دورية أكاديمية
A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma.
| العنوان: | A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma. |
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| المؤلفون: | Jonasch E; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Hasanov E; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Corn PG; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Moss T; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Shaw KR; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Stovall S; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Marcott V; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Gan B; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Bird S; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Wang X; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Do KA; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Altamirano PF; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Zurita AJ; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA., Doyle LA; Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA., Lara PN Jr; UC Davis Comprehensive Cancer Center, Sacramento, CA, USA., Tannir NM; Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson, Houston, TX, USA. |
| المصدر: | Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2017 Apr 01; Vol. 28 (4), pp. 804-808. |
| نوع المنشور: | Clinical Trial, Phase II; Journal Article; Multicenter Study; Randomized Controlled Trial |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: England NLM ID: 9007735 Publication Model: Print Cited Medium: Internet ISSN: 1569-8041 (Electronic) Linking ISSN: 09237534 NLM ISO Abbreviation: Ann Oncol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2020- : London : Elsevier Original Publication: Dordrecht ; Boston : Kluwer Academic Publishers, c1990- |
| مواضيع طبية MeSH: | Antineoplastic Agents/*therapeutic use , Carcinoma, Renal Cell/*drug therapy , Everolimus/*therapeutic use , Heterocyclic Compounds, 3-Ring/*therapeutic use , Kidney Neoplasms/*drug therapy, Aged ; Aged, 80 and over ; Carcinoma, Renal Cell/mortality ; Disease-Free Survival ; Female ; Humans ; Kidney Neoplasms/mortality ; Male ; Middle Aged ; Treatment Outcome |
| مستخلص: | 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. (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.) |
| التعليقات: | Comment in: Ann Oncol. 2017 May 1;28(5):914-916. (PMID: 28379379) |
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| معلومات مُعتمدة: | R01 CA190370 United States CA NCI NIH HHS; UM1 CA186717 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: MK-2206; PI3K pathway; RCC; everolimus; metastatic disease; renal cell carcinoma |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Heterocyclic Compounds, 3-Ring) 0 (MK 2206) 9HW64Q8G6G (Everolimus) |
| تواريخ الأحداث: | Date Created: 20170104 Date Completed: 20170502 Latest Revision: 20220408 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC5834088 |
| DOI: | 10.1093/annonc/mdw676 |
| PMID: | 28049139 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1569-8041 |
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| DOI: | 10.1093/annonc/mdw676 |