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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

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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)

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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

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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

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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

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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