2.50
Hdl Handle:
http://hdl.handle.net/10541/620406
Title:
AKT inhibition in solid tumors with AKT1 mutations.
Authors:
Hyman, D; Smyth, L; Donoghue, M; Westin, S; Bedard, P; Dean, Emma J ( 0000-0001-9956-257X ) ; Bando, H; El-Khoueiry, A; Pérez-Fidalgo, J; Mita, A; Schellens, J; Chang, M; Reichel, J; Bouvier, N; Selcuklu, S; Soumerai, T; Torrisi, J; Erinjeri, J; Ambrose, H; Barrett, J; Dougherty, B; Foxley, A; Lindemann, J; McEwen, R; Pass, M; Schiavon, G; Berger, M; Chandarlapaty, S; Solit, D; Banerji, U; Baselga, J; Taylor, B
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.
Affiliation:
Memorial Sloan Kettering Cancer Center
Citation:
AKT inhibition in solid tumors with AKT1 mutations. 2017 J Clin Oncol
Journal:
Journal of Clinical Oncology
Issue Date:
10-May-2017
URI:
http://hdl.handle.net/10541/620406
DOI:
10.1200/JCO.2017.73.0143
PubMed ID:
28489509
Type:
Article
Language:
en
ISSN:
1527-7755
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorHyman, Den
dc.contributor.authorSmyth, Len
dc.contributor.authorDonoghue, Men
dc.contributor.authorWestin, Sen
dc.contributor.authorBedard, Pen
dc.contributor.authorDean, Emma Jen
dc.contributor.authorBando, Hen
dc.contributor.authorEl-Khoueiry, Aen
dc.contributor.authorPérez-Fidalgo, Jen
dc.contributor.authorMita, Aen
dc.contributor.authorSchellens, Jen
dc.contributor.authorChang, Men
dc.contributor.authorReichel, Jen
dc.contributor.authorBouvier, Nen
dc.contributor.authorSelcuklu, Sen
dc.contributor.authorSoumerai, Ten
dc.contributor.authorTorrisi, Jen
dc.contributor.authorErinjeri, Jen
dc.contributor.authorAmbrose, Hen
dc.contributor.authorBarrett, Jen
dc.contributor.authorDougherty, Ben
dc.contributor.authorFoxley, Aen
dc.contributor.authorLindemann, Jen
dc.contributor.authorMcEwen, Ren
dc.contributor.authorPass, Men
dc.contributor.authorSchiavon, Gen
dc.contributor.authorBerger, Men
dc.contributor.authorChandarlapaty, Sen
dc.contributor.authorSolit, Den
dc.contributor.authorBanerji, Uen
dc.contributor.authorBaselga, Jen
dc.contributor.authorTaylor, Ben
dc.date.accessioned2017-06-29T10:16:33Z-
dc.date.available2017-06-29T10:16:33Z-
dc.date.issued2017-05-10-
dc.identifier.citationAKT inhibition in solid tumors with AKT1 mutations. 2017 J Clin Oncolen
dc.identifier.issn1527-7755-
dc.identifier.pmid28489509-
dc.identifier.doi10.1200/JCO.2017.73.0143-
dc.identifier.urihttp://hdl.handle.net/10541/620406-
dc.description.abstractPurpose 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.en
dc.language.isoenen
dc.rightsArchived with thanks to Journal of clinical oncology : official journal of the American Society of Clinical Oncologyen
dc.titleAKT inhibition in solid tumors with AKT1 mutations.en
dc.typeArticleen
dc.contributor.departmentMemorial Sloan Kettering Cancer Centeren
dc.identifier.journalJournal of Clinical Oncologyen

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