Journal
CLINICAL CANCER RESEARCH
Volume 18, Issue 11, Pages 3170-3179Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-11-3005
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Funding
- Pfizer
- Novartis
- Ariad
- Johnson Johnson
- Bristol-Myers Squibb
- Infinity
- Daiichi-Sankyo
- Cellgene
- Amgen
- Pfizer Inc.
- Pfizer Inc. (New York, NY)
- Virginia and Daniel K. Ludwig Trust for Cancer Research
- Rubenstein Foundation
- Katz Foundation
- Quick Family Fund for Cancer Research
- Ronald O. Perelman Fund for Cancer Research at Dana-Farber
- Stutman GIST Cancer Research Fund
- Paul's Posse
- Leslie's Links
- Spanish National Health Service [FIS PI 081156]
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Purpose: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. Experimental Design: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. Results: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P = 0.306) as expected, given the crossover design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. Conclusions: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events. Clin Cancer Res; 18(11); 3170-9. (C) 2012 AACR.
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