Combination signal transduction inhibition: a phase I/II trial of the oral mTOR-inhibitor everolimus (E, RAD001) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM

Abstract

3002 Background: Primary resistance to IM in advanced GIST pts occurs rarely (<15%), but eventually pts may develop secondary resistance, possibly due to other mutations of KIT, genomic amplification of KIT, as well as activation of alternative oncogenic signaling mechanisms. Signal-profiling studies of GIST lesions with initial response to IM and subsequent clonal evolution of IM-resistant disease demonstrate close association between KIT and AKT/mTOR activity. Synergism has been shown in-vitro between IM and E, slowing proliferation and inducing apoptosis in primary GIST cell lines resistant to IM. Methods: We have initiated a phase I/II clinical study to test feasibility of the combination of E + IM, and also to assess the effect of E+IM in combination in GIST pts refractory to IM. Pts with metastatic GIST are eligible if progressing after ≥4 months' IM therapy at optimal doses, including at least 2 months at ≥600mg/d. Initially, PK interaction was assessed by measuring drug levels of IM alone (600mg/d), then E alone (20mg once weekly), and then of the combination. Serial assessments include FDG-PET and CT or MRI. Tumor biopsies are performed before and on therapy to evaluate changes in intratumoral signaling. Results: In 12 patients evaluated for PK interaction, IM increased levels of E (mean AUC by 3.7 fold, Cmax by 2.2 fold) but E did not effect levels of IM or its main metabolite. Tolerability was good overall. PET demonstrated dramatically increased tumoral FDG-avidity on interruption of IM, and then reduced FDG-avidity with the combination. One patient maintains objectively stable disease after 10 months on study. Conclusions: The increase in E bioavailability could be via competition with IM for CYP3A4 and/or P-glycoprotein. The initial increase in tumor FDG uptake on PET demonstrates residual suppression of GIST clones by IM and their reactivation upon IM interruption. To achieve more consistent exposure to E, this study is ongoing with subsequent intercohort dose escalation testing daily E (2.5–10mg/d) with 600mg/d IM. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis; Amgen; Aventis; Roche; Schering-Plough; PharmaMar; Pfizer