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2017 ; 35
(20
): 2251-2259
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AKT Inhibition in Solid Tumors With AKT1 Mutations
#MMPMID28489509
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
J Clin Oncol
2017[Jul]; 35
(20
): 2251-2259
PMID28489509
show ga
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.
|*Mutation
[MESH]
|Adult
[MESH]
|Aged
[MESH]
|Alleles
[MESH]
|Antineoplastic Agents/*adverse effects/therapeutic use
[MESH]
|Biomarkers, Tumor/blood/genetics
[MESH]
|DNA, Neoplasm/*blood
[MESH]
|Diarrhea/chemically induced
[MESH]
|Disease-Free Survival
[MESH]
|Drug Eruptions/etiology
[MESH]
|Exanthema/chemically induced
[MESH]
|Female
[MESH]
|Humans
[MESH]
|Hyperglycemia/chemically induced
[MESH]
|Loss of Heterozygosity
[MESH]
|Male
[MESH]
|Middle Aged
[MESH]
|Neoplasms/blood/*drug therapy/*genetics
[MESH]
|Phosphatidylinositol 3-Kinases/metabolism
[MESH]
|Protein Kinase Inhibitors/*adverse effects/therapeutic use
[MESH]
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