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