Oral MEK 1/2 Inhibitor Trametinib in Combination with AKT Inhibitor GSK2141795 in Patients with Acute Myeloid Leukemia with RAS Mutations: A Phase II Study

Abstract With proven single-agent activity and favorable toxicity profile of MEK-1/2 inhibition in advanced leukemia, investigation into combination strategies to overcome proposed resistance pathways is warranted. Resistance to MEK inhibition is secondary to upstream hyperactivationof RAS/RAF or activation of the PI3K/PTEN/AKT/mTOR pathway. This phase II multi-institution CTEP-sponsored study was conducted to determine efficacy and safety of the combination of ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and MEK inhibitor trametinibin RAS-mutated relapsed/refractory acute myeloid leukemia (AML). The primary objective was to determine the proportion of patients achieving a complete remission (CR). Secondary objectives included assessment of toxicity profile and biologic effects of this combination. Twenty-three patients with RAS-mutated AML received the combination. Two dose levels were explored (dose level 1: 2 mg trametinib, 25 mg GSK2141795 and dose level 2: 1.5 mg trametinib, 50 mg GSK2141795). Dose level 1 was identified as the recommended phase II dose. No CRs were identified in either cohort. Minor responses were recognized in 5 patients (22%). The most common drug-related toxicities included rash and diarrhea, with dose-limiting toxicities of mucositis and colitis. Longitudinal correlative assessment of the modulation of MEK and AKT pathways using reverse-phase protein array and phospho-flow analysis revealed significant and near-significant down-modulation of pERK and pS6, respectively. Combined MEK and AKT inhibition had no clinical activity in patients with RAS-mutated AML. Further investigation is required to explore the discrepancy between activity of this combination on leukemia cells and the lack of clinical efficacy.