KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours
Introduction
Gastrointestinal stromal tumours (GISTs), the most frequent mesenchymal tumours of the gastrointestinal tract, commonly show oncogenic activating mutations of the KIT tyrosine kinase.1, 2, 3, 4, 5 Imatinib mesylate (Glivec®/Gleevec®, formerly STI571, Novartis Pharma AG, Basel, Switzerland), a small-molecule inhibitor of BCR-ABL, KIT and PDGFR tyrosine kinases, targets the aberrant signalling pathways that are critical for tumour cell proliferation and survival.5, 6 Recent advances in understanding the molecular pathogenesis of GISTs has led to the remarkably successful use of imatinib in the treatment of advanced tumours, inducing high response rates leading to unprecedented improvements in overall survival.
The clinical activity of imatinib has been confirmed in GISTs, both in an EORTC (European Organization for Research and Treatment of Cancer) phase I study,7 in which the highest feasible dose of imatinib was defined as 400 mg twice a day, and in phase II studies with doses of 400–800 mg daily.8 Today, imatinib is approved worldwide for treatment of patients with GISTs, with a recommended dose of 400 mg daily.9
Two large randomized phase III trials, comparing imatinib 400 mg once a day with 400 mg twice daily have confirmed the high effectiveness of imatinib in terms of progression-free survival and overall survival.10, 11 One of these studies has also documented a significant advantage of the high-dose regimen (400 mg twice daily) in terms of progression-free survival.9 The second study by Rankin showed a similar result, albeit the difference did not reach statistical significance.11 Benefits in progression-free survival and response rate were seen following crossover to high-dose imatinib.12 Clinical characteristics that are prognostic for response and survival are presented elsewhere.13 Potentially even more important, a variety of biological mechanisms may also be responsible for initial or late drug resistance.14 The early clinical observations link imatinib sensitivity to the presence and the type of KIT/PDGFRA mutations in the tumour.15, 16 If and how the apparent better rate of progression-free survival with the highest feasible imatinib dose (800 mg daily) is related to the genomic profile of the tumour is currently unknown.
In this report, we aimed to correlate clinical response to imatinib with the mutational status of pretreatment GIST specimens from patients recruited in randomized EORTC-ISG-AGITG phase III study to explore if the response to highest feasible imatinib dose is linked to tumour genotype.
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Patients and methods
Between February 2001 and February 2002, three cooperative groups (EORTC STBSG, ISG and AGITG) randomized 946 patients with advanced Gastro-Intestinal Stromal Tumours (GIST) to receive imatinib at a daily dose of 400 mg (400 mg o.d.) versus 800 mg (400 mg b.i.d.). Details on eligibility criteria, treatment and follow-up have been published elsewhere.10 Patients assigned the once a day regimen who had progression were subsequently offered the option of crossover. Patients had regular physical
Statistical analysis
Patients were classified into subgroups, according to the mutations identified in the analysis, taking into account the presence or absence of any specific type of KIT mutation, presence or absence of PDGFRA mutation, and absence of any KIT or PDGFRA mutation (wild-type cases). Distribution of previously identified prognostic factors10, 13 has been tabulated for each group.
Results
Paraffin-embedded tumour blocks were retrospectively collected for 532 patients included in the trial. After central pathology review, 56 cases were reclassified as non-GISTs and excluded from the study. Amongst the 476 tumours with confirmed GIST diagnosis, 377 yielded DNA of adequate quality and quantity for full KIT genotype analysis. Characteristics for the 377 patients included in the current analysis are given in Table 1. The distribution of those factors was similar in those 377 patients
Discussion
Our series of 377 patients is the largest available series with advanced malignant GISTs treated with imatinib that has been analyzed for the importance of tumour genotype as an independent prognostic factor in predicting progression and survival. Moreover, it is the largest series currently available to also assess the relevance of initial dose of treatment with imatinib.
We have identified KIT-activating mutations in 83.6% of analyzed cases, PDGFRA-activating mutations in 2.6% of cases, and
Conflict of interest statement
M.D.-R. and R.S. have received from Novartis travel reimbursement for participation in symposia. A.v.O., J.Y.B. and J.V. have received honoraria from Novartis for consultancy. PC has received honoraria from Novartis for lectures, written contributions, and participation in advisory boards, has received travel reimbursement for meetings, and research or educational grants for his institution. J.Z. has received honoraria for lectures from Novartis and a study grant for the Australasian
Study investigators
The following investigators also contributed to the study:
Dr. P.C.W. Hogendoorn, Leiden, The Netherlands; Dr. R. Issels, Munich, Germany; Dr. P. Schöffski, Hannover, Germany; Dr. D. Kotasek, Ashford, Australia; Dr. S. Rodenhuis, Amsterdam, The Netherlands; Dr. W. Ruka, Warsaw, Poland; Dr. F. Duffaud, Marseilles, France; Dr. J. Radford, Manchester, UK; Dr. D. Hossfeld, Hamburg, Germany; Dr. J. Wheelan, London (Middelsex), UK; Dr. M. Leahy, Leeds, UK; Dr. A. Krarup-Hansen, Herlev, Denmark; Dr. B.
Acknowledgements
This study was supported by an EORTC SBST Group Grant TRF/02/01 and by an unrestricted grant from Novartis Oncology. The authors thank Novartis Oncology for a generous gift of D-HPLC system. This publication was supported by Grant(s) No. 2U10CA11488-30 (through 2U10CA11488-35) from the National Cancer Institute (Bethesda, MD, USA). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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