AKT Inhibition in Solid Tumors With AKT1 Mutations.
Date
2017-07-10ICR Author
Author
Hyman, DM
Smyth, LM
Donoghue, MTA
Westin, SN
Bedard, PL
Dean, EJ
Bando, H
El-Khoueiry, AB
Pérez-Fidalgo, JA
Mita, A
Schellens, JHM
Chang, MT
Reichel, JB
Bouvier, N
Selcuklu, SD
Soumerai, TE
Torrisi, J
Erinjeri, JP
Ambrose, H
Barrett, JC
Dougherty, B
Foxley, A
Lindemann, JPO
McEwen, R
Pass, M
Schiavon, G
Berger, MF
Chandarlapaty, S
Solit, DB
Banerji, U
Baselga, J
Taylor, BS
Type
Journal Article
Metadata
Show full item recordAbstract
Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K-mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor-positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.
Collections
Subject
Humans
Neoplasms
Drug Eruptions
Exanthema
Hyperglycemia
Diarrhea
Pyrimidines
Pyrroles
DNA, Neoplasm
Antineoplastic Agents
Protein Kinase Inhibitors
Disease-Free Survival
Signal Transduction
Mutation
Loss of Heterozygosity
Alleles
Adult
Aged
Middle Aged
Female
Male
Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
Response Evaluation Criteria in Solid Tumors
Biomarkers, Tumor
Research team
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Language
eng
Date accepted
2017-05-10
License start date
2017-07
Citation
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017, 35 (20), pp. 2251 - 2259
Publisher
AMER SOC CLINICAL ONCOLOGY