AKT inhibition in solid tumors with AKT1 mutations Journal Article


Authors: Hyman, D. M.; Smyth, L. M.; Donoghue, M. T. A.; Westin, S. N.; Bedard, P. L.; Dean, E. J.; Bando, H.; El-Khoueiry, A. B.; Pérez-Fidalgo, J. A.; Mita, A.; Schellens, J. H. M.; Chang, M. T.; Reichel, J. B.; Bouvier, N.; Selcuklu, S. D.; Soumerai, T. E.; Torrisi, J.; Erinjeri, J. P.; Ambrose, H.; Barrett, C. J.; Dougherty, B.; Foxley, A.; Lindemann, J. P. O.; McEwen, R.; Pass, M.; Schiavon, G.; Berger, M. F.; Chandarlapaty, S.; Solit, D. B.; Banerji, U.; Baselga, J.; Taylor, B. S.
Article Title: AKT inhibition in solid tumors with AKT1 mutations
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. © 2017 by American Society of Clinical Oncology.
Journal Title: Journal of Clinical Oncology
Volume: 35
Issue: 20
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2017-07-10
Start Page: 2251
End Page: 2259
Language: English
DOI: 10.1200/jco.2017.73.0143
PROVIDER: scopus
PMCID: PMC5501365
PUBMED: 28489509
DOI/URL:
Notes: Article -- Export Date: 2 August 2017 -- Source: Scopus
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MSK Authors
  1. David Solit
    420 Solit
  2. David Hyman
    176 Hyman
  3. Nancy Bouvier
    28 Bouvier
  4. Michael Forman Berger
    373 Berger
  5. Barry Stephen Taylor
    135 Taylor
  6. Jose T Baselga
    389 Baselga
  7. Matthew   Chang
    21 Chang
  8. Lillian   Smyth
    20 Smyth