Reference Detail

Ref Type Journal Article
PMID (28489509)
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
Title AKT Inhibition in Solid Tumors With AKT1 Mutations.
Journal Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Vol 35
Issue 20
Date 2017 Jul 10
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
AKT1 E17K lung adenocarcinoma predicted - sensitive Capivasertib Case Reports/Case Series Actionable In a Phase I trial, a patient with lung adenocarcinoma harboring AKT1 E17K demonstrated a partial response when treated with Capivasertib (AZD5363) (PMID: 28489509; NCT01226316). 28489509
AKT1 E17K endometrial cancer predicted - sensitive Capivasertib Case Reports/Case Series Actionable In a Phase I trial, two patients with endometrial cancer harboring AKT1 E17K demonstrated a partial response when treated with Capivasertib (AZD5363) (PMID: 28489509; NCT01226316). 28489509
AKT1 E17K breast cancer sensitive Capivasertib Case Reports/Case Series Actionable In a Phase I trial, four patients with ESR1-positive breast cancer harboring AKT1 E17K demonstrated a partial response when treated with Capivasertib (AZD5363) (PMID: 28489509; NCT01226316). 28489509
AKT1 E17K estrogen-receptor positive breast cancer predicted - sensitive Capivasertib Phase I Actionable In a Phase I trial, Capivasertib (AZD5363) treatment resulted in confirmed partial response in 20% (4/20) and unconfirmed partial response in 10% (2/20) of patients with ESR1-positive breast cancer harboring AKT1 E17K (PMID: 28489509; NCT01226316). 28489509
AKT1 E17K granulosa cell tumor sensitive Capivasertib Case Reports/Case Series Actionable In a Phase I trial, a patient with ovarian granulosa cell tumor cancer harboring subclonal AKT E17K demonstrated an overall tumor regression of 24% when treated with AZD5363, which lasted 253 days (PMID: 28489509). 28489509
AKT1 Q79K ovarian cancer predicted - sensitive Capivasertib Case Reports/Case Series Actionable In a Phase I trial, an ovarian cancer patient harboring AKT1 Q79K demonstrated tumor regression that lasted 14 months when treated with Capivasertib (AZD5363) (PMID: 28489509; NCT01226316). 28489509
AKT1 E17K cervical cancer predicted - sensitive Capivasertib Case Reports/Case Series Actionable In a Phase I trial, a patient with cervical cancer harboring AKT1 E17K demonstrated a partial response when treated with Capivasertib (AZD5363) (PMID: 28489509; NCT01226316). 28489509
AKT1 E17K triple-receptor negative breast cancer predicted - sensitive Capivasertib Case Reports/Case Series Actionable In a Phase I trial, a patient with triple-receptor negative breast cancer harboring AKT1 E17K demonstrated a partial response when treated with Capivasertib (AZD5363) (PMID: 28489509; NCT01226316). 28489509