Transcript Document

Challenging Cases in Cancer:
Integration of Findings from ASCO 2007
Gastrointestinal Stromal Tumors
Charles D. Blanke, MD, FACP
Associate 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
>5
>5/50 HPF
>10
Any
Any
>10/50 HPF
High
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
R. DeMatteo et al. ASCO 2007 Abstract: 10079
Z9001 Randomized Trial
Primary GIST > 3 cm
Complete Gross Resection
Tumor KIT +
Placebo
x 1 yr
Imatinib
x 1 yr
Double-blind
Cross-over if recur
1° - Recurrence-free survival
2° - Overall survival, Safety
Courtesy Ron DeMatteo
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
Study Design
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
400 mg/d
(N = 73)
Progression
Core
Study
3 Yrs
Extension
4 Yrs
(total 7 Yrs)
600 mg/d
(N = 74)
(N = 147)
Progression
800 mg/d
Follow-up of > 52 Months
NEJM Volume 347:472-480 August 15, 2002
Best Response
400 mg N=73
600 mg N=74
All Patients N=147
n (%)
n (%)
n (%)
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)
2 (2.7)
5 (6.8)
7 (4.8)
Complete
Response
Not evaluable/
Unknown
NEJM Volume 347:472-480 August 15, 2002
Overall Survival
(Kaplan-Meier Estimate)
Hazard Ratio: 0.887, Log-Rank test p=0.6274
1.0
All Patients:
Median OS 248 wks (58 months)
0.9
0.8
0.7
0.6
0.5
0.4
Number at Risk
0.3
Treatment
0.2
0.1
Wks: 0
Median
95% CI
40
80
Duration
LL UL
248 Wks
150 N/A
400mg
73
63
60
600mg
74
70
62
Pooled
147 133 122
N/A
190 N/A
248 Wks
190 N/A
0.0
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
192
204
216
228
240
252
264
Weeks Post First Dose
NEJM Volume 347:472-480 August 15, 2002
Overall Survival by Best Response
(Kaplan-Meier Estimate)
Number at Risk
Best Response
1.0
0.9
Wks: 0
40
80
Median
95% CI
Duration
LL UL
N/A
172 N/A
CR
2
2
2
PR
98
97
92
SD
23
22
20
PD
17
7
4
36 Wks
15 56
UNK
7
5
4
144 Wks
18 223
216
228
248 Wks
N/A
226 N/A
149 N/A
0.8
PD (N=17):
Median 36 wks
0.7
0.6
0.5
0.4
PR (N=98):
Median 248 wks
0.3
0.2
0.1
0.0
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
192
204
240
252
264
Weeks Post First Dose
CR (N=2; median OS n/a) and unknown/NE (N=7; median OS 144 wks) are not displayed
NEJM Volume 347:472-480 August 15, 2002
Comparison of Two Doses of Imatinib
for 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
Design
Phase 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
R
A
N
D
O
M
I
Z
E
PD
Imatinib mesylate
400 mg/day
until progression
Crossover
Off study
Imatinib mesylate
800 mg/day
until progression
PD
Primary end point: overall survival (US-CDN) / progression-free survival (EU-AUS)
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 doseincrease
– 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
Estimated survival probability (%)
Sunitinib Phase III Trial: Overall Survival
100
90
80
70
60
50
40
SU11248 (N=207)
Placebo (N=105)
30
Hazard ratio = 0.491
P=0.00674
20
10
0
0
3
6
Time (Months)
9
12
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
• BAY43-9006-Raf, KIT, VEGFR,
PDGFRβ, FLT3, RET
• AMG706-VEGFR, PDGFR,
KIT, Ret
• BMS 354825-Src, abl, KIT,
PDGFR
• PKC412-PKC
• IPI-504-Heat shock protein 90
• AMN107-KIT, PDGFRA,
BCR/ABL
• 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