AKT Inhibition in Solid Tumors With <i>AKT1</i> Mutations

David M. Hyman, Lillian M. Smyth, Mark T.A. Donoghue, Shannon N. Westin, Philippe L. Bedard, Emma J. Dean, Hideaki Bando, Anthony B. El-Khoueiry, José A. Pérez-Fidalgo, Alain Mita, Jan H.M. Schellens, Matthew T. Chang, Jonathan B. Reichel, Nancy Bouvier, S. Duygu Selcuklu, Tara E. Soumerai, Jean Torrisi, Joseph P. Erinjeri, Helen Ambrose, J. Carl Barrett, Brian Dougherty, Andrew Foxley, Justin P.O. Lindemann, Robert McEwen, Martin Pass, Gaia Schiavon, Michael F. Berger, Sarat Chandarlapaty, David B. Solit, Udai Banerji, José Baselga, Barry S. Taylor

doi:10.1200/jco.2017.73.0143

<jats:sec><jats:title>Purpose</jats:title><jats:p> 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. </jats:p></jats:sec><jats:sec><jats:title>Patients and Methods</jats:title><jats:p> 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. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> 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%). </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> 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. </jats:p></jats:sec>

AKT Inhibition in Solid Tumors With <i>AKT1</i> Mutations

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