Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033.
OBJECTIVE
To assess potential differences in progression-free or overall survival when imatinib mesylate is administered to patients with incurable gastrointestinal stromal tumors (GIST) at a standard dose (400 mg daily) versus a high dose (400 mg twice daily).


METHODS
Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial. At registration, patients were randomly assigned to either standard or high-dose imatinib, with close interval follow-up. If objective progression occurred by Response Evaluation Criteria in Solid Tumors, patients on the standard-dose arm could reregister to the trial and receive the high-dose imatinib regimen.


RESULTS
Seven hundred forty-six patients with advanced GIST from 148 centers across the United States and Canada were enrolled onto this trial in 9 months. With a median follow-up of 4.5 years, median progression-free survival was 18 months for patients on the standard-dose arm, and 20 months for those receiving high-dose imatinib. Median overall survival was 55 and 51 months, respectively. There were no statistically significant differences in objective response rates, progression-free survival, or overall survival. After progression on standard-dose imatinib, 33% of patients who crossed over to the high-dose imatinib regimen achieved either an objective response or stable disease. There were more grade 3, 4, and 5 toxicities noted on the high-dose imatinib arm.


CONCLUSIONS
This trial confirms the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST but did not show any advantage to higher dose treatment. It appears reasonable to initiate therapy with 400 mg daily and to consider dose escalation on progression of disease.
Blanke
Charles D
CD
Oregon Health & Science University Cancer Institute, 3181 SW Sam Jackson Park Rd, L-586, Portland, OR 97239, USA. blankec@ohsu.edu
Rankin
Cathryn
C
Demetri
George D
GD
Ryan
Christopher W
CW
von Mehren
Margaret
M
Benjamin
Robert S
RS
Raymond
A Kevin
AK
Bramwell
Vivien H C
VH
Baker
Laurence H
LH
Maki
Robert G
RG
Tanaka
Michael
M
Hecht
J Randolph
JR
Heinrich
Michael C
MC
Fletcher
Christopher D M
CD
Crowley
John J
JJ
Borden
Ernest C
EC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage*; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage*; D012189:Retrospective Studies; D015996:Survival Rate
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit