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Clinical Activity of Mitogen-Activated Protein Kinase Inhibitors in Patients With MAP2K1 (MEK1)-Mutated Metastatic

Matthew Dankner1,2,3, Emmanuelle Rousselle2,4, Sarah Petrecca1

  • 1McGill University Faculty of Medicine, Montréal, QC, Canada.

JCO Precision Oncology
|January 27, 2025
PubMed
Abstract

Insights

Class 2 MAP2K1 mutations in cancer patients may benefit from mitogen-activated protein kinase pathway inhibitors (MAPKi). Further clinical studies are needed to confirm efficacy in this specific patient subgroup.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • MAP2K1/MEK1 mutations are identified as actionable drivers in various cancers.
  • MAP2K1 mutations are functionally classified into three groups based on their dependency on upstream RAS/RAF signaling.
  • The clinical effectiveness of mitogen-activated protein kinase pathway inhibitors (MAPKi) in MAP2K1-mutant tumors remains incompletely understood.

Purpose of the Study:

  • To characterize the genomic and clinical landscape of MAP2K1-mutant tumors.
  • To evaluate the relationship between MAP2K1 mutation class and the clinical activity of MAPKi.
  • To define the efficacy of MAPKi in patients with MAP2K1-mutant cancers.

Main Methods:

  • Analysis of solid tumors with MAP2K1 mutations using the AACR GENIE database (v13).
  • Systematic review and meta-analysis of published studies on MAP2K1-mutant cancers treated with MAPKi.
  • Primary endpoint: progression-free survival (PFS); Secondary endpoints: overall treatment response rate (ORR), duration of response (DOR), and overall survival.

Main Results:

  • Class 2 MAP2K1 mutations were most prevalent (63%) in the AACR GENIE dataset.
  • Meta-analysis of 46 patients showed an overall ORR of 28% and median PFS of 3.9 months with MAPKi.
  • Patients with class 2 MAP2K1 mutations demonstrated significantly longer PFS (5.0 months) and DOR (23.8 months) compared to other classes.

Conclusions:

  • Patients with class 2 MAP2K1 mutations represent a distinct subgroup potentially benefiting from MAPKi.
  • The findings suggest MAPKi may be a viable treatment option for this specific patient population.
  • Prospective clinical trials investigating novel MAPKi regimens are warranted for patients with class 2 MAP2K1 mutations.

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