This document discusses gastrointestinal stromal tumors (GIST) and the use of adjuvant imatinib therapy. It provides background on GIST epidemiology and risk factors for recurrence. Studies show adjuvant imatinib for 1 year after surgery significantly reduces recurrence rates compared to placebo, especially for high-risk patients. The SSGXVIII trial found adjuvant imatinib for 3 years further reduced recurrence rates compared to 1 year of treatment, with no significant difference in overall survival yet. Adjuvant imatinib for 3 years may provide additional benefit over 1 year, especially for high-risk GIST patients.

1. Συστηματικη θεραπεία όγκων
GIST
ΑΛΕΞΗΣ ΣΤΡΙΜΠΑΚΟΣ
Παθολόγος Ογκολόγος
Δ/της Δ’Ογκολογικής Κλινικής
Ευρωκλινική Αθηνών

2. EPIDEMIOLOGY
 GIST represents a form of sarcoma that comprises
approx. 1% to 3% of all malignant GI tumors.
 GIST occurs predominantly in adults .
 The incidence has been slightly higher in men than
women.
 Small asymptomatic GISTs are found at autopsy in
more than 50 % of individuals over the age of 50
 GIST treatment trials estimate an annual incidence
of 4,500 – 6,000 new cases (USA)

4. Συστηματική θεραπεία όγκων GIST
 Επικουρική θεραπεία
 Θεραπεία προχωρημένης νόσου
– Unresectable
• ?potentially resectable
– metastatic

5. Risk of Recurrence After
Resection of Primary GIST
DeMatteo RP et al. Cancer. 2008;112:608-615.
Approximately 40% of patients who undergo complete resection
of primary GIST have a recurrence within 5 years
0
10
20
30
40
50
60
70
80
90
100
1 Year 2 Years 5 Years 10 Years
Recurrence-FreeSurvival,%

6. 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.

7. Primary GIST: Risk Factors for
Recurrence After Surgery
Adapted with permission from DeMatteo RP et al. Cancer. 2008;112:608-615.
Rates of RFS were independently predicted by mitotic index,
tumour size, and tumour location

8. 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.
CumulativeSurvival

9. Specific KIT Mutations Have Prognostic Importance
RFS in 127 patients with completely
resected localized GIST based on mutation type
ProportionRecurrence-Free
Years After Resection
1.0
0.8
0.6
0.4
0.2
0.0
0 1 2 3 4 5 6 7 8 9 10
P<0.001
KIT exon 9 mutation (n=4)
KIT exon 11 DEL557/8 (n=35)
No mutation (n=29)
KIT exon 11 PM/INS (n=32)
Other KIT exon 11 deletion (n=17)
PDGFRA mutation (n=8)
DeMatteo RP et al. Cancer. 2008;112:608-615.

11. Imatinib: Selective TKI Targeting KIT,
PDGFRA, and Abl
 Approved for treatment of
unresectable, advanced
KIT-positive GIST[33,34]
and
as adjuvant therapy for
resectable GIST[35]
32. Rubin BP, et al. Lancet. 2007;369:1731-1741. 33. Demetri GD, et al. N Engl J Med. 2002;347:472-480.
34. Blanke CD, et al. J Clin Oncol. 2008;26:626-632. 35. DeMatteo RP, et al. Lancet. 2009;373:1097-1104.
Mechanism of action: Imatinib binds to the same site as ATP, thereby preventing
phosphorylation of downstream substrates and inhibiting KIT or PDGFRA signaling[32]
Imatinib Mesylate
N
N
N
H
N
H
N
N
N
O CH3So3H
Inhibition of KIT activated signal
transduction, causing reduced GIST
proliferation or induction of apoptosis
KIT-activated signal transduction
resulting in GIST proliferation
and survival
P
P
ADP P Y Substrate
ADP
P
P
P
IMATY SubstrateADPADP
P
P
P
P
P
P
A B
IMAT
ADP
P
P
P
Y Substrate

12. Επικουρική θεραπεία

13. Adjuvant Studies of Imatinib
Trial N Phase Regimen Setting Primary
Endpoint Statusa
ACOSOG Z90001
107 2 Imatinib 400 mg/d Adjuvant OS 4-year
results
ACOSOG Z90012
708b
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
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.

14. ACOSOG Z9001: Trial Schema
(Phase III)
778 patients
Placebo
(354 randomised)
(345 treated)
87 discontinued
treatment early
Imatinib
(359 randomised)
(337 treated)
97 discontinued
treatment early
30 events
5 GIST-unrelated deaths
713 patients
randomised
• Phase III, randomised, double-blind, placebo-controlled multi-centre trial
IM 400 mg/day or placebo for 1 yr
70 events
5 GIST-related deaths
3 GIST-unrelated deaths
DeMatteo RP et al. Lancet. 2009; 373: 1097-1104

15. 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

16. 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)
Recurrence-free Survival (RFS)*
*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).

17. • Imatinib adjuvant therapy results in
significantly longer RFS in each of the
tumour size categories compared to
placebo
Recurrence-free Survival (Tumour size)
size >10cm
size >3 and <6 cm size >6cm and <10cm

18. • No difference in OS between imatinib and placebo adjuvant therapies
Overall Survival (OS)*
*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).

19.  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
Summary

20. Adjuvant Imatinib:
Beyond 1 Year of Treatment

21. Imatinib
400mg/d for
12 months
An open-label Phase III study
Imatinib 400mg/d for 36
months
Follow-up
Follow-up
SSGXVIII: Study design
Random
assignment
1:1
Stratification:
1) R0 resection, no
tumor rupture
2) R1 resection or
tumor rupture

22. SSGXVIII: Objectives
 Primary: RFS
Time from randomization to GIST
recurrence or death
 Secondary objectives included:
Safety
Overall survival

23. 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

24. SSGXVIII: Recurrence-free survival (ITT)
No. at risk (n=397)
36 Months of imatinib 198 184 173 133 82 39 8 0
12 Months of imatinib 199 177 137 88 49 27 10 0
60.1%
47.9%
86.6%
65.6%
36 Months
12 Months
Hazard ratio 0.46
(95% CI, 0.32-0.65)
P <.0001
0 1 2 3 4 5 6 7
0
20
40
60
80
100%
Median follow-up
time 54 months
Years

25. Subgroup No. of patients Hazard ratio (95% CI), RFS P value
Age
≤65 256 0.47 (0.30-0.74) .001
>65 141 0.49 (0.28-0.85) .01
Sex
Male 201 0.46 (0.28-0.76) .002
Female 196 0.46 (0.28-0.76) .002
Tumor site
Stomach 202 0.42 (0.23-0.78) .005
Other 193 0.47 (0.31-0.73) <.001
Tumor size
≤ 10 cm 219 0.40 (0.23-0.69) <.001
>10 cm 176 0.47 (0.29-0.76) .002
Mitoses/50 HPF (local)
≤ 10 mitoses 209 0.76 (0.43-1.32) .33
> 10 mitoses 154 0.29 (0.17-0.49) <.001
Mitoses/50 HPF (central)
≤ 10 mitoses 256 0.58 (0.34-0.99) .04
> 10 mitoses 137 0.37 (0.23-0.61) <.001
Tumor rupture
No 318 0.43 (0.28-0.66) <.001
Yes 79 0.47 (0.25-0.89) .02
Tumor mutation site
KIT exon 9 26 0.61 (0.22-1.68) .34
KIT exon 11 256 0.35 (0.22-0.56) <.001
Wild type 33 0.41 (0.11-1.51) .16
Other 51 0.78 (0.22-2.78) .70
0.1 1.0 10
36 mo better 12 mo better
0.1 1.0 10

26. 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
SIZE
<10 cm. 219 0.40 (0.24-0.69) <0.001
>10 cm. 176 0.47 (0.29-0.76) 0.002
Mitoses/50 HPF
<10 238 0.53 (0.30-0.94) 0.03
>10 133 0.36 (0.22-0.59) <0.001

27. No. at risk (n=397)
36 Months of imatinib 198 192 184 152 100 56 13 0
12 Months of imatinib 199 188 176 140 87 46 20 0
SSGXVIII: Overall survival (ITT)
Hazard ratio 0.45
(95% CI, 0.22-0.89)
P = .019
96.3% 92.0%
94.0%
81.7%
36 Months
12 Months
0 1 2 3 4 5 6 7
0
20
40
60
80
100%
Years

28. Treatment safety
Category 12-month group
(n=194)
No. (%)
36-month group
(n=198)
No. (%)
P
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
Death, possibly imatinib-related 1* (1) 0 (0) .49
Discontinued imatinib, no
GIST recurrence
25 (13) 51 (26) .001
*Lung injury

29. Most frequent adverse events
Adverse event Any Grade P Grade 3 or 4 P
12 Mo % 36 Mo % 12 Mo % 36 Mo %
Anemia 72 80 .08 1 1 1.00
Periorbital edema 59 74 .002 1 1 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

30. 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.

31. Θεραπεία προχωρημένης νόσου

34. Beyond imatinib

35. Sunitinib in GIST: Selective Targeting of
VEGFR and KIT
 Mechanism of action:
Sunitinib binds to the
same site as ATP,
thereby preventing
phosphorylation of
downstream
substrates and
inhibiting VEGFR,
PDGFR, KIT, CSF-1R,
and FLT signaling
 Approved for
treatment of GIST
after disease
progression on or with
intolerance to imatinib
38. Wolter P, et al. Acta Oncol. 2010;49:13-23. 39. Faivre S, et al. Nat Rev Drug Discov. 2007;6:734-745.
PDGFRA PDGFRB KIT FLT3
CSF R
(FMS)
VEGFR
(FLT)
VEGFR2
(FLK)
VEGFR3
(KDR/FLT4)

38. Regorafenib: Novel Multitargeted TKI
 Regorafenib has a wide spectrum of
target inhibition: KIT; PDGFR; VEGFR-1,
-2, -3; TIE2; RET, fibroblast growth factor
receptor 1; RAF; and p38 MAPK[63]
 Phase II study (N = 33) in metastatic
GIST: 4 PRs, 22 SD ≥ 22 wks, median
PFS: 10 mos[63]
 Phase III GRID study[64]
– Significant PFS improvement vs
placebo in 199 pts with metastatic
or unresectable GIST and
progression on imatinib and
sunitinib
– Most common grade 3/4 events:
hand-foot skin reaction, hypertension,
diarrhea
63. George S, et al. J Clin Oncol. 2012;30:2401-2407.
64. Demetri G, et al. ASCO 2012. Abstract LBA10008.
ProportionWithoutProgression
1.00
0.75
0.50
0.25
0
0 50 100 150 200 250 300
Days From Randomization
Placebo
Regorafenib
HR: 0.27 (95% CI: 0.19-0.39)
1-sided P < .0001
Regorafenib
(n = 133)
Placebo
(n = 66)
Median PFS,
mos (95% CI)
4.8
(4.1-5.8)
0.9
(0.9-1.1)
Events, n (%) 81 (60.9) 63 (95.5)

39. Treatment algorithm in metastatic GIST
KIT exon 9 mutation1–4
KIT/PDGFRA wild-type1–4
KIT exon 11 mutation1–4
1. Reichardt P, et al. ASCO 2014 (abstract 10549)
2. Heinrich MC, et al. J Clin Oncol 2008;26:5352–5359
3. Debiec-Rychter M, et al. Eur J Cancer 2006;42:1093-
1103
4. The ESMO/European Sarcoma Network Working Group.
Ann Oncol 2014;25 (Suppl 3): iii21–iii26
*Switch treatment upon confirmed progression
*
*
*
*
*
*
*
*
*
*
Imatinib 400 mgImatinib 800 mg Imatinib 400 mg
Imatinib
800 mg
Sunitinib
Sunitinib Sunitinib
Regorafenib Regorafenib
Imatinib
800 mg
Sunitinib
Regorafenib
Sunitinib