A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma

E. Jonasch, E. Hasanov, P. G. Corn, T. Moss, K. R. Shaw, S. Stovall, V. Marcott, B. Gan, S. Bird, X. Wang, K. A. Do, P. F. Altamirano, A. J. Zurita, L. A. Doyle, Primo N Lara, N. M. Tannir

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Background: 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. Patients and methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article numbermdw676
Pages (from-to)804-808
Number of pages5
JournalAnnals of Oncology
Issue number4
StatePublished - Apr 1 2017


  • Everolimus
  • Metastatic disease
  • MK-2206
  • PI3K pathway
  • RCC
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Hematology
  • Oncology


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