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

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.

[1]  A. Ravaud,et al.  Randomized Open-Label Phase II Trial of Apitolisib (GDC-0980), a Novel Inhibitor of the PI3K/Mammalian Target of Rapamycin Pathway, Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  P. Stephens,et al.  Genomic Characterization of Renal Cell Carcinoma with Sarcomatoid Dedifferentiation Pinpoints Recurrent Genomic Alterations. , 2016, European urology.

[3]  E. V. Van Allen,et al.  A phase 1 study of buparlisib and bevacizumab in patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor‐targeted therapies , 2016, Cancer.

[4]  R. Motzer,et al.  A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma , 2016, The oncologist.

[5]  A. Belldegrun,et al.  Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma , 2016, Proceedings of the National Academy of Sciences.

[6]  Martin O. Leach,et al.  Interrogating Two Schedules of the AKT Inhibitor MK-2206 in Patients with Advanced Solid Tumors Incorporating Novel Pharmacodynamic and Functional Imaging Biomarkers , 2014, Clinical Cancer Research.

[7]  C. Porta,et al.  Targeting PI3K/Akt/mTOR Signaling in Cancer , 2014, Front. Oncol..

[8]  Li Ma,et al.  FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway. , 2014, Cancer research.

[9]  R. Figlin,et al.  Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: New strategies for overcoming resistance to VEGFR and mTORC1 inhibitors , 2013, International journal of cancer.

[10]  Carol Prives,et al.  Mutant p53: one name, many proteins. , 2012, Genes & development.

[11]  R. Figlin,et al.  Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor‐targeted therapy , 2012, Cancer.

[12]  P. Argani,et al.  Immunoexpression Status and Prognostic Value of mTOR and Hypoxia-Induced Pathway Members in Primary and Metastatic Clear Cell Renal Cell Carcinomas , 2011, The American journal of surgical pathology.

[13]  G. Mills,et al.  Gene and protein expression markers of response to combined antiangiogenic and epidermal growth factor targeted therapy in renal cell carcinoma. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[14]  M. Okada,et al.  [New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1)]. , 2009, Gan to kagaku ryoho. Cancer & chemotherapy.

[15]  P. Tamboli,et al.  Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low‐dose interferon alfa in patients with advanced renal cell carcinoma , 2009, Cancer.

[16]  C. Kolbitsch,et al.  Increased activated Akt expression in renal cell carcinomas and prognosis , 2009, Journal of cellular and molecular medicine.

[17]  M. Kuczyk,et al.  Activation of PI3K Is Associated with Reduced Survival in Renal Cell Carcinoma , 2008, Urologia Internationalis.

[18]  W. Kaelin,et al.  Role of VHL gene mutation in human cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Toshiyuki Obata,et al.  Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53* , 2002, The Journal of Biological Chemistry.

[20]  P. Schirmacher,et al.  VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. , 2000, Cancer research.

[21]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[22]  K. Harada,et al.  Expression of molecular markers associated with the mammalian target of rapamycin pathway in nonmetastatic renal cell carcinoma: Effect on prognostic outcomes following radical nephrectomy. , 2014, Urologic oncology.