Complete Longitudinal Analyses of the Randomized, Placebo-Controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor following Imatinib Failure

作者：Demetri George D^*; Garrett Christopher R; Schoffski Patrick; Shah Manisha H; Verweij Jaap; Leyvraz Serge; Hurwitz Herbert I; Lopez Pousa Antonio; Le Cesne Axel; Goldstein David; Paz Ares Luis; Blay Jean Yves; McArthur Grant A; Xu Qiang; Huang Xin; Harmon Charles S; Tassell Vanessa; Cohen Darrel P; Casali Paolo G

来源：Clinical Cancer Research, 2012, 18(11): 3170-3179.

DOI：10.1158/1078-0432.CCR-11-3005

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. %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;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.

• 出版日期2012-6-1