Dataset Information

Prognostic Biomarkers for Response to Vascular Endothelial Growth Factor-Targeted Therapy for Renal Cell Carcinoma.

ABSTRACT: Improved understanding of renal carcinoma disease biology has led to the discovery and approval of five novel therapies targeting specific molecules in the vascular endothelial growth factor (VEGF) biochemical pathway. Biomarker studies attempting to predict response to VEGF-targeted therapies have largely focused on circulating proteins, tissue-based molecules, and germline polymorphisms. Thus far studies have yielded conflicting results that require prospective validation; therefore no definitive biomarker has yet been integrated into the clinician's armamentarium. However, early analyses featuring genomic biomarkers have generated promising findings. This article provides an overview of available biomarkers evaluated with respect to VEGF-targeted therapies in patients with advanced renal cell carcinoma.

SUBMITTER: Winer AG

PROVIDER: S-EPMC4864362 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Prognostic Biomarkers for Response to Vascular Endothelial Growth Factor-Targeted Therapy for Renal Cell Carcinoma.

Winer Andrew G AG Motzer Robert J RJ Hakimi A Ari AA

The Urologic clinics of North America 20151031 1

Improved understanding of renal carcinoma disease biology has led to the discovery and approval of five novel therapies targeting specific molecules in the vascular endothelial growth factor (VEGF) biochemical pathway. Biomarker studies attempting to predict response to VEGF-targeted therapies have largely focused on circulating proteins, tissue-based molecules, and germline polymorphisms. Thus far studies have yielded conflicting results that require prospective validation; therefore no definit ...[more]

PMID: 26614032

Similar Datasets

Project description:ContextContradictory data exist with regard to adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted therapy in surgically managed patients for localized renal cell carcinoma (RCC).ObjectiveTo systematically evaluate the current evidence regarding the therapeutic benefit (disease-free survival [DFS] and overall survival [OS]) and grade 3-4 adverse events (AEs) for adjuvant VEGFR-targeted therapy for resected localized RCC.Evidence acquisitionA critical review of PubMed/Medline, Embase, and the Cochrane Library in January 2018 according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement was performed. We identified reports and reviewed them according to the Consolidated Standards of Reporting Trials and Standards for the Reporting of Diagnostic Accuracy Studies criteria. Of eight full-text articles that were eligible for inclusion, five studies (two of five were updated analyses) were retained in the final synthesis. Study characteristics were abstracted and the number needed to treat (NNT) per trial was estimated.Evidence synthesisThe three randomized controlled phase III trials included the following comparisons: sunitinib versus placebo or sorafenib versus placebo (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma [ASSURE] study, n=1943), sunitinib versus placebo (S-TRAC, n=615), and pazopanib versus placebo (Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy study, n=1135). The NNT ranged from 10 (S-TRAC) to 137 (ASSURE study). The pooled analysis showed that VEGFR-targeted therapy was not statistically significantly associated with improved DFS (hazard ratio [HRrandom]: 0.92, 95% confidence interval [CI]: 0.82-1.03, p=0.16) or OS (HRrandom: 0.98, 95% CI: 0.84-1.15, p=0.84) compared with the control group. The adjuvant therapy group experienced significantly higher odds of grade 3-4 AEs (ORrandom: 5.89, 95% CI: 4.85-7.15, p<0.001). In exploratory analyses focusing on patients who started on the full-dose regimen, DFS was improved in patients who received adjuvant therapy (HRrandom: 0.83, 95% CI: 0.73-0.95, p=0.005).ConclusionsThis pooled analysis of reported randomized trials did not reveal a statistically significant effect between adjuvant VEGFR-targeted therapy and improved DFS or OS in patients with intermediate/high-risk local or regional fully resected RCC. Improvement in DFS may be more likely with the use of full-dose regimens, pending further results. However, adjuvant treatment was associated with high-grade AEs.Patient summaryVascular endothelial growth factor receptor-targeted therapy after nephrectomy for localized kidney cancer is not associated with consistent improvements in delaying cancer recurrence or prolonging life and comes at the expense of potentially significant side effects.

Project description:Cabozantinib is an oral multitargeted tyrosine kinase inhibitor (TKI) that potently inhibits MET and AXL, both associated with poor prognosis in renal cell carcinoma (RCC), next to vascular endothelial growth factor receptor 2, KIT, FLT3 and RET. Chronic treatment with vascular endothelial growth factor receptor (VEGFR)-targeting sunitinib upregulates MET and AXL in RCC, indicating that cabozantinib may be particularly effective in patients with advanced RCC whose disease progressed on prior VEGFR-targeted treatment. Cabozantinib (60 mg once daily) has been investigated in comparison to everolimus (10 mg once daily) in a phase III randomized controlled trial (RCT) in 658 patients with advanced RCC of whom 71% had received one prior and 29% had received at least two prior lines of VEGR-targeted therapy. This study demonstrated highly significant improved progression-free survival of 7.4 months versus 3.9 months with a hazard ratio (HR) of 0.51 [95% confidence interval (CI) 0.41-0.62] in favour of cabozantinib. Cabozantinib also showed a superior overall survival of 21.4 months versus 16.5 months (HR 0.66; 95% CI 0.53-0.83). Objective response rate was higher in cabozantinib-treated patients, 17% versus 3%. Clinical benefit was shown in all subgroups of patients, including in patients with bone or visceral metastases. The safety profile was acceptable with manageable side effects. Based on this study, cabozantinib is a highly effective approved second-line treatment option for patients with advanced RCC with a manageable toxicity profile. Other recently approved second-line agents include checkpoint inhibitor nivolumab and VEGF-targeting agent lenvatinib combined with everolimus. In the absence of predictive markers as well as head-to-head comparisons of these three recently approved treatments, the choice between these drugs in second-line treatment will probably be made based on comorbidities, tolerability of previous treatment and presence of high tumour burden with rapidly progressive disease. Future pretreatment assessment of MET and AXL tumour aberration may aid clinicians to make a rational choice between currently approved second-line treatment options.

Dataset Information

Prognostic Biomarkers for Response to Vascular Endothelial Growth Factor-Targeted Therapy for Renal Cell Carcinoma.

Publications

Prognostic Biomarkers for Response to Vascular Endothelial Growth Factor-Targeted Therapy for Renal Cell Carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets