AKT Inhibition in Solid Tumors With AKT1 Mutations

Area of Science:

• Oncology
• Molecular Biology
• Clinical Trials

Background:

• AKT1 E17K mutations are oncogenic drivers found in various cancers.
• The therapeutic potential of targeting AKT signaling in these mutations remains largely unexplored.

Purpose of the Study:

• To assess the preliminary clinical activity and safety of AZD5363, a pan-AKT kinase inhibitor, in patients with advanced solid tumors harboring AKT1 E17K mutations.
• To identify predictive biomarkers of response to AZD5363.

Main Methods:

• A multihistology basket study treated 58 patients with advanced solid tumors.
• Primary endpoint was safety; secondary endpoints included progression-free survival (PFS) and response (RECIST).
• Tumor biopsies and plasma cell-free DNA (cfDNA) were analyzed for biomarkers.

Main Results:

• In 52 patients with AKT1 E17K-mutant tumors, median PFS varied by cancer type (e.g., 5.5 months in breast cancer).
• Exploratory analyses revealed that allele imbalance and PI3K pathway mutations were associated with longer PFS.
• Declines in cfDNA AKT1 E17K correlated with improved PFS and response.

Conclusions:

• This study provides the first clinical evidence that AKT1 E17K is a druggable target in human cancers.
• The genomic context of AKT1 E17K mutations influences response to AKT inhibition with AZD5363.