Allosteric inhibition of AKT with MK-2206 is not superior to everolimus for the treatment of patients with advanced renal cell carcinoma (RCC) refractory to anti-vascular endothelial growth factor (VEGF) therapy, according to a study published in the Annals of Oncology.1

Upregulation of the phosphoinositide-3 phosphate kinase (PI3K) pathway is associated with worse outcomes for patients with advanced RCC. Researchers hypothesized that inhibiting AKT in patients refractory to anti-VEGF therapy would eliminate key drivers of tumor growth and cancer pathway signaling, prolonging progression-free survival.

Researchers enrolled 43 patients with metastatic or unresectable RCC refractory to anti-VEGF treatment. In this open-label, phase 2 study ( Identifier: NCT01239342), participants were randomly assigned 2:1 to receive MK-2206, a selective allosteric inhibitor of AKT, or everolimus.

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Results of the first futility analysis showed that median progression-free survival was 3.68 months with MK-2206 compared with 5.98 months with everolimus, leading to study closure.

Researchers observed 1 complete response and 3 partial responses in the MK-2206 treatment arm vs no complete or partial responses in the everolimus arm, though progressive disease was the best response in 44.8% of patients treated with MK-2206 and 14.3% of those given everolimus.

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Treatment with MK-2206 was associated with a significantly higher incidence of rash and pruritus than everolimus. About 38% of patients in the experimental arm required dose reduction vs 21.4% of everolimus-treated patients.

MK-2206 is being studied in a variety of solid tumors and hematologic malignancies, including in the I-SPY 2 adaptive clinical trial for breast cancer.


  1. Jonasch E, Hasanov E, Corn P, et al. A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma. Ann Oncol. 2017 Jan 3. doi: 10.1093/annonc/mdw676 [Epub ahead of print]