Comprehensive Molecular and Genomic Analysis of NCI-MATCH Subprotocol Y: Capivasertib in Patients With an AKT1 E17K –Mutated Tumor

PURPOSE 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 AKT1 E17K –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. METHODS Eligible patients had AKT1 E17K –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). RESULTS 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 TP53 gene were more frequent in responders, whereas the PI3K/AKT/mTOR pathway genes TYRO3 , SYNJ1 , and CDIPT 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, ANKRD30A , SUSD4 , TTC6 , POTEJ , and POTEI , that were significantly higher in responders and lower in nonresponders. In addition, EGFR expression was significantly increased in nonresponders. CONCLUSION In patients with AKT1 E17K –mutated tumors, capivasertib achieved a clinically significant ORR. TP53 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.