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.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

G.D. Demetri: commercial research support, Pfizer, Novartis, Ariad, Johnson & Johnson, Bristol-Myers Squibb, Infinity, Daiichi-Sankyo; honoraria from speakers bureau, Pfizer, Novartis; consultant/advisory board, Pfizer, Novartis, Ariad, Johnson & Johnson, Genentech, Infinity, Bayer, EMD-Serono, GlaxoSmithKline, Amgen, Daiichi-Sankyo, ArQule, Enzon, Millenium/Takeda; expert testimony, Pfizer, Novartis, Johnson & Johnson, Ariad/Merck, Infinity. C.R. Garrett, L. Paz-Arez, and J. Verweij: consultant/advisory board, Pfizer. P. Schöffski: commercial research grant, other commercial research support, honoraria from speakers bureau, and consultant/advisory board, Pfizer. M.H. Shah: commercial research grant, Pfizer. H.I. Hurwitz: commercial research grant and consultant/advisory board, Pfizer. A. Le Cesne: honoraria from speakers bureau: Pfizer, Novartis, and Pharmamar. D. Goldstein: commercial research grant: Pfizer, Cellgene, Amgen; consultant/advisory board, Pfizer, Novartis, Bayer, GlaxoSmithKline, Roche. J.-Y. Blay: honoraria from speakers bureau and consultant/advisory board, Pfizer and Novartis. G. McArthur: commercial research grant, Pfizer, Novartis. Q. Xu: consultant, Pfizer. X. Huang, C.S. Harmon, V. Tassell, and D.P. Cohen: employment and ownership interest, Pfizer. P.G. Casali: honoraria from speakers bureau and consultant/advisory board, Pfizer, Novartis, Bayer.

Figures

Fig. 1

OS across the entire study: A, final analysis; B, final and interim analyses. KM, Kaplan– Meier method; RPSFT, rank-preserving structural failure time method.

Fig. 2

Significant associations found between levels of circulating biomarkers of angiogenesis and TTP or OS. A–E, sunitinib arm. F, placebo arm. Median values used for stratification: A, B (baseline sVEGFR-2), 9,159 pg/mL; C, D (sVEGFR-2 ratio to baseline, C1;D14), 0.727; E (sVEGFR-3 ratio to baseline, C1;D14), 0.694; F (VEGF-A ratio to baseline, C1;D28), 0.957.