TY - JOUR
T1 - AKT inhibition in solid tumors with AKT1 mutations
AU - Hyman, David M.
AU - Smyth, Lillian M.
AU - Donoghue, Mark T.A.
AU - Chang, Matthew T.
AU - Reichel, Jonathan B.
AU - Bouvier, Nancy
AU - Selcuklu, S. Duygu
AU - Soumerai, Tara E.
AU - Torrisi, Jean
AU - Erinjeri, Joseph P.
AU - Berger, Michael F.
AU - Chandarlapaty, Sarat
AU - Solit, David B.
AU - Baselga, Jose
AU - Taylor, Barry S.
AU - Barrett, J. Carl
AU - Dougherty, Brian
AU - Ambrose, Helen
AU - Foxley, Andrew
AU - Lindemann, Justin P.O.
AU - McEwen, Robert
AU - Pass, Martin
AU - Schiavon, Gaia
AU - Dean, Emma J.
AU - Banerji, Udai
AU - Westin, Shannon N.
AU - Bedard, Philippe L.
AU - Bando, Hideaki
AU - El-Khoueiry, Anthony B.
AU - Mita, Alain
AU - Perez-Fidalgo, Jose A.
AU - Schellens, Jan H.M.
N1 - Publisher Copyright:
© 2017 by American Society of Clinical Oncology.
PY - 2017/7/10
Y1 - 2017/7/10
N2 - 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.
AB - 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.
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U2 - 10.1200/JCO.2017.73.0143
DO - 10.1200/JCO.2017.73.0143
M3 - Article
C2 - 28489509
AN - SCOPUS:85023764187
SN - 0732-183X
VL - 35
SP - 2251
EP - 2259
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 20
ER -