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

Clin Lymphoma Myeloma Leuk. 2019 Jul;19(7):431-440.e13. doi: 10.1016/j.clml.2019.03.015. Epub 2019 Mar 26.

Abstract

Background: 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 hyperactivation of RAS/RAF or activation of the PI3K/PTEN/AKT/mTOR pathway. This phase II multi-institution Cancer Therapy Evaluation Program-sponsored study was conducted to determine efficacy and safety of the combination of the ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and the MEK inhibitor trametinib in RAS-mutated relapsed/refractory acute myeloid leukemia (AML).

Patients and methods: The primary objective was to determine the proportion of patients achieving a complete remission. 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).

Results: Dose level 1 was identified as the recommended phase II dose. No complete remissions were identified in either cohort. Minor responses were recognized in 5 (22%) patients. 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.

Conclusion: Further investigation is required to explore the discrepancy between the activity of this combination on leukemia cells and the lack of clinical efficacy.

Keywords: AML; Developmental therapeutics; Drug resistance; Neoplasia-myeloid leukemias and dysplasias; Phase II clinical trials.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Diamines / administration & dosage
  • Female
  • Genes, ras*
  • Humans
  • Leukemia, Myeloid, Acute / diagnosis
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics*
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 2 / antagonists & inhibitors*
  • Male
  • Middle Aged
  • Mutation*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Pyrazoles / administration & dosage
  • Pyridones / administration & dosage
  • Pyrimidinones / administration & dosage
  • Treatment Outcome
  • Young Adult

Substances

  • Diamines
  • GSK2141795
  • Pyrazoles
  • Pyridones
  • Pyrimidinones
  • trametinib
  • MAP2K2 protein, human
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human