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ASCO 2019 Annual Meeting

ASCO 2019: Randomized, Double-Blind Phase III Study of Pazopanib versus Placebo in Patients with Metastatic Renal Cell Carcinoma who have no Evidence of Disease Following Metastasectomy - Medical Oncologist Perspective

Chicago, IL (UroToday.com) Pazopanib is a multi-targeted tyrosine kinase inhibitor which was approved in 2009 for the treatment of patients with advanced renal cell carcinoma (RCC). In the front line setting, pazopanib was compared with sunitinib and has been found to be non-inferior with respect to progression-free survival.1 Some patients with limited metastatic disease receive metastasectomy – this has been associated with improved outcomes in some studies.2   In one study of 38 patients who received metastasectomy, the median survival was 4.7 years with a median time to progression of 1.8 months.3  The role of adjuvant therapy after metastasectomy is not well defined. This study examines the role of pazopanib compared with placebo for patients who have no evidence of disease following metastasectomy. 
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This abstract provides data on 129 patients who were randomized to receive pazopanib 800 mg daily vs. placebo for 52 weeks. Eligibility criteria are shown below.
E2810Eligibility.png
To help balance the cohorts, patients were also stratified by the number of sites of resected disease (1 or more than 1) as well as disease-free interview (more than or less than 1 year). Baseline characteristics shown below.
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The primary endpoint of this study was to determine whether or not there could be a 42% improvement in disease-free survival (DFS) from 25% to 45% at 3 years. After 83 DFS events, the study was unblinded – unfortunately, the study did not meet its primary endpoint as DFS was 0.85 (95% CI 0.55, 1.31), p= 0.47.
Pazopanib_DiseaseFreeSurvival.png
The HR for overall survival was in favor of placebo, HR 2.65 (95% CI 1.02, 6.9), p= 0.05.  
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Patients who receive metastasectomy are at high risk for metastatic recurrence but there are currently no standard of care options for these patients to further decrease their risk of disease recurrence. Even in the non-metastatic high-risk population, adjuvant therapy that prolongs overall survival does not yet exist.4 In this study, Pazopanib did not improve disease-free survival when given for 1 year after metastasectomy and actually resulted in worse overall survival. While this study was negative, there are several other ongoing studies examining this unmet need, including the use of immune checkpoint inhibitors such as atezolizumab (NCT03024996). Another study is evaluating upfront nivolumab followed by surgery and then maintenance nivolumab for 36 weeks (NCT03055013). 

Presented by: Leonard Joseph Appleman, MD, Ph.D., Associate Professor of Medicine, University of Pittsburgh Department of Medicine, Pittsburgh, PA 

Written by: Jason Zhu, MD, Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma. New England Journal of Medicine 2013;369:722-31.
  2. Karam JA, Rini BI, Varella L, et al. Metastasectomy after targeted therapy in patients with advanced renal cell carcinoma. The Journal of Urology 2011;185:439-44.
  3. Daliani DD, Tannir NM, Papandreou CN, et al. Prospective assessment of systemic therapy followed by surgical removal of metastases in selected patients with renal cell carcinoma. BJU international 2009;104:456-60.
  4. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. New England Journal of Medicine 2016;375:2246-54.