LESSONS LEARNED: The combination of pexidartinib and binimetinib was safe and 
tolerable and demonstrated encouraging signs of efficacy in two patients with 
advanced gastrointestinal stromal tumor (GIST) refractory to tyrosine kinase 
inhibitors (TKIs).Molecular profiling of GISTs at diagnosis and upon progression 
may provide insight into the mechanisms of response or resistance to targeted 
therapies.Additional trials are needed to further explore combined KIT and MEK 
inhibition in treatment-naïve and TKI-refractory patients with advanced GIST.
BACKGROUND: Nearly all patients with advanced gastrointestinal stromal tumor 
(GIST) develop resistance to imatinib, and subsequent treatments have limited 
efficacy. Dual inhibition of KIT and MAPK pathways has synergistic antitumor 
activity in preclinical GIST models.
METHODS: This was an investigator-initiated, phase I, dose escalation study of 
the MEK inhibitor binimetinib combined with pexidartinib, a potent inhibitor of 
CSF1R, KIT, and FLT3, in patients with advanced or metastatic GIST who 
progressed on imatinib. The primary endpoint was phase II dose determination; 
secondary endpoints included safety, tolerability, and efficacy. An expansion 
cohort to further evaluate safety and efficacy was planned.
RESULTS: Two patients were treated at dose level one (binimetinib 30 mg b.i.d. 
and pexidartinib 400 mg every morning and 200 mg every evening), after which the 
study was terminated by the manufacturer. No dose-limiting toxicities (DLTs) 
were reported, and treatment was well tolerated. The only grade ≥3 
treatment-emergent adverse event (TEAE) was asymptomatic elevated creatine 
phosphokinase (CPK). Both patients had a best response of stable disease (SD) by 
RECIST. Progression-free survival (PFS) and overall survival (OS) were 6.1 and 
14.6 months, respectively, in one patient with five prior lines of therapy. The 
second patient with NF1-mutant GIST had a 27% decrease in tumor burden by RECIST 
and remains on study after 19 months of treatment.
CONCLUSION: Pexidartinib combined with binimetinib was tolerable, and meaningful 
clinical activity was observed in two imatinib-refractory patients.