Comprehensive Molecular and Genomic Analysis of NCI-MATCH Subprotocol Y: Capivasertib in Patients With an -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 -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 -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 gene were more frequent in responders, whereas the PI3K/AKT/mTOR pathway genes , , and 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, , , , , and , that were significantly higher in responders and lower in nonresponders. In addition, EGFR expression was significantly increased in nonresponders.

Conclusion: In patients with -mutated tumors, capivasertib achieved a clinically significant ORR. 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.