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Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.

ABSTRACT: Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or "personalized") medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.

SUBMITTER: Wagle N

PROVIDER: S-EPMC4122326 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.

Wagle Nikhil N Grabiner Brian C BC Van Allen Eliezer M EM Hodis Eran E Jacobus Susanna S Supko Jeffrey G JG Stewart Michelle M Choueiri Toni K TK Gandhi Leena L Cleary James M JM Elfiky Aymen A AA Taplin Mary Ellen ME Stack Edward C EC Signoretti Sabina S Loda Massimo M Shapiro Geoffrey I GI Sabatini David M DM Lander Eric S ES Gabriel Stacey B SB Kantoff Philip W PW Garraway Levi A LA Rosenberg Jonathan E JE

Cancer discovery 20140313 5

Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient w ...[more]

PMID: 24625776

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Project description:BackgroundMajor challenges in clinical trials of ultra-orphan oncology diseases include limited patient availability and paucity of reliable prior data for estimating the treatment effect and, therefore, determining optimal sample size. Angiosarcoma (AS), a particularly aggressive form of soft tissue sarcoma with an incidence of about 2000 cases per year in the United States and Europe is poorly addressed by current systemic therapies. Pazopanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) is approved for the treatment of AS, with modest benefit. TRC105 (carotuximab) is a monoclonal antibody to endoglin, an essential angiogenic target highly expressed on proliferating endothelium and both tumor vessels and tumor cells in AS, that has the potential to complement VEGFR tyrosine kinase inhibitors. In a phase I/II study of soft tissue sarcoma, TRC105 combined safely with pazopanib and the combination demonstrated durable complete responses and encouraging progression-free survival (PFS). In addition, there was a suggestion of superior benefit in patients with cutaneous lesions versus those with the non-cutaneous lesions.Patients and methodsThis article describes the design of a recently initiated phase III trial of TRC105 And Pazopanib versus Pazopanib alone in patients with advanced AngioSarcoma (TAPPAS trial). Given the ultra-orphan status of the disease and the paucity of reliable prior data on PFS or overall survival (end points required for regulatory approval as a pivotal trial), an adaptive design incorporating population enrichment and sample size re-estimation was implemented. The design incorporated regulatory input from the Food and Drug Administration (FDA) and European Medicines Agency and proceeded following special protocol assessment designation by the FDA.ConclusionsIt is shown that the benefit of the adaptive design as compared with a conventional single-look design arises from the learning and subsequent improvements in power that occur after an unblinded analysis of interim data.Registered on clinicaltrials.govNCT02979899.

Dataset Information

Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.

Publications

Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.

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