dc.contributor.author | Hyman, DM | |
dc.contributor.author | Smyth, LM | |
dc.contributor.author | Donoghue, MTA | |
dc.contributor.author | Westin, SN | |
dc.contributor.author | Bedard, PL | |
dc.contributor.author | Dean, EJ | |
dc.contributor.author | Bando, H | |
dc.contributor.author | El-Khoueiry, AB | |
dc.contributor.author | Pérez-Fidalgo, JA | |
dc.contributor.author | Mita, A | |
dc.contributor.author | Schellens, JHM | |
dc.contributor.author | Chang, MT | |
dc.contributor.author | Reichel, JB | |
dc.contributor.author | Bouvier, N | |
dc.contributor.author | Selcuklu, SD | |
dc.contributor.author | Soumerai, TE | |
dc.contributor.author | Torrisi, J | |
dc.contributor.author | Erinjeri, JP | |
dc.contributor.author | Ambrose, H | |
dc.contributor.author | Barrett, JC | |
dc.contributor.author | Dougherty, B | |
dc.contributor.author | Foxley, A | |
dc.contributor.author | Lindemann, JPO | |
dc.contributor.author | McEwen, R | |
dc.contributor.author | Pass, M | |
dc.contributor.author | Schiavon, G | |
dc.contributor.author | Berger, MF | |
dc.contributor.author | Chandarlapaty, S | |
dc.contributor.author | Solit, DB | |
dc.contributor.author | Banerji, U | |
dc.contributor.author | Baselga, J | |
dc.contributor.author | Taylor, BS | |
dc.date.accessioned | 2017-08-31T14:18:39Z | |
dc.date.issued | 2017-07-10 | |
dc.identifier.citation | Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017, 35 (20), pp. 2251 - 2259 | |
dc.identifier.issn | 0732-183X | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/805 | |
dc.identifier.eissn | 1527-7755 | |
dc.identifier.doi | 10.1200/jco.2017.73.0143 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 2251 - 2259 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER SOC CLINICAL ONCOLOGY | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Humans | |
dc.subject | Neoplasms | |
dc.subject | Drug Eruptions | |
dc.subject | Exanthema | |
dc.subject | Hyperglycemia | |
dc.subject | Diarrhea | |
dc.subject | Pyrimidines | |
dc.subject | Pyrroles | |
dc.subject | DNA, Neoplasm | |
dc.subject | Antineoplastic Agents | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Disease-Free Survival | |
dc.subject | Signal Transduction | |
dc.subject | Mutation | |
dc.subject | Loss of Heterozygosity | |
dc.subject | Alleles | |
dc.subject | Adult | |
dc.subject | Aged | |
dc.subject | Middle Aged | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Proto-Oncogene Proteins c-akt | |
dc.subject | Phosphatidylinositol 3-Kinases | |
dc.subject | Response Evaluation Criteria in Solid Tumors | |
dc.subject | Biomarkers, Tumor | |
dc.title | AKT Inhibition in Solid Tumors With AKT1 Mutations. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-05-10 | |
rioxxterms.funder | The Institute of Cancer Research | |
rioxxterms.identifier.project | Unspecified | |
rioxxterms.versionofrecord | 10.1200/jco.2017.73.0143 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2017-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | |
pubs.issue | 20 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono) | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono) | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 35 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology – Adaptive Therapy | |
icr.researchteam | Medicine Drug Development Unit (de Bono) | |
dc.contributor.icrauthor | Banerji, Udai | |