Abstract
BACKGROUND: Relapsed and refractory (R/R) acute myeloid leukemia (AML) continues to be a therapeutic challenge with poor outcomes. Dysregulation of the mitogen-activated protein (MAP) kinase/extracellular-signal regulated kinase (ERK) pathway frequently occurs in AML and myelodysplastic syndrome (MDS). Preclinical studies and early-phase trials have shown promise for MAP-ERK kinase (MEK) inhibition in AML. We evaluated the safety and efficacy of the MEK 1/2 inhibitor binimetinib in advanced myeloid malignancies. PATIENTS AND METHODS: Nineteen patients with R/R AML and MDS, who were not candidates for intensive chemotherapy or with disease resistance or intolerance to standard treatment were enrolled in the present phase II study of binimetinib dosed twice daily continuously in 28-day cycles. RESULTS: The median age of the cohort was 64 years (range, 31-85 years). These patients had received a median of 3 previous lines of therapy (range, 1-6). The median bone marrow blast percentage was 49% (range, 2%-94%), and 14 patients had RAS mutations. The patients received a median of 2 cycles (range, 1-4 cycles) of binimetinib and received treatment for a median duration of 1.2 months (range, 0.1-3.4 months). Sixteen patients (84%) received the 45-mg twice daily dose. The most common grade 3/4 treatment-emergent adverse events were hypokalemia (6%), hypotension (6%), lung infection (6%), and febrile neutropenia (6%). No treatment-related deaths occurred. One of the 13 evaluable patients (8%) achieved a complete response with incomplete blood count recovery lasting 2.1 months. The other 12 patients (92%) did not have a response. Six patients could not be evaluated. CONCLUSION: Binimetinib had tolerable safety profile with a minimal response in RAS-mutant AML. Future studies should focus on better patient selection and synergistic combination therapies involving MEK inhibition.