McCourt Carolyn K, Gross Jacob, Kalinsky Kevin, Guan Ping, McShane Lisa M, Wang Victoria, O'Dwyer Peter J, Lahey Matthew T, Maican Cayden, Bu Xiangning, Patton David, Harris Lyndsay N
Department of Obstetrics & Gynecology, Washington University School of Medicine, St Louis, MO.
Center for Biomedical Informatics & Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
JCO Precis Oncol. 2025 Mar;9:e2400614. doi: 10.1200/PO-24-00614. Epub 2025 Mar 28.
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.
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).
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.
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.
NCI-MATCH（EAY131）是一项精准医学试验，利用基因组检测将晚期恶性肿瘤患者分配至靶向治疗。Y组评估了泛AKT抑制剂卡匹西利，用于治疗携带 -突变肿瘤的患者。在此，我们报告该研究的转化目标，即对标本进行分子和基因组分析，以识别对卡匹西利反应或耐药的潜在生物标志物。
符合条件的患者患有 -突变的转移性肿瘤，经标准治疗后病情进展，接受卡匹西利480mg口服，每日两次，连续服用4天，每周停药3天，以28天为一个周期。主要终点是客观缓解率（ORR）。我们对25份治疗前组织样本进行了全外显子组测序、RNA测序以及基因集和通路富集分析，并评估了缓解者（完全缓解[CR]，n = 0，部分缓解，n = 9）和未缓解者（疾病稳定，n = 13，疾病进展，n = 3）的结果。
在报告的主要试验中，ORR为28.6%（35例中的10例），在这个转化队列中为36%（25例中的9例）。 基因的突变在缓解者中更常见，而PI3K/AKT/mTOR通路基因 、 和 在未缓解者中发生了显著改变。DNA修复、p53、E2F和Wnt-β连环蛋白通路在缓解者组中富集。基因表达的无监督聚类识别出五个基因 、 、 、 和 ，它们在缓解者中显著升高，在未缓解者中显著降低。此外，未缓解者中EGFR表达显著增加。
在携带 -突变肿瘤的患者中，卡匹西利实现了具有临床意义的ORR。 突变似乎与反应相关，而某些额外的PI3K/AKT/mTOR通路突变和EGFR过表达似乎与对卡匹西利无反应相关。有必要进一步研究预测性生物标志物。
