title: A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer.
abstract: PI3K/AKT pathway activation is an important endocrine resistance mechanism in estrogen receptor-positive (ER(+)) breast cancer. After promising preclinical modeling of MK-2206, an allosteric pan-AKT inhibitor, with either estrogen deprivation or fulvestrant, we conducted a phase I trial in patients with metastatic ER(+)HER2(-) breast cancer to determine the recommended phase II treatment dose (RPTD) of MK-2206 when combined with either anastrozole, fulvestrant, or anastrozole/fulvestrant.
  
  
  
  ER(+) breast cancer cell lines were exposed in vitro to MK-2206 plus estrogen deprivation with or without fulvestrant and monitored for apoptosis. A standard 3+3 design was employed to first determine the maximum tolerated dose (MTD) of MK-2206 plus anastrozole based on cycle 1 toxicity. Each cycle was 28 days. The RPTD was determined on the basis of toxicities observed at MTD level during the first 3 cycles. Subsequent patients received MK-2206, at the RPTD determined above, plus fulvestrant or anastrozole/fulvestrant to define RPTD for these additional regimens.
  
  
  
  MK-2206 induced apoptosis in parental ER(+) but not in long-term estrogen-deprived cell lines, for which fulvestrant was required for apoptosis induction. Thirty-one patients enrolled. The RPTD was defined as MK-2206 150 mg orally weekly with prednisone prophylaxis for each combination. Grade 3 rash was dose limiting. 42% (95% CI, 23%-63%) patients derived clinical benefit without progression within 6 months. Response was not associated with tumor PIK3CA mutation.
  
  
  
  MK-2206 plus endocrine treatments were tolerable. MK-2206 in combination with anastrozole is being further evaluated in a phase II neoadjuvant trial for newly diagnosed ER(+)HER2(-) breast cancer. Clin Cancer Res; 22(11); 2650-8. ©2016 AACRSee related commentary by Jansen et al., p. 2599.
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. cma@dom.wustl.edu mjellis@bcm.edu.
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Cesar
authors.initials: C
authors.lastname: Sanchez
authors.affiliation: Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Robert
authors.initials: R
authors.lastname: Crowder
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Michael
authors.initials: M
authors.lastname: Naughton
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Timothy
authors.initials: T
authors.lastname: Pluard
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Allison
authors.initials: A
authors.lastname: Creekmore
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Zhanfang
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hoog
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
authors.affiliation: Cancer Therapy Evaluation Program, NCI, Bethesda, MD.
authors.forename: Austin
authors.initials: A
authors.lastname: Doyle
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. cma@dom.wustl.edu mjellis@bcm.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
mesh_terms: D000328:Adult; D000368:Aged; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D000077267:Fulvestrant; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011960:Receptors, Estrogen / Q000378:metabolism; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D006575:Heterocyclic Compounds, 3-Ring; D007004:Hypoglycemic Agents; C548887:MK 2206; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol; D051057:Proto-Oncogene Proteins c-akt