Challenging Cases in Cancer:Integration of Findings from ASCO 2007
Gastrointestinal Stromal Tumors
Charles D. Blanke, MD, FACPAssociate Professor of Medicine
Director of the Oregon Cancer Center’s Gastrointestinal Malignancies Focus Group
Case 1: Fully Resected Tumor
• Patient is a 63-year-old male
– Presents with fatigue, headache, light-headedness
– Mild HTN but no other medical history
– Physical exam benign except guiac-positive stool
• Laboratory data:
– Hemoglobin: 6.6 g/dL
– Normal WBC, platelets
– Normal liver function tests
• CT scan: 2.8 cm mass arising from small bowel
Decision Point
• What is your major differential diagnosis?
• Are there any other tests you would like to do?
• Do you want a biopsy?
Case 1: Fully Resected Tumor (cont.)
• Patient goes directly to surgery
• Small mass arising from the small bowel is resected– No metastases are seen
• Recovery is uneventful
• Pathology: 2.0 cm GIST, CD-117+, arising from small bowel– Ulcerated
– negative margins
– <1 mitosis/10 HPFs
Case 1: Additional Decisions
• Do you want additional testing on the specimen?
• Do you tell the patient his tumor is benign or malignant?
• Do you treat the patient adjuvantly?
• How do you monitor him?
Case 1: Therapeutic Options
• Observe only
• Imatinib mesylate 400 mg/day for 1-year
• Imatinib mesylate 800 mg/day for 1-year
• Sunitinib malate 50 mg/day weeks 4/6 for 1-year
• Clinical trial
Resected GIST: Defining Risk Categories
Risk Size (cm) Mitotic Rate
Very Low <2 <5/50 HPF
Low 2-5 <5/50 HPF
Intermediate <5 6-10/50 HPF
5-10 <5/50 HPF
High >5 >5/50 HPF
>10 Any
Any >10/50 HPF
R. DeMatteo et al. ASCO 2007 Abstract: 10079
Adjuvant Imatinib Mesylate Increases Recurrence Free Survival (RFS) in Patients with Completely Resected
Localized Primary Gastrointestinal Stromal Tumor (GIST): North American Intergroup Phase III Trial ACOSOG Z9001
R. DeMatteo, K. Owzar, R. Maki, P. Pisters, M. Blackstein, C. Antonescu,
C. Blanke, G. Demetri, M. von Mehren, K. Ballman, and the
American College of Surgeons Oncology Group (ACOSOG)
Intergroup Adjuvant GIST Study Team
Primary GIST > 3 cm
Complete Gross ResectionTumor KIT +
1° - Recurrence-free survival2° - Overall survival, Safety
Imatinibx 1 yr
Placebox 1 yr
Double-blindCross-over if recur
Courtesy Ron DeMatteo
Z9001 Randomized Trial
R. DeMatteo et al. ASCO 2007 Abstract: 10079
Z9001: Results
• One-year RFS 83% (placebo) versus 97% imatinib
– HR 0.33, P <0.001
• No difference in overall survival seen
• 33% of patients on imatinib arm could not complete one year of therapy
R. DeMatteo et al. ASCO 2007 Abstract: 10079
Case 1: Therapeutic Options
Which treatment option would you recommend? Observe only Imatinib mesylate 400 mg/day for 1-year Imatinib mesylate 800 mg/day for 1-year Sunitinib malate 50 mg/day weeks 4/6 for 1-year Clinical trial
Case 1: Therapeutic Recommendation
Which treatment option would you recommend?
Observe only
Imatinib mesylate 400 mg/day for 1-year
Imatinib mesylate 800 mg/day for 1-year
Sunitinib malate 50 mg/day weeks 4/6 for 1-year
Clinical trial
Recommended Approach:
• Observe only
Case 1 Variant
• Fully resected Tumor
• Tumor is 3.2 cm in size
Decisions Point
• Do you want additional testing on the specimen?
• Do you tell the patient his tumor is benign or malignant?
• Do you treat the patient adjuvantly?
• How do you monitor him?
Case 1 Variant: Therapeutic Options
Which treatment option would you recommend?
Observe only
Imatinib mesylate 400 mg/day for 1-year
Imatinib mesylate 800 mg/day for 1-year
Sunitinib malate 50 mg/day weeks 4/6 for 1-year
Clinical trial
Case 1 Variant: Therapeutic Recommendation
Which treatment option would you recommend?
Observe only
Imatinib mesylate 400 mg/day for 1-year
Imatinib mesylate 800 mg/day for 1-year
Sunitinib malate 50 mg/day weeks 4/6 for 1-year
Clinical trial
Recommended Approach:• Imatinib mesylate 400 mg/day for 1-year
Monitoring Patients with GIST
• Depends on risk of recurrence
• Includes labs, CT; not PET
• Different time-table if on imatinib
Case 1b: Treatment
• Patient develops weight loss, abdominal pain, early satiety 3 years later
• Physical exam shows hepatomegaly
• Labs essentially normal
• CT: multiple liver and peritoneal masses
Decision Point
• What is your major differential diagnosis?
• Are there any other tests you would like to do?
• Do you want a biopsy?
Case 1b: Therapeutic Options
• Observe only
• Imatinib mesylate 400 mg/day
• Imatinib mesylate 800 mg/day
• Sunitinib malate 50 mg/day weeks 4/6
• Clinical trial
• Debulk
SCREEN
RANDOMIZE
400 mg/d(N = 73)
600 mg/d(N = 74)
Progression
Progression
800 mg/d(N = 147)
Core Study 3 Yrs
Extension 4 Yrs
(total 7 Yrs)
Follow-up of > 52 Months
Study Design
NEJM Volume 347:472-480 August 15, 2002
400 mg N=73
n (%)
600 mg N=74
n (%)
All Patients N=147
n (%)
Complete Response
0 2 (2.7) 2 (1.4)
Partial Response 50 (68.5) 48 (64.9) 98 (66.7)
Stable Disease 10 (13.7) 13 (17.6) 23 (15.6)
Progression 11 (15.1) 6 (8.1) 17 (11.6)
Not evaluable/ Unknown
2 (2.7) 5 (6.8) 7 (4.8)
Best Response
NEJM Volume 347:472-480 August 15, 2002
Number at Risk
0
73
40
63
80
60
Wks:Treatment
400mg
Median
Duration
248 Wks
95% CI
LL UL
150 N/A
0
74
40
70
80
62
Wks:Treatment
600mg
Median
Duration
N/A
95% CI
LL UL
190 N/A
0
147
40
133
80
122
Wks:Treatment
Pooled
Median
Duration
248 Wks
95% CI
LL UL
190 N/A
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Weeks Post First Dose
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 252 264
Hazard Ratio: 0.887, Log-Rank test p=0.6274
All Patients: Median OS 248 wks (58 months)
Overall Survival(Kaplan-Meier Estimate)
NEJM Volume 347:472-480 August 15, 2002
PD (N=17):Median 36 wks
PR (N=98):Median 248 wks
CR (N=2; median OS n/a) and unknown/NE (N=7; median OS 144 wks) are not displayed
Overall Survival by Best Response(Kaplan-Meier Estimate)
Number at Risk
0
2
40
2
80
2
Wks:Best Response
CR
Median
Duration
N/A
95% CI
LL UL
172 N/A
0
98
40
97
80
92
Wks:Best Response
PR
Median
Duration
248 Wks
95% CI
LL UL
226 N/A
0
23
40
22
80
20
Wks:Best Response
SD
Median
Duration
N/A
95% CI
LL UL
149 N/A
0
17
40
7
80
4
Wks:Best Response
PD
Median
Duration
36 Wks
95% CI
LL UL
15 56
0
7
40
5
80
4
Wks:Best Response
UNK
Median
Duration
144 Wks
95% CI
LL UL
18 223
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Weeks Post First Dose
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 252 264
NEJM Volume 347:472-480 August 15, 2002
Comparison of Two Doses of Imatinibfor the Treatment of Gastrointestinal Stromal Tumors
(GIST): A Meta-analysis Based on 1640 Patients
M.M. Van Glabbeke, K. Owzar, C. Rankin, J. Simes, J. Crowley,GIST Meta-analysis Group (MetaGIST)
M.M. Van Glabbeke et al. ASCO 2007: 10004
DesignPhase 3 randomized, intergroup, international trials assessing the clinical activity of imatinib at 2 dose levels in patients with unresectable or metastatic gastrointestinal
stromal tumors (GIST) expressing the KIT receptor tyrosine kinase (CD117)
2 trials originally planned together
Primary end point: overall survival (US-CDN) / progression-free survival (EU-AUS)
Imatinib mesylate400 mg/day
until progression
Imatinib mesylate400 mg/day
until progression
Imatinib mesylate800 mg/day
until progression
Imatinib mesylate800 mg/day
until progression
PDPD
Cross-over
Cross-over
RANDOMIZE
RANDOMIZE PDPD
Off studyOff study
PD, progressive disease. M.M. Van Glabbeke et al. ASCO 2007: 10004
MetaGIST Results
400 mg/day 800 mg/day P
Med PFS (mo) 19 23 0.04
Med OS (mo) 49 49 0.97
Med PFS exon 9 6 19 0.017
Med PFS other ~24 ~24 NS
Med OS exon 9 28 35 0.15
M.M. Van Glabbeke et al. ASCO 2007: 10004
Case 1b: Therapeutic Recommendation
Which treatment option would you recommend?
Observe only
Imatinib mesylate 400 mg/day
Imatinib mesylate 800 mg/day
Sunitinib malate 50 mg/day weeks 4/6
Clinical trial
Debulk
Recommended Approach:
• Imatinib mesylate 400 mg/day or 800 mg/day
Case 2: Advanced GIST
• 54-year-old female presents for “screening” CT
– 6 cm peritoneal mass found
– Biopsy: CD-117+ GIST, exon 11 mutant
– No other disease
– No major PMH
Case 2: Therapeutic Options
Which treatment option would you recommend?
Observation
Imatinib mesylate 400 mg/day indefinitely
Imatinib followed by resection
Sunitinib malate 50 mg/day weeks 4/6
Immediate resection
Case 2: Therapeutic Recommendation
Which treatment option would you recommend?
Observation
Imatinib mesylate 400 mg/day indefinitely
Imatinib followed by resection
Sunitinib malate 50 mg/day weeks 4/6
Immediate resection
Recommended Approach:
• Imatinib followed by resection
Case 2 Variant
• Everything identical EXCEPT:
– PMH Small bowel leiomyosarcoma resected 6 years ago
Case 2 Variant: Therapeutic Options
Which treatment option would you recommend?
Observation
Imatinib mesylate 400 mg/day indefinitely
Imatinib followed by resection
Sunitinib malate 50 mg/day weeks 4/6
Immediate resection
Case 2 Variant: Therapeutic Recommendation
Which treatment option would you recommend?
Observation
Imatinib mesylate 400 mg/day indefinitely
Imatinib followed by resection
Sunitinib malate 50 mg/day weeks 4/6
Immediate resection
Recommended Approach:
• Imatinib followed by resection
Case 2 Variant 2
• Patient receives imatinib mesylate, 400 mg/day, neoadjuvantly
• Tumor rapidly progresses
Case 2 Variant 2: Therapeutic Options
Which treatment option would you recommend?
Continue imatinib mesylate 400 mg/day
Increase imatinib to 800 mg/day
Sunitinib malate 50 mg/day weeks 4/6
Sunitinib malate 37.5 mg/day continuously
Case 2 Variant 2: Therapeutic Recommendation
Which treatment option would you recommend?
Continue imatinib mesylate 400 mg/day
Increase imatinib to 800 mg/day
Sunitinib malate 50 mg/day weeks 4/6
Sunitinib malate 37.5 mg/day continuously
Recommended Approach:
• Increase imatinib to 800 mg/day
• Sunitinib malate 50 mg/day weeks 4/6
• Sunitinib malate 37.5 mg/day continuously
Resistant GIST
• 25-33% of patients benefit from an imatinib dose-increase
– However, actual responses are rare
• Sunitinib malate has activity against multiple receptor tyrosine kinases + anti-angiogenic activity
• A phase III trial showed marked survival benefits for salvage sunitinib versus placebo
Sunitinib Phase III Trial: Overall Survival
Time (Months)
Est
imat
ed s
urv
ival
pro
bab
ilit
y (%
) 100
90
80
70
60
50
40
30
20
10
00 3 6 9 12
SU11248 (N=207)Placebo (N=105)
Hazard ratio = 0.491P=0.00674
Additional ASCO 2007 Findings
• Continuous daily sunitinib dosing @ 37.5 mg is probably as safe and effective as 50 mg intermittently
– George et al. PASCO 2007, abstr #10015
• Nilotinib (TKR-inhibitor of KIT, PDGFR) has promising activity in GIST pts resistant to imatinib
– Von Mehren et al. PASCO 2007, abstr #10023
• IPI-504 (inhibitor of heat shock protein 90 chaperone) has potential activity in pts resistant to imatinib and sunitinib
– Demetri et al. PASCO 2007, abstr #10024
Other Drugs/Targets in GIST
• SU11248-PDGFR, VEGFR, KIT, and FLT3
• AMG706-VEGFR, PDGFR, KIT, Ret
• PKC412-PKC
• AMN107-KIT, PDGFRA, BCR/ABL
• BAY43-9006-Raf, KIT, VEGFR, PDGFRβ, FLT3, RET
• BMS 354825-Src, abl, KIT, PDGFR
• IPI-504-Heat shock protein 90
• Genasense-bcl-2
ASCO 2007: GIST Conclusions
• Treat patients with resected tumors ≥ 3 cm with at least 1-year of imatinib
• 400 mg/day remains the standard dose in metastatic disease
– Exon 9 patients should probably get 800 mg/day
• Sunitinib malate is the standard of care salvage drug for patients with imatinib resistance
– Treat with 37.5 mg/day continuously
• New drugs are expected