BACKGROUND: Avapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the 
U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or 
metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety 
of avapritinib and provide evidence-based guidance on management of 
avapritinib-associated adverse events (AEs), including cognitive effects and 
intracranial bleeding.
MATERIALS AND METHODS: We performed a post hoc analysis of data from a two-part, 
single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in 
patients with U/M GISTs treated with oral avapritinib 30-600 mg once daily. The 
primary endpoints were safety and tolerability; the impact of dose modification 
(interruption and/or reduction) on progression-free survival (PFS) was a 
secondary endpoint. Efficacy analyses were limited to patients who started 
avapritinib at 300 mg (approved dose).
RESULTS: Of 250 patients enrolled in the study, 74.0% presented with KIT 
mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started 
avapritinib at 300 mg. The most common treatment-related AEs (any grade) were 
nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), 
diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No 
treatment-related deaths occurred. Among 167 patients starting on 300 mg 
avapritinib, all-cause cognitive effects rate (grade 1-2) was 37.0% in all 
patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower 
grade more quickly with dose modification (1.3-3.1 weeks) than without 
(4.9-7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 
months without.
CONCLUSION: Tolerability-guided dose modification of avapritinib is an effective 
strategy for managing AEs in patients with GISTs.
IMPLICATIONS FOR PRACTICE: Early recognition of adverse events and tailored dose 
modification appear to be effective approaches for managing treatment-related 
adverse events and maintaining patients on avapritinib. Dose reduction does not 
appear to result in reduced efficacy. Patients' cognitive function should be 
assessed at baseline and monitored carefully throughout treatment with 
avapritinib for the onset of cognitive adverse events. Dose interruption is 
recommended at the first sign of any cognitive effect, including grade 1 events.