whom to treat and how long to treat after resection of gist professor john r zalcberg chief medical...
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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
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
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1 Year 2 Years 5 Years 10 Years
Rec
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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
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
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.
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Specific KIT Mutations Have Prognostic Importance
RFS in 127 patients with completely resected localized GIST based on mutation type
Pro
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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.
Risk Stratification of Primary GIST: Miettinen (AFIP)
Original source: Miettinen M, Lasota J. Semin Diagn Pathol. 2006;23:70-83.
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.
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
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.
Additional factors:
- Mutational status1
- Rupture2
- Necrosis3
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/AdImatinib 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/day12 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.
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
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
ParametersPlacebo(n=354)
Imatinib(n=359)
Tumour size, n (%)
>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%)
Margins, n (%)
R0 330 (93.2%) 325 (90.5%)
R1 23 (6.5%) 34 (9.5%)
Unknown 1 (0.3%) 0 (0.0%)
Tumour origin, n (%)
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%)
R0 – negative microscopic margins; R1 – positive microscopic margins
Patient characteristics (continued)
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 frompatient 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).
• 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
• 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).
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
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
1:1Stratification:
1) R0 resection, no tumor rupture
2) R1 resection or tumor rupture
SSGXVIII: Objectives
Primary: RFS
Time from randomization to GIST recurrence or death
Secondary objectives included:
SafetyOverall 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 dispositionCategory 12 Months 36 Months
No. (%) 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 12-Mo group 36-Mo group
Median age (range) - years 62 (23-84) 60 (22-81)
Male - (%) 52 49
ECOG performance status 0 - (%) 85 86
Gastric primary tumor - (%) 49 53
Median tumor size (range) - cm 9 (2-35) 10 (2-40)
Median mitosis count - /50 HPFs 10 (0-250) 8 (0-165)
Tumor rupture - (%) 18 22
GIST gene mutation site - (%)*
- KIT exon 9 6 7
- KIT exon 11 69 71
- KIT exon 13 2 1
- PDGFRA (D842V) 13 (10) 12 (8)
- wild type 10 8
*Available for 366 (92%) out of the 397 tumors
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 70
20
40
60
80
100%
Median follow-up time 54 months
Years
Subgroup No. of patients Hazard ratio (95% CI), RFS P valueAge ≤65 256 0.47 (0.30-0.74) .001 >65 141 0.49 (0.28-0.85) .01Sex Male 201 0.46 (0.28-0.76) .002 Female 196 0.46 (0.28-0.76) .002Tumor site Stomach 202 0.42 (0.23-0.78) .005 Other 193 0.47 (0.31-0.73) <.001Tumor size ≤ 10 cm 219 0.40 (0.23-0.69) <.001 >10 cm 176 0.47 (0.29-0.76) .002Mitoses/50 HPF (local) ≤ 10 mitoses 209 0.76 (0.43-1.32) .33 > 10 mitoses 154 0.29 (0.17-0.49) <.001Mitoses/50 HPF (central) ≤ 10 mitoses 256 0.58 (0.34-0.99) .04 > 10 mitoses 137 0.37 (0.23-0.61) <.001Tumor rupture No 318 0.43 (0.28-0.66) <.001 Yes 79 0.47 (0.25-0.89) .02Tumor 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
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
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 70
20
40
60
80
100%
Years
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
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 1.00Periorbital 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
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
EORTC. http://clinicaltrials.gov/ct/show/NCT00103168.
ObjectivesObjectives
Primary Time to secondary resistance
Secondary Overall survival Relapse-free survival Relapse-free interval Drug safety
TreatmentTreatment
Imatinib 400 mg/day for 2 years
Inclusion criteriaInclusion criteria
Intermediate- or high-risk GIST Completely resected KIT-positive GIST
Phase 3 Adjuvant Trial (EORTC 62024): Design
Follow for 5 years after treatment to evaluate TTSR, PFS, and OS
Observation(for 2 years)
Imatinib (400 mg/day for 2 years)
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.
Complete resection of
primary GIST
Discontinued treatmenta
Post-Resection Evaluation of Recurrence-Free Survival for Gastro-Intestinal Stromal Tumors Treated with Adjuvant Imatinib:
PERSIST-5
Phase II
N = 85 patients
Primary objective: Recurrence-free survival
Imatinib 400 mg/d x 5 years
Resected GIST >2 cm and mitotic rate >5
orNon-gastric primary >5 cm
Register
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
* Adapted from discussion by Charles Blanke, ASCO 2011