AKT Inhibition in Solid Tumors With AKT1 Mutations.
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Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2017-07-10
Date Accepted
2017-05-10
Abstract
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.
Citation
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017, 35 (20), pp. 2251 - 2259
Source Title
Publisher
LIPPINCOTT WILLIAMS & WILKINS
ISSN
0732-183X
eISSN
1527-7755
Collections
Research Team
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Medicine Drug Development Unit (de Bono)