PURPOSE: In advanced gastrointestinal stromal tumor (GIST), there is an unmet 
need for therapies that target both primary and secondary mutations of 
pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase 
inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations.
PATIENTS AND METHODS: This first-in-human, to our knowledge, phase I study of 
ripretinib (ClinicalTrials.gov identifier: NCT02571036) included a 
dose-escalation phase and subsequent expansion phase at the recommended phase II 
dose (RP2D). Eligible patients included those with advanced GIST, intolerant to 
or experienced progression on ≥ 1 line of systemic therapy, and other advanced 
malignancies. Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose 
(MTD), and preliminary antitumor activity were evaluated.
RESULTS: At data cutoff (August 31, 2019), 258 patients (n = 184 GIST) were 
enrolled, with 68 patients in the dose-escalation phase. Three DLTs were 
reported: grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and 
grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). MTD was not 
reached (maximum dose evaluated, 200 mg twice a day); 150 mg once daily was 
established as the RP2D. The most frequent (> 30%) treatment-emergent adverse 
events in patients with GIST receiving ripretinib 150 mg once daily (n = 142) 
were alopecia (n = 88 [62.0%]), fatigue (n = 78 [54.9%]), myalgia (n = 69 
[48.6%]), nausea (n = 65 [45.8%]), palmar-plantar erythrodysesthesia (n = 62 
[43.7%]), constipation (n = 56 [39.4%]), decreased appetite (n = 48 [33.8%]), 
and diarrhea (n = 47 [33.1%]). Objective response rate (confirmed) of 11.3% (n = 
16/142) ranging from 7.2% (n = 6/83; fourth line or greater) to 19.4% (n = 6/31; 
second line) and median progression-free survival ranging from 5.5 months 
(fourth line or greater) to 10.7 months (second line), on the basis of 
investigator assessment, were observed.
CONCLUSION: Ripretinib is a well-tolerated, novel inhibitor of KIT and PDGFRA 
mutant kinases with promising activity in patients with refractory advanced 
GIST.