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Treatment Options in Metastatic Renal Cell Carcinoma: Focus on mTOR Inhibitors.

Pal SK, Figlin RA - Clin Med Insights Oncol (2010)

Bottom Line: THE AGENTS CURRENTLY APPROVED FOR USE IN METASTATIC RENAL CELL CARCINOMA (MRCC) CAN BE DIVIDED BROADLY INTO TWO CATEGORIES: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR).The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC.Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.

ABSTRACT
THE AGENTS CURRENTLY APPROVED FOR USE IN METASTATIC RENAL CELL CARCINOMA (MRCC) CAN BE DIVIDED BROADLY INTO TWO CATEGORIES: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR). The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC. Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib. In contrast, temsirolimus was approved on the basis of a phase III trial in treatment-naïve patients with poor-risk mRCC, demonstrating an improvement in overall survival relative to interferon-alfa. While these pivotal trials have created unique positions for everolimus and temsirolimus in current clinical algorithms, the role of mTOR inhibitors in mRCC is being steadily revised and expanded through ongoing trials testing novel sequences and combinations. The clinical development of mTOR inhibitors is outlined herein.

No MeSH data available.


Related in: MedlinePlus

Ongoing clinical trials evaluating optimal combinations of mTOR inhibitors with VEGFR-directed therapy.
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f3-cmo-2010-043: Ongoing clinical trials evaluating optimal combinations of mTOR inhibitors with VEGFR-directed therapy.

Mentions: Several studies may change these paradigms. For instance, the RECORD-3 trial utilizes a unique design, randomizing patients with treatment-naive mRCC to receive either sunitinib or everolimus as initial therapy, followed by crossover to the opposite regimen (Fig. 2).62 The primary endpoint is PFS, and the study is powered to determine non-inferiority of either regimen. If positive, the results of this study could suggest interchangeable use of sunitinib and everolimus as first-line therapy. mTOR inhibitors may also become incorporated in first-line algorithms when used in combination with VEGFR-directed therapy (Fig. 3). The aforementioned INTORACT and RECORD-2 studies, evaluating bevacizumab in combination with temsirolimus and everolimus, respectively, may alter the current recommendation of using bevacizumab in combination with IFN-α.29,44 Notably, INTORACT is structured as a phase IIIb study and is expected to enroll a total of 800 patients. In contrast, RECORD-2 (a randomized phase II effort) will include approximately 360 patients. The primary completion date of both studies is February 2012. Given the larger scope, INTORACT may have a more tangible impact on therapeutic decision-making. As previously noted, the BeST study will also include arms evaluating mTOR inhibitors in combination with VEGFR-directed therapy.31 Two of the four arms in this study include such a combination (sorafenib with temsirolimus, and bevacizumab with temsirolimus). However, in this randomized phase II effort, only 90 patients will be accrued to each arm.


Treatment Options in Metastatic Renal Cell Carcinoma: Focus on mTOR Inhibitors.

Pal SK, Figlin RA - Clin Med Insights Oncol (2010)

Ongoing clinical trials evaluating optimal combinations of mTOR inhibitors with VEGFR-directed therapy.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2902205&req=5

f3-cmo-2010-043: Ongoing clinical trials evaluating optimal combinations of mTOR inhibitors with VEGFR-directed therapy.
Mentions: Several studies may change these paradigms. For instance, the RECORD-3 trial utilizes a unique design, randomizing patients with treatment-naive mRCC to receive either sunitinib or everolimus as initial therapy, followed by crossover to the opposite regimen (Fig. 2).62 The primary endpoint is PFS, and the study is powered to determine non-inferiority of either regimen. If positive, the results of this study could suggest interchangeable use of sunitinib and everolimus as first-line therapy. mTOR inhibitors may also become incorporated in first-line algorithms when used in combination with VEGFR-directed therapy (Fig. 3). The aforementioned INTORACT and RECORD-2 studies, evaluating bevacizumab in combination with temsirolimus and everolimus, respectively, may alter the current recommendation of using bevacizumab in combination with IFN-α.29,44 Notably, INTORACT is structured as a phase IIIb study and is expected to enroll a total of 800 patients. In contrast, RECORD-2 (a randomized phase II effort) will include approximately 360 patients. The primary completion date of both studies is February 2012. Given the larger scope, INTORACT may have a more tangible impact on therapeutic decision-making. As previously noted, the BeST study will also include arms evaluating mTOR inhibitors in combination with VEGFR-directed therapy.31 Two of the four arms in this study include such a combination (sorafenib with temsirolimus, and bevacizumab with temsirolimus). However, in this randomized phase II effort, only 90 patients will be accrued to each arm.

Bottom Line: THE AGENTS CURRENTLY APPROVED FOR USE IN METASTATIC RENAL CELL CARCINOMA (MRCC) CAN BE DIVIDED BROADLY INTO TWO CATEGORIES: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR).The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC.Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.

ABSTRACT
THE AGENTS CURRENTLY APPROVED FOR USE IN METASTATIC RENAL CELL CARCINOMA (MRCC) CAN BE DIVIDED BROADLY INTO TWO CATEGORIES: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR). The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC. Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib. In contrast, temsirolimus was approved on the basis of a phase III trial in treatment-naïve patients with poor-risk mRCC, demonstrating an improvement in overall survival relative to interferon-alfa. While these pivotal trials have created unique positions for everolimus and temsirolimus in current clinical algorithms, the role of mTOR inhibitors in mRCC is being steadily revised and expanded through ongoing trials testing novel sequences and combinations. The clinical development of mTOR inhibitors is outlined herein.

No MeSH data available.


Related in: MedlinePlus