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


METHODS
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.
Center for Sarcoma and Bone Oncology, Ludwig Center at Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, 450 Brookline Ave., Dana 1212, Boston, MA 02215, USA. gdemetri@partners.org
George D
GD
Demetri
Christopher R
CR
Garrett
Patrick
P
Schöffski
Manisha H
MH
Shah
Jaap
J
Verweij
Serge
S
Leyvraz
Herbert I
HI
Hurwitz
Antonio Lopez
AL
Pousa
Axel
A
Le Cesne
David
D
Goldstein
Luis
L
Paz-Ares
Jean-Yves
JY
Blay
Grant A
GA
McArthur
Qiang Casey
QC
Xu
Xin
X
Huang
Charles S
CS
Harmon
Vanessa
V
Tassell
Darrel P
DP
Cohen
Paolo G
PG
Casali
D000328:Adult; D000368:Aged; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000097:blood; D018592:Cross-Over Studies; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000097:blood; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use; D010919:Placebos; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects* / Q000627:therapeutic use*; D019233:Retreatment; D000077210:Sunitinib; D016019:Survival Analysis; D055815:Young Adult
D001549:Benzamides; D014408:Biomarkers, Tumor; D007211:Indoles; D010879:Piperazines; D010919:Placebos; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D000077210:Sunitinib