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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