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Clinical Trial
. 2017 Apr 1;28(4):804-808.
doi: 10.1093/annonc/mdw676.

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

E Jonasch  1 , E Hasanov  1 , P G Corn  1 , T Moss  1 , K R Shaw  1 , S Stovall  1 , V Marcott  1 , B Gan  1 , S Bird  1 , X Wang  1 , K A Do  1 , P F Altamirano  1 , A J Zurita  1 , L A Doyle  2 , P N Lara Jr  3 , N M Tannir  1
Affiliations
Clinical Trial

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

E Jonasch et al. Ann Oncol. .

Abstract

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.

Keywords: MK-2206; PI3K pathway; RCC; everolimus; metastatic disease; renal cell carcinoma.

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Figures

Figure 1.
Figure 1.
(A) Kaplan–Meier estimates for PFS by treatment arm (P value = 0.27; log-rank test). (B) Kaplan–Meier estimates for OS by treatment arm (P value = 0.66; log-rank test).
See this image and copyright information in PMC

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