Twelve vs. 36 months of adjuvant imatinib as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO) H. Joensuu, M. Eriksson, J.Hartmann, K. Sundby Hall, J. Schütte, A. Reichardt, M. Schlemmer, E. Wardelmann, G. Ramadori, S. Al-Batran, B.E.Nilsson, O. Monge, R. Kallio, M. Sarlomo- Rikala, P. Bono, M. Leinonen, P. Hohenberger, T.Alvegård, P. Reichardt
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Twelve vs. 36 months of adjuvant imatinib
as treatment of operable GIST with a high risk of recurrence:
Final results of a randomized trial (SSGXVIII/AIO)
H. Joensuu, M. Eriksson, J.Hartmann, K. Sundby Hall, J. Schütte, A. Reichardt, M. Schlemmer, E. Wardelmann, G. Ramadori, S. Al-Batran, B.E.Nilsson, O. Monge, R. Kallio, M. Sarlomo-Rikala, P. Bono, M. Leinonen, P. Hohenberger, T.Alvegård, P. Reichardt
Gastrointestinal stromal tumor (GIST)
• Most common mesenchymal tumor of the GI-tract– Incidence ~10 cases/million/year
• GISTs have variable malignancy potential• High-risk GIST
– Consist of large (>5 cm) tumors with a high cell proliferation rate
– Associated with ≥50% 5-year risk of recurrence after surgery1-3
1Nilsson B et al. Cancer 2005; 103:821-9; 2Hassan I et al. Ann Surg Oncol 2008; 15:52-9; 3Rutkowski P et al. Ann Surg Oncol 2007; 14:2018-27
Adjuvant imatinib in GIST: Rationale
• Inhibits the tyrosine kinases frequently mutated in GIST: KIT and PDGFR
• Effective in the treatment of advanced GIST
• One year of adjuvant imatinib improved RFS compared to placebo in the ACOSOG Z9001 trial1
KIT
Mutated in ~75% of GISTS
PDGFRA
Mutated in ~10% of GISTs
1DeMatteo RP et al. Lancet 2009; 373:1097-104
SSGXVIII: Study hypothesis
• Three years of adjuvant imatinib may result in longer RFS as compared to 1 year of imatinib
Imatinib for 12 months
An open-label Phase III study
Imatinib 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:
– Safety– Overall 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
SSGXVIII: Key exclusion criteria
• Inoperable, recurrent or metastatic GIST*
• Age <18
• ECOG** performance status >2
• >12 weeks between the date of surgery and study entry
• Clinically significant cardiac, hepatic, renal or bone marrow disease*Patients with operable metastases were allowed to enter until protocol amendment in October 2006; **Eastern Cooperative Oncology Group
Imatinib administration
• 400 mg daily orally with food
• Dose reduced to 300 mg/day when
– Grade 3/4 non-hematological toxicity occurred
– Grade 2 non-hematological or Grade 3/4 hematological toxicity recurred
Clinical assessment
Assessment Interval between assessments Study months 1-36 Study months >36
Clinical examination 1 to 3 months 6 months
Blood cell counts and chemistry
2 to 12 weeks 6 months
CT/MRI of the abdomen and pelvis
6 months 6 months
Grading of adverse events: the National Cancer Institute Common Toxicity Criteria version 2.0
Tumor pathology review
• Performed by 1 of the 2 study pathologists*
after study entry– Confirmation of GIST diagnosis– Counting of tumor mitoses
• KIT and PDGFRA** mutation analysis performed centrally after study entry
*E. Wardelmann, Univ. Cologne; M. Sarlomo-Rikala, Univ. of Helsinki
**Platelet-derived growth factor A gene
Study analysis populations
• Intention-To-Treat Population (ITT)
– Patients who signed informed consent
Study analysis populations
• Intention-To-Treat Population (ITT)
– Patients who signed informed consent
• Efficacy Population
– Patients who signed informed consent,
– had GIST at pathology review, and
– had no overt metastases at study entry
Study analysis populations
• Intention-To-Treat Population (ITT)– Patients who signed informed consent
• Efficacy Population– Patients who signed informed consent,– had GIST at pathology review, and – had no overt metastases at study entry
• Safety Population – Patients who took ≥1 dose of imatinib
Estimation of the sample size
• 110 RFS events required in the Efficacy Population
• 400 patients to be entered – Assuming a hazard ratio (HR) of 0.44 in
favor of the 36-month group – Using a significance level of .05, power 0.80,
20% drop-out rate, 2-sided testing
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
RFS events and deaths* (ITT)
Event 12-Month group
(n=199)
No. (%)
36-Month group
(n=198)
No. (%)
RFS events (recurrences or deaths) 84 (42) 50 (25)