A phase I/II trial of the oral mTOR-inhibitor everolimus (E) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM: Study update

Abstract

9033 Background: Primary resistance to IM in advanced GIST pts is rare but after durable benefit, most pts eventually develop secondary resistance. Molecular pathways of resistance may activate alternate oncogenic signaling mechanisms, including AKT/mTOR pathway. Synergism in-vitro between IM and E has been shown in human GIST cell lines resistant to IM, serving as the basis for this targeted phase I/II trial which previously reported a 3-fold increase in exposure of E when dosed concurrently with IM due to a PK interaction. PET imaging noted increased tumoral FDG uptake with interruption of IM, with subsequent reduced FDG uptake when combined dosing with IM and E. Methods: GIST pts refractory to IM were treated with continuous dose of IM (600 mg/day) in combination with E dosed either weekly (20 mg) or daily (2.5, 5 mg). Serial assessments include FDG-PET and CT. Tumor biopsies were performed before and on drug therapy to evaluate proteomic and genetic biomarkers of clinical benefit. Results: 31 pts were treated in different E dosing cohorts: 13 (20 mg/week), 13 (2.5 mg/day) and 5 (5 mg/day). Grade 3–4 DLTs occurred in 3 pts at 5 mg/day E with IM: stomatitis and thrombocytopenia (1), gastritis (1) and hemorrhagic gastritis (1). Thus the 2.5 mg/day E cohort was expanded to include 13 pts. The most frequent suspected AEs were CTC grade 1–2 fatigue, diarrhea, vomiting, nausea, anemia, edema, headache and rash. The median duration of treatment was 14 weeks (range 3–60). 17 pts withdrew due to PD, 9 due to AE, 2 withdrew consent and 3 are ongoing. Stable disease (SD) was observed in 8 pts for more than 4 months (1 pt at 20 mg/week, 5 pts at 2.5 mg/day and 2 pts at 5 mg/day E). 2 of the ongoing pts (at 2.5 mg/day E) have improved to partial response (PR). Molecular analyses are ongoing to identify responding pts prospectively. Conclusions: The dose of E was identified as 2.5 mg/day in combination with IM (600 mg/day). Prolonged SD and 2 episodes of PR suggest potential benefit in a subset of pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharma AG Novartis, Pfizer Novartis Pharma AG Novartis Novartis Novartis