Patel_edit.qxp 13/7/09 14:35 Page 62
unresectable or metastatic GIST to receive 400 or 600mg/day of median follow-up of 4.5 years, there were no statistically significant
imatinib. Patients who progressed on 400mg/day had their dose differences in ORR (45% for both doses), PFS (18 months for 400mg
increased to 600mg/day.
After a median follow-up of 21 months, versus 20 months for 800mg), or OS (55 months for 400mg versus
partial response and stable disease were achieved in 66 and 17% of 51 months for 800mg).
the total patient population, respectively.
Progressive disease led to
death in 14% of patients. Although median survival was not reached, Neither of these two large studies found any major clinical benefits
researchers estimated 85% to be alive at 19 months. One-third of with initiation of higher-dose imatinib, with no apparent improvement
patients who progressed on the lower dose sustained a partial in response rates or rates of disease stabilization. Furthermore,
response upon cross-over. Similar results were reported by a phase II increased initial imatinib dosage conferred no apparent advantage in
study testing the efficacy of imatinib at the dose of 400mg twice daily terms of OS. These two study groups with intentionally similar designs
in 27 patients with histologically proven advanced and/or metastatic agreed to a prospectively defined combined analysis of the studies.
GIST characterized by KIT expression.
Of these patients, 89% The primary end-points of this ‘metaGIST’ project were PFS and OS. At
experienced some degree of symptomatic improvement: 4% had a median follow-up of 45 months, the investigators found a small but
complete remission, 67% partial remission, and 18% stable disease, significant advantage in terms of PFS with high-dose imatinib, but no
while 11% had progressive disease. Clinical trials have reported a advantage in OS.
Heterogeneity between the two studies is currently
median time to objective response ranging from 13 to 16 weeks under investigation.
for patients with advanced GIST treated with imatinib,
some patients have shown dramatic symptomatic improvement Optimizing Imatinib Dosing—Less May Be More
within days, along with evidence of reduced metabolic activity on The EORTC and SWOG studies saw a confirmation of clinical activity at
positron emission tomography (PET) scans. Biopsy specimens from a both the standard dose and the higher dose of imatinib, where
patient with metastatic GIST have also shown a marked decrease in imatinib was well-tolerated overall. However, the higher dose of
tumor cells, myxoid degeneration, and scarring within one month.
800mg/day was associated with more dose reductions than the dose
These tumor cells did not stain for the proliferation marker Ki-67, of 400mg/day in both studies (EORTC: 60 versus 16%; SWOG: 44
suggesting an absence of active cell division. versus 10%).
Furthermore, severe toxicities were more common in
patients treated with 800mg/day than in those treated with
Long-term efficacy data on treatment with imatinib in patients with 400mg/day (EORTC: 50 versus 32%; SWOG: 63 versus 43%).
advanced disease have since been made available. Two large, cross-over design of the studies showed that increasing the dosage
randomized, controlled phase III trials compared the effects of for patients who progress on the standard dose of imatinib is feasible,
400mg/day imatinib with 800mg/day imatinib (400mg twice daily). In with approximately one-third of patients experiencing clinical
both studies, patients were allowed to cross over from the low-dose benefits—typically disease stabilization, although a minority do
arm to the high-dose arm at disease progression. In the study led by achieve partial responses. Data from EORTC at a median follow-up of
the European Organization for Research and Treatment of Cancer 25 months showed that of the 133 patients who crossed over, three
(EORTC), which included the Australasian Gastro-Intestinal Trials (2%) had a partial response and 36 (27%) achieved stable disease for
Group and the Italian Sarcoma Group, 946 patients with advanced a median duration of 153 days.
Similarly, three of the 117 assessable
GIST were randomized to the two study arms to evaluate the primary patients (3%) in SWOG had partial response following cross-over, and
end-point of progression-free survival (PFS).
After a median follow-up 33 (28%) had stable disease.
Median and one-year PFS following
of 25 months, objective response rates (ORRs) were similar between cross-over in EORTC were 81 days and 18%, respectively.
treatment arms: 50% for the low-dose group and 54% for the high- median PFS was five months after cross-over, with a median OS of 19
dose group. A median follow-up of 40 months allowed for an analysis months.
The incidence of dose reductions in cross-over patients was
of overall survival (OS), and found no significant difference in OS lower than that observed in the treatment group assigned to receive
between the two arms.
Furthermore, the previously reported high-dose imatinib: 17 and 16% of patients in EORTC and SWOG,
advantage for PFS for 800mg/day at 25-month follow-up
was no respectively, had a dose reduction following cross-over, suggesting
longer statistically significant at this 40-month follow-up.
The other that patients who escalate their dose from the initial 400mg/day
phase III study, led by the Southwest Oncology Group (SWOG), appear to be better able to tolerate high doses. The severity of
included the Cancer and Leukemia Group B, the Eastern Cooperative toxicities did not differ significantly before and after cross-over,
Oncology Group, and the National Cancer Institute of Canada, and except for worsening of anemia and fatigue and possible
randomized 746 patients to evaluate the primary end-point of OS.
improvement in the severity of neutropenia.
Early interim results after a median follow-up of 14 months showed
no difference between the dosage groups in PFS or OS and a When analyzed separately, the outcomes of the individual EORTC and
similar proportion of patients achieving an objective response (43% SWOG studies suggest that the higher dose of 800mg/day is more
for 400mg/day versus 41% for 800mg/day) or stable disease (32% for toxic but not more effective than 400mg/day. However, approximately
both groups). At a median follow-up of 25 months, two-year survival one-third of patients do benefit from a dose increase upon disease
was 74 and 78% for the 400 and 800mg treatment arms, respectively, progression. Furthermore, a separate study compared a dose of
while the two-year PFS was 50 and 53%, respectively.
Of the 88 400mg/day with 600mg/day, although it was not powered to
patients who progressed and crossed over to the higher dose, 3% distinguish between the efficacies of the two doses and PFS data
exhibited partial response and 28% achieved stable disease. After a were not reported.
Although no significant difference was found
62 US ONCOLOGY
| Page 2
| Page 3
| Page 4
| Page 5
| Page 6
| Page 7
| Page 8
| Page 9
| Page 10
| Page 11
| Page 12
| Page 13
| Page 14
| Page 15
| Page 16
| Page 17
| Page 18
| Page 19
| Page 20
| Page 21
| Page 22
| Page 23
| Page 24
| Page 25
| Page 26
| Page 27
| Page 28
| Page 29
| Page 30
| Page 31
| Page 32
| Page 33
| Page 34
| Page 35
| Page 36
| Page 37
| Page 38
| Page 39
| Page 40
| Page 41
| Page 42
| Page 43
| Page 44
| Page 45
| Page 46
| Page 47
| Page 48
| Page 49
| Page 50
| Page 51
| Page 52
| Page 53
| Page 54
| Page 55
| Page 56
| Page 57
| Page 58
| Page 59
| Page 60
| Page 61
| Page 62
| Page 63
| Page 64
| Page 65
| Page 66
| Page 67
| Page 68
| Page 69
| Page 70
| Page 71
| Page 72
| Page 73
| Page 74
| Page 75
| Page 76
| Page 77
| Page 78
| Page 79
| Page 80
| Page 81
| Page 82
| Page 83
| Page 84
| Page 85
| Page 86
| Page 87
| Page 88
| Page 89
| Page 90
| Page 91
| Page 92
| Page 93
| Page 94
| Page 95
| Page 96
| Page 97
| Page 98
| Page 99
| Page 100