
therapies (n = 103) was 17% (95% confidence interval [CI], 10-25). Median 
duration of response was 10.2 months (95% CI, 7.2-10.2), and median 
progression-free survival was 3.7 months (95% CI, 2.8-4.6).
CONCLUSION: Avapritinib has manageable toxicity with meaningful clinical 
activity as fourth-line or later treatment in some patients with GIST with KIT 
or PDGFRA mutations.
IMPLICATIONS FOR PRACTICE: In the NAVIGATOR trial, avapritinib, an inhibitor of 
KIT and platelet-derived growth factor receptor A tyrosine kinases, provided 
durable responses in a proportion of patients with advanced gastrointestinal 
stromal tumors (GIST) who had received three or more prior therapies. 
Avapritinib had a tolerable safety profile, with cognitive adverse events 
manageable with dose interruptions and modification in most cases. These 
findings indicate that avapritinib can elicit durable treatment responses in 
some patients with heavily pretreated GIST, for whom limited treatment options 
exist.