Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial

Abstract

PURPOSE Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

Safety and Efficacy of Pazopanib Therapy Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer

“…Adverse events were in line with those previously reported with pazopanib 10 . Grade 3 /4 adverse events occurred in 28% of patients.…”

“…The aim was to induce stability of disease prior to nephrectomy in over 75% of patients, avoiding potential progression and clinical deterioration during the preoperative surgical period. The PFS and OS results [7.1 months and 22.7 months respectively] were acceptable and in line with those seen for similar risk groups in the pivotal randomized VEGF targeted therapy trials in which the majority of patients previously had nephrectomy [10][11][12] . Survival analysis showed that the prognostic factors in this specific group of patients are similar to those in unselected patients.…”

“…A 2 nd smaller group did not have nephrectomy because of the development of morbidity. Pazopanib is associated with a spectrum of side effects, which may have contributed to this 10 . This group of patients is a concern as nephrectomy prior to pazopanib may have been possible and may have improved outcome.…”

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

“…1 Recently, overall survival benefits gained from small molecule tyrosine kinase inhibitors (TKI) directed against the VEGF receptor (VEGFR) have been observed in several randomized clinical trials (RCTs) among variety of solid tumors. [2][3][4][5][6][7][8][9][10] In addition, the United States Food and Drug Administration (FDA) has approved four VEGF TKIs, sunitinib (Sutent, Pfizer, New York, NY), sorafenib (Nexavar, Bayer Pharmaceuticals, West Haven, CT, and Onyx Pharmaceuticals, Richmond, CA), pazopanib (Votrient, GlaxoSmithKline, Middlesex, UK), and vandetanib (Caprelsa, AstraZeneca, London, UK), for use in cancer therapy. 11 As a result, the use of VEGFR-TKIs is expected to increase in the near future, and an appreciation for the differences in toxicity profiles between traditional cytotoxic agents and targeted agents is therefore urgently needed.…”

Can we develop effective combination antiangiogenic therapy for patients with hepatocellular carcinoma?

“…This novel class of agents was designed to inhibit the vascular endothelial growth factor (VEGF) pathway; as VEGF is the most prevalent and dominant proangiogenic growth factor in the tumor microenvironment [7–10]. FDA approved agents that directly target the VEGF pathway include the anti-VEGF antibody bevacizumab and the multitargeted tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib), which inhibit VEGFRs along with other receptor tyrosine kinases [11–16]. …”