Transcript Gastrointestinal Stromal Tumours (GIST)

Whom to treat and how long to treat
after resection of GIST
Professor John R Zalcberg
Chief Medical Officer &
Director, Division of Cancer Medicine
Peter MacCallum Cancer Centre
Chair, Australasian Gastro-Intestinal Trials Group
Disclosures
Research / Travel Support / Advisory Board
 Novartis
 Pfizer
 Bayer
 Amgen
 BMS
Risk of Recurrence After
Resection of Primary GIST
Recurrence-Free Survival, %
Approximately 40% of patients who undergo complete resection
of primary GIST have a recurrence within 5 years
100
90
80
70
60
50
40
30
20
10
0
1 Year
DeMatteo RP et al. Cancer. 2008;112:608-615.
2 Years
5 Years
10 Years
Risk Assessment
 Accurate assessment of risk of aggressive malignant
behaviour in GIST poses a challenge1
 Morphologic features most predictive of outcome1,2
- Mitotic index
- Tumour size
 Tumour site and rupture also affect risk of recurrence and
progression2,3
 Mutational status is useful in predicting treatment
response in the metastatic setting4,5
 ?applicable in the adjuvant setting
1. Fletcher CD et al. Hum Pathol. 2002;33:459-465.
2. Demetri GD et al. J Natl Compr Cancer Netw. 2007;5(suppl 2):S1-S29.
3. Miettinen M, Lasota J. Arch Pathol Lab Med. 2006;130:1466-1478.
4. Debiec-Rychter M et al. Eur J Cancer. 2006;42:1093-1103.
5. Heinrich MC et al. J Clin Oncol. 2003;21:4342-4349.
Primary GIST: Risk Factors for
Recurrence After Surgery
Rates of RFS were independently predicted by mitotic index,
tumour size, and tumour location
Adapted with permission from DeMatteo RP et al. Cancer. 2008;112:608-615.
Cumulative Survival
Overall Survival by Risk Group
AFIP, Armed Forces Institute of Pathology.
Adapted with permission from Goh BKP et al. Ann Surg Oncol. 2008;15:2153-2163.
Specific KIT Mutations Have Prognostic Importance
Proportion Recurrence-Free
RFS in 127 patients with completely
resected localized GIST based on mutation type
1.0
KIT exon 11 PM/INS (n=32)
0.8
Other KIT exon 11 deletion (n=17)
PDGFRA mutation (n=8)
0.6
No mutation (n=29)
KIT exon 11 DEL557/8 (n=35)
0.4
0.2
KIT exon 9 mutation (n=4)
P<0.001
0.0
0
1
2
DeMatteo RP et al. Cancer. 2008;112:608-615.
3
4
5
6
7
Years After Resection
8
9
10
Risk Stratification of Primary GIST: Miettinen (AFIP)
Data are based on long-term follow-up of 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs.
† Denotes small numbers of cases.
≈ Tumour size categories combined for both duodenal and rectal GISTs because of small numbers.
∂ No tumours of such category were included in this study.
Original source: Miettinen M, Lasota J. Semin Diagn Pathol. 2006;23:70-83.
Nomogram to Predict RFS Following Complete
Surgical Resection of Primary GIST
Gold JS et al. Lancet Oncol. 10; 1045-1052, 2009
Risk Classification – Room for
Refinement
 Additional factors:
- Mutational status1
- Rupture2
- Necrosis3
1. Wardelmann E et al. Virchoves Arch. 2007;451:743-749.
2. Joensuu H. Hum Path. 2008;39:1411-1419.
3. Dei Tos AP et al. J Clin Oncol. 2009;27(suppl). Abstract 10555.
Joensuu H et al. Lancet Oncol, 13; 265-274, 2012
Adjuvant Studies of Imatinib
N
Phase
Regimen
Setting
Primary
Endpoint
Statusa
ACOSOG Z90001
107
2
Imatinib 400 mg/d
Adjuvant
OS
4-year
results
ACOSOG Z90012
708
b
3
Imatinib 400 mg/day
vs placebo
Adjuvant
RFS
2-year
results
Nilsson3
23
2
Imatinib 400 mg/day
vs historical control
Adjuvant
RFS
3-year
results
LI J4
105
N/Ad
Imatinib 400 mg/day
vs control (refused
therapy)
Adjuvant
RFS
2-year
results
Kang B5
47
2
Imatinib 400 mg/day
(until progression)
Adjuvant
RFS
2-year
results
EORTC 620246
900
3
Imatinib 400 mg/day
vs observation
Adjuvant
TTSR
Enrollment
Completed
SSGXVIII/AIO6
400
3
Imatinib 400 mg/day
12 vs 36 months
Adjuvant
RFS
Reported
Trial
1. DeMatteo RP et al. ASCO GI Cancers Symposium; 2004. Abstract 8.
2. DeMatteo RP et al. J Clin Oncol. 2005;23:818s. Abstract 9009.
3. Nilsson B et al. Br J Cancer. 2007;96:1656-1658.
4. Li J et al. J Clin Oncol. 2009;27(suppl). Abstract 10556.
5. Kang Y et al. J Clin Oncol. 2009;27(suppl). Abstract e21515.
6. ClinicalTrials.gov. Accessed August 26, 2009.
ACOSOG Z9001: Trial Schema
Imatinib
(359 randomised)
30 events
97 discontinued
treatment early
5 GIST-unrelated deaths
(337 treated)
(Phase III)
778 patients
713 patients
randomised
IM 400 mg/day or placebo for 1 yr
Placebo
(354 randomised)
(345 treated)
70 events
87 discontinued
treatment early
5 GIST-related deaths
3 GIST-unrelated deaths
• Phase III, randomised, double-blind, placebo-controlled multi-centre trial
DeMatteo RP et al. Lancet. 2009; 373: 1097-1104
ACOSOG Z9001: Study Design/Methods
Key Eligibility Criteria:
• Patients ≥18 years with localised and primary GIST
• KIT-positive tumours ≥3 cm
• Complete surgical resection
Endpoints:
• Primary: Recurrence-free Survival (RFS)
• Secondary: Overall Survival (OS) and safety
Other Key Elements:
• Dose modifications upon grade 3 or 4 events
• PD patients unblinded:
- If placebo  IM 400 mg/day or
- If IM 400 mg/day  IM 800 mg/day
Patient characteristics (continued)
Placebo
(n=354)
Imatinib
(n=359)
>3 and <6 cm
149 (42.1%)
143 (39.8%)
>6 and <10 cm
119 (33.6%)
123 (34.3%)
>10 cm
86 (24.3%)
93 (25.9%)
R0
330 (93.2%)
325 (90.5%)
R1
23 (6.5%)
34 (9.5%)
Unknown
1 (0.3%)
0 (0.0%)
Stomach
235 (66.4%)
209 (58.2%)
Small intestine
102 (28.8%)
125 (34.8%)
Rectum
5 (1.4%)
5 (1.4%)
Other
12 (3.4%)
18 (5.0%)
Unknown
0 (0.0%)
2 (0.6%)
Parameters
Tumour size, n (%)
Margins, n (%)
Tumour origin, n (%)
R0 – negative microscopic margins; R1 – positive microscopic margins
Recurrence-free Survival (RFS)*
Median follow-up: 19.7 months
Estimated 1-year RFS (95% CI):
Imatinib: 98% (96-100)
Placebo: 83% (78-88)
HR = 0.35 (0.22-0.53)
p < 0.0001
CI, confidence interval; HR, hazard ratio
Events experienced:
Imatinib: 8.0% (30)
Placebo: 20.0% (70)
*All randomised patients were included in the analysis; recurrence-free survival was defined as the time from
patient registration to the development of tumour recurrence or death from any cause. Intention-to-treat analyses were done
for recurrence-free survival (ie, analysed patients by randomised group).
Recurrence-free Survival (Tumour size)
size >6cm and <10cm
size >3 and <6 cm
•
size >10cm
Imatinib adjuvant therapy results in
significantly longer RFS in each of the
tumour size categories compared to
placebo
Overall Survival (OS)*
•
No difference in OS between imatinib and placebo adjuvant therapies
*All randomised patients were included in the analysis; Overall survival was defined as the time from patient registration
to death from any cause. Intention-to-treat analyses were done for overall survival (ie, analysed patients by randomised group).
Summary
 Imatinib at 400 mg/day is safe and well tolerated when
administered as adjuvant therapy after complete resection of
primary GIST
 Adjuvant imatinib resulted in an improvement in RFS in patients
with all tumour sizes
- Especially relevant for high-risk patients (e.g. tumour size ≥10
cm or high mitotic rate) since this patient population has a 50%
higher chance of recurrence at 2 years without adjuvant
therapy
 OS between imatinib and placebo groups comparable at this time
 A longer follow-up period is likely required to observe
differences
 Ongoing trials in the adjuvant setting are under way to determine
appropriate treatment duration of imatinib and impact on OS
– SSGXVIII/AIO
– EORTC 62024
Adjuvant Imatinib:
Beyond 1 Year of Treatment
SSGXVIII: Study design
An open-label Phase III study
Random
assignment
1:1
Imatinib
400mg/d for
12 months
Follow-up
Stratification:
1) R0 resection, no
tumor rupture
2) R1 resection or
tumor rupture
Imatinib 400mg/d for 36
months
Follow-up
SSGXVIII: Objectives
 Primary: RFS
Time from randomization to GIST
recurrence or death
 Secondary objectives included:
Safety
Overall survival
SSGXIII: Key inclusion criteria
 Histologically confirmed GIST, KIT-positive
 High risk of recurrence according to the modified
Consensus Criteria*:
–
–
–
–
Tumor diameter >10 cm or
Tumor mitosis count >10/50 HPF** or
Size >5 cm and mitosis count >5/50 HPFs or
Tumor rupture spontaneously or at surgery
*Fletcher CD et al. Hum Pathol 2002; 33:459-65
**HPF, High Power Field of the microscope
Patient disposition
Category
12 Months
No. (%)
36 Months
No. (%)
Randomized (Feb 2004 to Sep 2009)
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
194
198
- On treatment at data collection cut-off
0 (0)
19 (10)
Discontinued assigned treatment
29 (15)
63 (32)
- GIST recurred during treatment
4 (2)
12 (6)
- Adverse event
15 (8)
27 (14)
- Other reason
10 (5)
24 (12)
*3 patients who withdrew consent excluded
Baseline characteristics (ITT)
Characteristic
Median age (range) - years
Male - (%)
ECOG performance status 0 - (%)
Gastric primary tumor - (%)
Median tumor size (range) - cm
Median mitosis count - /50 HPFs
Tumor rupture - (%)
GIST gene mutation site - (%)*
- KIT exon 9
- KIT exon 11
- KIT exon 13
- PDGFRA (D842V)
- wild type
12-Mo group
36-Mo group
62 (23-84)
52
85
49
9 (2-35)
10 (0-250)
18
60 (22-81)
49
86
53
10 (2-40)
8 (0-165)
22
6
69
2
13 (10)
10
7
71
1
12 (8)
8
*Available for 366 (92%) out of the 397 tumors
SSGXVIII: Recurrence-free survival (ITT)
% 100
86.6%
36 Months
80
60
60.1%
47.9%
40
Median follow-up
time 54 months
Hazard ratio 0.46
(95% CI, 0.32-0.65)
20
0
12 Months
65.6%
P <.0001
0
1
2
3
4
5
6
7
36 Months of imatinib
198
184
173
133
82
39
8
0
12 Months of imatinib
199
177
137
88
49
27
10
0
No. at risk (n=397)
Years
Subgroup
No. of patients Hazard ratio (95% CI), RFS
Age
≤65
256
>65
141
Sex
Male
201
Female
196
Tumor site
Stomach
202
Other
193
Tumor size
≤ 10 cm
219
>10 cm
176
Mitoses/50 HPF (local)
≤ 10 mitoses
209
> 10 mitoses
154
Mitoses/50 HPF (central)
≤ 10 mitoses
256
> 10 mitoses
137
Tumor rupture
No
318
Yes
79
Tumor mutation site
KIT exon 9
26
KIT exon 11
256
Wild type
33
Other
51
36 mo better
0.1
0.1
P value
12 mo better
1.0
1.0
0.47 (0.30-0.74)
0.49 (0.28-0.85)
.001
.01
0.46 (0.28-0.76)
0.46 (0.28-0.76)
.002
.002
0.42 (0.23-0.78)
0.47 (0.31-0.73)
.005
<.001
0.40 (0.23-0.69)
0.47 (0.29-0.76)
<.001
.002
0.76 (0.43-1.32)
0.29 (0.17-0.49)
.33
<.001
0.58 (0.34-0.99)
0.37 (0.23-0.61)
.04
<.001
0.43 (0.28-0.66)
0.47 (0.25-0.89)
<.001
.02
0.61 (0.22-1.68)
0.35 (0.22-0.56)
0.41 (0.11-1.51)
0.78 (0.22-2.78)
.34
<.001
.16
.70
10
10
Clinical Risk Factors and Risk-Reduction
with 3 Years of Adjuvant Imatinib
Risk Factor
No. Patients
Hazard Ratio (95% CI,
RFS)
P-Value
TUMOUR SITE
Gastric
202
0.42 (0.23-0.78)
0.006
Non-Gastric
195
0.47(0.31-0.73)
<0.001
<10 cm.
219
0.40 (0.24-0.69)
<0.001
>10 cm.
176
0.47 (0.29-0.76)
0.002
<10
238
0.53 (0.30-0.94)
0.03
>10
133
0.36 (0.22-0.59)
<0.001
SIZE
Mitoses/50 HPF
SSGXVIII: Overall survival (ITT)
%
96.3%
100
92.0%
94.0%
80
81.7%
60
36 Months
Hazard ratio 0.45
40
12 Months
(95% CI, 0.22-0.89)
P = .019
20
0
0
1
2
3
4
5
6
7
198
199
192
188
184
176
152
140
100
87
56
46
13
20
0
0
No. at risk (n=397)
36 Months of imatinib
12 Months of imatinib
Years
Treatment safety
12-month group
36-month group
(n=194)
No. (%)
(n=198)
No. (%)
Any adverse event
192 (99)
198 (100)
.24
Grade 3 or 4 event
39 (20)
65 (33)
.006
Cardiac event
8 (4)
4 (2)
.26
Second cancer
14 (7)
13 (7)
.84
1* (1)
0 (0)
.49
25 (13)
51 (26)
.001
Category
Death, possibly imatinib-related
Discontinued imatinib,
GIST recurrence
*Lung injury
no
P
Most frequent adverse events
Adverse event
Any Grade
12 Mo
P
% 36 Mo %
Grade 3 or 4
12 Mo
P
% 36 Mo %
Anemia
Periorbital edema
72
59
80
74
.08
.002
1
1
1
1
1.00
1.00
Elevated LDH*
43
60
.001
0
0
-
Fatigue
48
48
1.00
1
1
.62
Nausea
45
51
.23
2
1
.37
Diarrhea
44
54
.044
1
2
.37
Leukopenia
35
47
.014
2
3
.75
Muscle cramps
31
49
<0.001
1
1
1.00
Conclusions
 Compared to 1 year of adjuvant imatinib, 3 years of imatinib
improves
- RFS
- Overall survival
as treatment of GIST patients who have a high estimated risk of
recurrence after surgery.
 Adjuvant imatinib is relatively well tolerated; severe adverse
events are infrequent.
Phase 3 Adjuvant Trial (EORTC 62024):
Overview
Objectives
Treatment
Primary
 Time to secondary resistance
 400 mg/day for 2 years
Secondary




Imatinib
Overall survival
Relapse-free survival
Relapse-free interval
Drug safety
Inclusion criteria
 Intermediate- or high-risk GIST
 Completely resected
 KIT-positive GIST
EORTC. http://clinicaltrials.gov/ct/show/NCT00103168.
Phase 3 Adjuvant Trial (EORTC 62024):
Design
Observation
(for 2 years)
Follow for 5 years
after treatment to
evaluate TTSR, PFS,
and OS
Complete
resection of
primary
GIST
Imatinib
(400 mg/day
for 2 years)
Discontinued treatmenta
aDue
to progression or unacceptable toxicity.
TTSR, time to secondary resistance; PFS, progression-free survival; OS, overall survival
EORTC. http://clinicaltrials.gov/ct/show/NCT00103168.
Post-Resection Evaluation of Recurrence-Free Survival for Gastro-Intestinal
Stromal Tumors Treated with Adjuvant Imatinib:
PERSIST-5
Resected GIST
>2 cm and mitotic rate >5
or
Non-gastric primary >5 cm
Register
Imatinib 400 mg/d x 5 years
Phase II
N = 85 patients
Primary objective: Recurrence-free survival
Adapted DeMatteo
Conclusions from SSGXVIII *
 In GIST, 3 years of adjuvant imatinib are better than
one in terms of recurrence-free and overall survival
 Three years of post-operative imatinib treatment
represent the new gold standard for patients with
resected “high-risk” GISTs
 The overall risk at which adjuvant imatinib should
be commenced requires further clarification