A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors

作者:Saura Cristina; Roda Desamparados; Rosello Susana; Oliveira Mafalda; Macarulla Teresa; Alejandro Perez Fidalgo Jose; Morales Barrera Rafael; Manuel Sanchis Garcia Juan; Musib Luna; Budha Nageshwar; Zhu Jin; Nannini Michelle; Chan Wai Y; Bohorquez Sandra M Sanabria; Meng Raymond D; Lin Kui; Yan Yibing; Patel Premal; Baselga Jose; Tabernero Josep*; Cervantes Andres
来源:Cancer Discovery, 2017, 7(1): 102-113.
DOI:10.1158/2159-8290.CD-16-0512

摘要

Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of AKT. Ipatasertib (GDC-0068) is a novel selective ATP-competitive small-molecule inhibitor of AKT that preferentially targets active phosphorylated AKT (pAKT) and is potent in cell lines with evidence of AKT activation. In this phase I study, ipatasertib was well tolerated; most adverse events were gastrointestinal and grade 1-2 in severity. The exposures of ipatasertib >= 200 mg daily in patients correlated with preclinical TGI(90), and pharmacodynamic studies confirmed that multiple targets (i.e., PRAS40, GSK3 beta, and mTOR) were inhibited in paired on-treatment biopsies. Preliminary antitumor activity was observed; 16 of 52 patients (30%), with diverse solid tumors and who progressed on prior therapies, had radiographic stable disease, and many of their tumors had activation of AKT. SIGNIFICANCE: Potent inhibition of AKT signaling with ipatasertib was associated with a tolerable safety profi le and meaningful disease control in a subgroup of patients. Targeting pAKT with an ATP-competitive inhibitor provides a greater therapeutic window than allosteric inhibitors. Further investigation with ipatasertib is ongoing in phase II studies. Cancer Discov; 7( 1); 102-13.

  • 出版日期2017-1