title: 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.
  
  
  
  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.
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Saura
authors.affiliation: Hematology and Medical Oncology Department, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Desamparados
authors.initials: D
authors.lastname: Roda
authors.affiliation: Hematology and Medical Oncology Department, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Roselló
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Oliveira
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Macarulla
authors.affiliation: Hematology and Medical Oncology Department, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: José Alejandro
authors.initials: JA
authors.lastname: Pérez-Fidalgo
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Morales-Barrera
authors.affiliation: Radiology Department, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Sanchis-García
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Luna
authors.initials: L
authors.lastname: Musib
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Nageshwar
authors.initials: N
authors.lastname: Budha
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Michelle
authors.initials: M
authors.lastname: Nannini
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Wai Y
authors.initials: WY
authors.lastname: Chan
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sanabria Bohórquez
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Meng
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Kui
authors.initials: K
authors.lastname: Lin
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Premal
authors.initials: P
authors.lastname: Patel
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain. jtabernero@vhio.net.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Hematology and Medical Oncology Department, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Cervantes
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C583616:ipatasertib; D051057:Proto-Oncogene Proteins c-akt