Comprehensive Molecular and Genomic Analysis of NCI-MATCH Subprotocol Y: Capivasertib in Patients With an <i>AKT1 E17K</i>-Mutated Tumor.

Abstract

NCI-MATCH (EAY131) is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatments. Arm Y evaluated capivasertib, a pan AKT inhibitor, in patients with an <i>AKT1 E17K</i>-mutated tumor. Here, we report on the translational objectives of the study, a molecular and genomic analysis of specimens to identify potential biomarkers of response or resistance to capivasertib. Eligible patients had <i>AKT1 E17K</i>-mutated metastatic tumors that progressed with standard treatment and received capivasertib 480 mg orally twice daily for 4 days on and 3 days off weekly in 28-day cycles. The primary end point was objective response rate (ORR). We performed whole-exome sequencing, RNA sequencing, and gene set and pathway enrichment analysis on 25 pretreatment tissue samples and evaluated findings in responders (complete response [CR], n = 0, and partial response, n = 9) and nonresponders (stable disease, n = 13, and progressive disease, n = 3). The ORR was 28.6% (10 of 35) in the reported primary trial and 36% (9 of 25) in this translational cohort. Mutations in the <i>TP53</i> gene were more frequent in responders, whereas the PI3K/AKT/mTOR pathway genes <i>TYRO3</i>, <i>SYNJ1</i>, and <i>CDIPT</i> were significantly altered in nonresponders. DNA repair, p53, E2F, and Wnt-beta catenin pathways were enriched in the responder group. Unsupervised clustering of gene expression identified five genes, <i>ANKRD30A</i>, <i>SUSD4</i>, <i>TTC6</i>, <i>POTEJ</i>, and <i>POTEI</i>, that were significantly higher in responders and lower in nonresponders. In addition, EGFR expression was significantly increased in nonresponders. In patients with <i>AKT1 E17K</i>-mutated tumors, capivasertib achieved a clinically significant ORR. <i>TP53</i> mutations appear to be associated with response, whereas certain additional PI3K/AKT/mTOR pathway mutations and EGFR overexpression appear to be associated with nonresponse to capivasertib. Further investigation of predictive biomarkers is warranted.