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 journalArticle

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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.

Original languageEnglish (US)
Article numbermdw676
Pages (from-to)804-808
Number of pages5
JournalAnnals of Oncology
Volume28
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

Renal Cell Carcinoma
DNA Repair
Vascular Endothelial Growth Factor A
Mutation
Disease-Free Survival
MK 2206
Everolimus
Medical Futility
Sequence Deletion
Sirolimus
Pruritus
Exanthema
Disease Progression
Phosphotransferases
Up-Regulation
Therapeutics
Phenotype

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Jonasch, E., Hasanov, E., Corn, P. G., Moss, T., Shaw, K. R., Stovall, S., ... Tannir, N. M. (2017). A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma. Annals of Oncology, 28(4), 804-808. [mdw676]. https://doi.org/10.1093/annonc/mdw676

A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma. / Jonasch, E.; Hasanov, E.; Corn, P. G.; Moss, T.; Shaw, K. R.; Stovall, S.; Marcott, V.; Gan, B.; Bird, S.; Wang, X.; Do, K. A.; Altamirano, P. F.; Zurita, A. J.; Doyle, L. A.; Lara, Primo N; Tannir, N. M.

In: Annals of Oncology, Vol. 28, No. 4, mdw676, 01.04.2017, p. 804-808.

Research output: Contribution to journalArticle

Jonasch, E, Hasanov, E, Corn, PG, Moss, T, Shaw, KR, Stovall, S, Marcott, V, Gan, B, Bird, S, Wang, X, Do, KA, Altamirano, PF, Zurita, AJ, Doyle, LA, Lara, PN & Tannir, NM 2017, 'A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma', Annals of Oncology, vol. 28, no. 4, mdw676, pp. 804-808. https://doi.org/10.1093/annonc/mdw676
Jonasch E, Hasanov E, Corn PG, Moss T, Shaw KR, Stovall S et al. A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma. Annals of Oncology. 2017 Apr 1;28(4):804-808. mdw676. https://doi.org/10.1093/annonc/mdw676
Jonasch, E. ; Hasanov, E. ; Corn, P. G. ; Moss, T. ; Shaw, K. R. ; Stovall, S. ; Marcott, V. ; Gan, B. ; Bird, S. ; Wang, X. ; Do, K. A. ; Altamirano, P. F. ; Zurita, A. J. ; Doyle, L. A. ; Lara, Primo N ; Tannir, N. M. / A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma. In: Annals of Oncology. 2017 ; Vol. 28, No. 4. pp. 804-808.
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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.",
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T1 - A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma

AU - Jonasch, E.

AU - Hasanov, E.

AU - Corn, P. G.

AU - Moss, T.

AU - Shaw, K. R.

AU - Stovall, S.

AU - Marcott, V.

AU - Gan, B.

AU - Bird, S.

AU - Wang, X.

AU - Do, K. A.

AU - Altamirano, P. F.

AU - Zurita, A. J.

AU - Doyle, L. A.

AU - Lara, Primo N

AU - Tannir, N. M.

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N2 - 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.

AB - 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.

KW - Everolimus

KW - Metastatic disease

KW - MK-2206

KW - PI3K pathway

KW - RCC

KW - Renal cell carcinoma

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