Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure.

Abstract

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 cross-over 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.

• Authors: George D Demetri, Christopher R Garrett, Patrick Schöffski, Manisha H Shah, Jaap Verweij, Serge Leyvraz, Herbert I Hurwitz, Antonio Lopez Pousa, Axel Le Cesne, David Goldstein, Luis Paz-Ares, Jean-Yves Blay, Grant A McArthur, Qiang Casey Xu, Xin Huang, Charles S Harmon, Vanessa Tassell, Darrel P Cohen, Paolo G Casali
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 11 Pg. 3170-9 (Jun 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22661587 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamides
• Biomarkers, Tumor
• Indoles
• Piperazines
• Placebos
• Pyrimidines
• Pyrroles
• Imatinib Mesylate
• Sunitinib

Topics

• Adult
• Aged
• Benzamides
• Biomarkers, Tumor (blood)
• Cross-Over Studies
• Female
• Gastrointestinal Neoplasms (drug therapy)
• Gastrointestinal Stromal Tumors (drug therapy)
• Humans
• Imatinib Mesylate
• Indoles (adverse effects, therapeutic use)
• Male
• Middle Aged
• Neovascularization, Pathologic (blood)
• Piperazines (adverse effects, therapeutic use)
• Placebos
• Pyrimidines (adverse effects, therapeutic use)
• Pyrroles (adverse effects, therapeutic use)
• Retreatment
• Sunitinib
• Survival Analysis
• Young Adult