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.

Abstract:

: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 TGI90, and pharmacodynamic studies confirmed that multiple targets (i.e., PRAS40, GSK3β, 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 profile 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. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

Saura C,Roda D,Roselló S,Oliveira M,Macarulla T,Pérez-Fidalgo JA,Morales-Barrera R,Sanchis-García JM,Musib L,Budha N,Zhu J,Nannini M,Chan WY,Sanabria Bohórquez SM,Meng RD,Lin K,Yan Y,Patel P,Baselga J,Tabernero J,

doi

10.1158/2159-8290.CD-16-0512

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

102-113

issue

1

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-16-0512

journal_volume

7

pub_type

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