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11
One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal TumorA Randomized Trial
Joensuu H, Eriksson M, Sundby Hall K, et al. JAMA. 2012;307(12):1265–1272
2
Imatinib for 12 months
An open-label Phase III study
Imatinib for 36 months
Follow-up
Follow-up
Random
Assignment
1:1Stratification:
1) R0 resection, no tumor rupture
2) R1 resection or tumor rupture
Joensuu H et al. JAMA 2012;307(12):1265–1272
N=400
SSGXVIII/AIO: Design
3
SSGXVIII/AIO: Methods
HPF, high-power field of the microscope.
1.Joensuu H et al. JAMA 2012;307(12):1265–1272 2.Fletcher CD et al. Hum Pathol 2002;33:459–4653.Joensuu H. Hum Pathol 2008;39:1411−1419.
EndpointsEndpoints11
Primary RFS
Secondary Treatment safety OS GIST-specific survival
TreatmentTreatment11
Imatinib 400 mg/d (12 vs 36 months)
Key inclusion criteriaKey inclusion criteria11
Histologically confirmed GIST, KIT-positive High risk of recurrence according to the modified
consensus criteria2,3
Tumor size >10 cm or Tumor mitosis count >10/50 HPF or Size >5 cm and mitosis count >5/50 HPF or Tumor rupture before surgery or at surgery
4
SSGXVIII/AIO: Patient Disposition
*Three patients who withdrew consent were excluded Joensuu H et al. JAMA 2012;307(12):1265–1272
Category 12 Monthsn (%)
36 Monthsn (%)
Randomized (Feb 2004 to Sep 2008) 200 200
Included in ITT population* 199 198
− No GIST at pathology review 5 (3) 10 (5)
− GIST metastases at study entry 13 (7) 11 (6)
Included in efficacy population 181 177
Included in safety population (SP) 194 198
Discontinued assigned treatment (SP) 29 (15) 63 (32)
− GIST recurred during treatment 4 (2) 12 (6)
− Adverse event 15 (8) 27 (14)
− Patient preference 0 (0) 11 (6)
− Tumor histology not GIST 6 (3) 6 (3)
− Other reason 4 (2) 7 (4)
5
SSGXVIII/AIO: Baseline Characteristics (ITT Population)
*Per 50 high power fields **Available for 366 (92%) out of the 397 tumors
Joensuu H et al. JAMA 2012;307(12):1265–1272
Characteristic 12-Month (n=199)
36-Month (n=198)
Median age (range), years 62 (23–84) 60 (22–81)
Male, % 52 49
ECOG performance status 0, % 85 86
Gastric primary tumor, % 49 53
Median tumor size (range), cm 9 (2–35) 10 (2–40)
Median mitosis count (central)* 10 (0−250) 8 (0−165)
Tumor rupture, % 18 22
GIST gene mutation site, %**
– KIT exon 9 6 7
– KIT exon 11 65 64
– PDGFRA exon 12 2 1
– PDGFRA exon 18 11 10
– PDGFRA exon 18 mutation D842V 9 7
– Wild type 10 7
6
SSGXVIII/AIO: Baseline Characteristics (ITT Population)
Characteristic 12-Month (n=199)
36-Month (n=198)
Modified Consensus Classification Risk Group. %
– High 89 91
– Intermediate 8 4
– Low risk 1 2
– Very low risk 0 0
– Not available 2 3
Joensuu H et al. JAMA 2012;307(12):1265–1272
7
SSGXVIII/AIO: RFS Events and Deaths (ITT Population)
Event 12-Month
(n=199)
No. (%)
36-Month
(n=198)
No. (%)
RFS events (recurrences or deaths) 84 (42) 50 (25)
Deaths 25 (13) 12 (6)
– From GIST 14 (7) 7 (4)
– Another cause 11 (6) 5 (3)
Median follow-up time: 54 months (from the date of randomization to the date of data cut-off, Dec 31, 2010)
Joensuu H et al. JAMA 2012;307(12):1265–1272
8
SSGXVIII/AIO: Recurrence-Free Survival (ITT Population)
Joensuu H et al. JAMA 2012;307(12):1265–1272
3-year survival : 36 months, 86.6% 12 months, 60.1%
5-year survival :36 months, 65.6%12 months, 47.9%
Per
cent
age
Time Since Randomisation, y
36 Months of imatinib 198 184 173 133 82 39 8
12 Months of imatinib 199 177 137 88 49 27 10
HR, 0.46 (95% CI, 0.32-0.65)Log-rank P<.001
No. of patients
36 Months of imatinib
12 Months of imatinib
9Excluded: consent withdrawn, no GIST at pathology review, or overt metastases at study entry
SSGXVIII/AIO: RFS in Efficacy Population
3-year survival : 36 months, 88.1% 12 months, 62.1%
5-year survival :36 months, 67.4%12 months, 50.3%
Joensuu H et al. JAMA 2012;307(12):1265–1272
HR, 0.46 (95% CI, 0.31-0.68)Log-rank P<.001
36 Months of imatinib
12 Months of imatinib
Per
cent
age
Time Since Randomisation, y
36 Months of imatinib 177 167 157 121 71 35 7
12 Months of imatinib 181 163 126 81 46 25 10
No. of patients
10Joensuu H et al. JAMA 2012;307(12):1265–1272
No. of Patients No. of Events HR
12-moGroup
36-moGroup
12-moGroup
36-moGroup
(95% CI)
Age, y
≤65 121 135 45 32 0.47 (0.30-0.74)
>65 78 63 39 18 0.49 (0.28-0.85)
Tumor site
Stomach 97 105 29 16 0.42 (0.23-0.78)
Other 101 92 55 34 0.47 (0.31-0.73)
Tumor size, cm
≤10 120 99 46 19 0.40 (0.23-0.69)
>10 78 98 38 31 0.47 (0.29-0.76)
Mitotic count/50 HPF Local
≤10 100 109 25 25 0.76 (0.73-1.32)
>10 85 69 53 18 0.29 (0.17-0.49)
Central
≤10 121 135 31 24 0.58 (0.34-0.99)
>10 77 60 52 24 0.37 (0.23-0.61)
Tumor rupture
No 164 154 63 32 0.43 (0.28-0.66)
Yes 35 44 21 18 0.47 (0.25-0.89)
Completeness of surgery
R0 169 160 66 37 0.45 (0.30-0.67)
R1 29 37 18 13 0.46 (0.22-0.94)
Tumor mutation site
KIT exon 9 12 14 8 8 0.61 (0.22-1.68)
KIT exon 11 129 127 55 28 0.35 (0.22-0.56)
Wild type 19 14 9 3 0.41 (0.11-1.51)
Other 28 23 6 4 0.78 (0.22-2.78)
P Value
<.001
.01
.005
<.001
<.001
.002
.33
<.001
.04
<.001
<.001
.02
<.001
.03
.34
<.001
.17
.70
SSGXVIII/AIO: RFS in Subgroups
Favors 36 moof Imatinib
Favors 12 mo of Imatinib
HR (95% CI)
0.1 1.0 10
11
Joensuu H et al. JAMA 2012;307(12):1265–1272
3-year survival : 36 months, 96.3% 12 months, 94.0%
5-year survival :36 months, 92.0%12 months, 81.7%
HR, 0.45 (95% CI, 0.22-0.89)Log-rank P = .02
Per
cent
age
Time Since Randomisation, y
36 Months of imatinib
12 Months of imatinib
SSGXVIII/AIO: Overall Survival (ITT Population)
36 Months of imatinib 198 192 184 152 100 56 13
12 Months of imatinib 199 188 176 140 87 46 20
No. of patients
12
SSGXVIII/AIO: Treatment Safety
Cardiac AEs and second malignancies were low and comparable in both treatment arms
Joensuu H et al. JAMA 2012;307(12):1265–1272
No. (%)
All Grades Grade 3 or 4
Events12-mo Group
(n = 194)36-mo Group
(n = 198)P
Valuea
12-mo Group(n = 194)
36-mo Group(n = 198)
PValuea
Any event 192 (99.0) 198 (100.0) .24 39 (20.1) 65 (32.8) .006
Hematological Anemia Leukopenia
140 (72.2) 67 (34.5)
159 (80.3) 93 (47.0)
.08 .01
1 (0.5) 4 (2.1)
1 (0.5) 6 (3.0)
>.99 .75
Nonhematological Periorbital edema Fatigue Nausea Diarrhea Muscle cramps Leg edema
115 (59.3) 94 (48.5) 87 (44.8) 85 (43.8) 60 (30.9) 64 (33.0)
147 (74.2) 96 (48.5) 101 (51.0) 107 (54.0) 97 (49.0) 81 (40.9)
.002 >.99 .23 .04 <.001 .12
1 (0.5) 2 (1.0) 3 (1.5) 1 (0.5) 1 (0.5) 1 (0.5)
2 (1.0) 1 (0.5) 1 (0.5) 4 (2.0) 2 (1.0) 2 (1.0)
>.99 .62 .37 .37 >.99 >.99
Biochemical Elevated blood lactate
dehydrogenase Elevated serum creatinine
84 (43.3) 59 (30.4)
119 (60.1) 88 (44.4)
.001 .005
0
0
0
0
aFisher exact test
13
SSGXVIII/AIO: Conclusions
Compared with 1 year of treatment, 3 years of adjuvant imatinib significantly improves RFS and OS for patients with GIST who are at a high risk of recurrence after surgery
Adjuvant imatinib is relatively well tolerated; severe adverse events are infrequent
This trial has established 3 years of 400 mg imatinib as the new standard of care for adjuvant treatment of patients with high-risk GIST
Both the US Food and Drug Administration and European commission approved label updates that include 3-year duration for adjuvant treatment of KIT+ GIST patients
The National Comprehensive Cancer Network updated recommendations to include 3 years of adjuvant imatinib therapy as the new standard of care for KIT+ GIST patients
Joensuu H et al. JAMA 2012;307(12):1265–1272