Quantifying the effect of everolimus on both tumor growth and new metastases in metastatic renal cell carcinoma (RCC): A dynamic tumor model of the RECORD-1 phase III trial.

Stein, Andrew M.; Carter, A.; Hollaender, Norbert; Motzer, Robert J.; Sarr, Céline

doi:10.1200/jco.2011.29.15_suppl.4602

Cited by 3 publications

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“…Anti-tumor activity of everolimus 10 mg daily was shown in a phase 2 trial of patients with mRCC [22,23], and results of the phase 3 RECORD-1 study demonstrated a progression-free survival (PFS) benefit of everolimus 10 mg daily over placebo in patients with VEGFr-TKI–refractory mRCC (4.9 vs 1.9 months; HR 0.33; 95% CI, 0.25-0.43; P < .001) [10]. In addition, pharmacodynamic modeling of tumor growth in patients enrolled in RECORD-1 demonstrated that everolimus 5 mg daily and 10 mg daily significantly slowed the growth of mRCC target lesions, non-target lesions, and new metastases compared with placebo ( P < .001) [24,25]. …”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study

Guo

Huang

et al. 2013

BMC Cancer

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BackgroundIn China, there are currently no approved therapies for the treatment of metastatic renal cell carcinoma (mRCC) following progression with vascular endothelial growth factor (VEGF)-targeted agents. In the phase 3 RECORD-1 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus afforded clinical benefit with good tolerability in Western patients with mRCC whose disease had progressed despite VEGF receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. This phase 1b study was designed to further evaluate the safety and efficacy of everolimus in VEGFr-TKI-refractory Chinese patients with mRCC.MethodsAn open-label, multicenter phase 1b study enrolled Chinese patients with mRCC who were intolerant to, or progressed on, previous VEGFr-TKI therapy (N = 64). Patients received everolimus 10 mg daily until objective tumor progression (according to RECIST, version 1.0), unacceptable toxicity, death, or study discontinuation for any other reason. The final data analysis cut-off date was November 30, 2011.ResultsA total of 64 patients were included in the study. Median age was 52 years (range, 19–75 years) and 69% of patients were male. Median duration of everolimus therapy was 4.1 months (range, 0.0-16.1 months). Expected known class-effect toxicities related to mTOR inhibitor therapy were observed, including anemia (64%), hypertriglyceridemia (55%), mouth ulceration (53%), hyperglycemia (52%), hypercholesterolemia (50%), and pulmonary events (31%). Common grade 3/4 adverse events were anemia (20%), hyperglycemia (13%), increased gamma-glutamyltransferase (11%), hyponatremia (8%), dyspnea (8%), hypertriglyceridemia (6%), and lymphopenia (6%). Median PFS was 6.9 months (95% CI, 3.7-12.5 months) and the overall tumor response rate was 5% (95% CI, 1-13%). The majority of patients (61%) had stable disease as their best overall tumor response.ConclusionsSafety and efficacy results were comparable to those of the RECORD-1 trial. Everolimus is generally well tolerated and provides clinical benefit to Chinese patients with anti-VEGF-refractory mRCC.Trial registrationclinicaltrials.gov, NCT01152801

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Section: Introductionmentioning

confidence: 99%

Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study

Guo

Huang

et al. 2013

BMC Cancer

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“…Our model assessed the effect of dose on growth of target lesions; thus, it did not capture any potential benefit that a reduced dose of everolimus may have on nontarget lesions and/or the prevention of new lesions. Subsequent efforts to model the dose–response of nontarget and new lesions demonstrated a marked difference between placebo and a 10-mg dose of everolimus, but no difference between 5-mg and 10-mg doses of everolimus was detected [ 22 ]. It may be that there is no difference between the two everolimus doses on nontarget and new lesions or that the lack of difference may have been because the measurements of these lesion types were categorical rather than continuous; characterization of the dose–response relationship for these variables requires additional data.…”

Section: Discussionmentioning

confidence: 99%

Dynamic tumor modeling of the dose–response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial

Stein¹,

Wang

Carter

et al. 2012

BMC Cancer

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BackgroundThe phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose–response relationship of everolimus.ResultsThe model predicts that after 1 year of continuous dosing, the change in SLD of target lesions will be +142.1% ± 98.3%, +22.4% ± 17.2%, and –15.7% ± 11.5% in the average patient treated with placebo, 5 mg everolimus, and 10 mg everolimus, respectively. This nonlinear, mixed-effects modeling approach can be used to describe the dynamics of each individual patient, as well as the overall population. This allows evaluation of how an actual dosing history and individual covariates impact on the observed drug effect, and offers the possibility of predicting clinical observations as a function of time.ConclusionsIn this pharmacodynamic model of tumor response, everolimus more effectively shrinks target lesions in mRCC when dosed 10 mg daily versus 5 mg daily, although a 5-mg dose still shows an antitumor effect. These data support earlier studies that established 10 mg daily as the preferred clinical dose of everolimus, and improve our understanding of the everolimus dose–response relationship.

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Reply to U.R. Mansmann et al and M.-W. An et al

Claret¹,

Bruno²

2013

JCO

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Quantifying the effect of everolimus on both tumor growth and new metastases in metastatic renal cell carcinoma (RCC): A dynamic tumor model of the RECORD-1 phase III trial.

Cited by 3 publications

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Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study

Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study

Dynamic tumor modeling of the dose–response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial

Reply to U.R. Mansmann et al and M.-W. An et al

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