title: A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma.
abstract: Activation of the phosphoinisitide-3 kinase (PI3K) pathway through mutation and constitutive upregulation has been described in renal cell carcinoma (RCC), making it an attractive target for therapeutic intervention. We performed a randomized phase II study in vascular endothelial growth factor (VEGF) therapy refractory patients to determine whether MK-2206, an allosteric inhibitor of AKT, was more efficacious than the mammalian target of rapamycin inhibitor everolimus.
  
  
  
  A total of 43 patients were randomized in a 2:1 distribution, with 29 patients assigned to the MK-2206 arm and 14 to the everolimus arm. Progression-free survival (PFS) was the primary endpoint.
  
  
  
  The trial was closed at the first futility analysis with an observed PFS of 3.68 months in the MK-2206 arm and 5.98 months in the everolimus arm. Dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm. On the other hand, progressive disease was best response in 44.8% of MK2206 versus 14.3% of everolimus-treated patients. MK-2206 induced significantly more rash and pruritis than everolimus, and dose reduction occurred in 37.9% of MK-2206 versus 21.4% of everolimus-treated patients. Genomic analysis revealed that 57.1% of the patients in the PD group had either deleterious TP53 mutations or ATM mutations or deletions. In contrast, none of the patients in the non-PD group had TP53 or ATM defects. No predictive marker for response was observed in this small dataset.
  
  
  
  Dichotomous outcomes are observed when VEGF therapy refractory patients are treated with MK-2206, and MK-2206 does not demonstrate superiority to everolimus. Additionally, mutations in DNA repair genes are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC.
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Jonasch
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Hasanov
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Corn
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Moss
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Shaw
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Stovall
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Marcott
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Gan
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bird
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Do
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Altamirano
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Zurita
authors.affiliation: Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Doyle
authors.affiliation: UC Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors.forename: P N
authors.initials: PN
authors.lastname: Lara
authors.affiliation: Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Tannir
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000627:therapeutic use*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D000068338:Everolimus
keywords: MK-2206; PI3K pathway; RCC; everolimus; metastatic disease; renal cell carcinoma