Gastrointestinal stromal tumors (GISTs) arise from mesenchymal stem cells which also give rise to the interstitial cells of Cajal within the GI tract. A large majority of GIST tumors harbour activating mutations in the proto-oncogenes KIT and/or PDGFRA, both coding cell-surface cytokine receptors with tyrosine-protein kinase activity.~Imatinib mesilate (Glivec®, Novartis Pharma SAS) is a selective tyrosine kinase inhibitor, leading to inhibition of KIT and PDGFRA signalling pathways. The introduction of imatinib has revolutionised the therapeutic management of GIST patients and has provided an unprecedented demonstration of the clinical benefit of a targeted therapy for patients with advanced/metastatic solid tumors.~Several studies have investigated the optimal duration of imatinib treatment in the advanced phase. The BFR14 trial demonstrated that 31% of advanced GIST patients treated with continuous imatinib beyond 1 year had documented disease progression compared to 81% in the interrupted imatinib group (p<0.0001). The authors concluded that treatment interruption resulted in rapid progression in most patients with advanced GIST and therefore should not be recommended in standard practice unless the patient experienced significant toxicity or disease progression. An update of the BFR14 trial at a median follow-up of 37 months showed that 91% of patients in the interrupted arm versus 62% in the continuous arm experienced progressive disease (p<0.0001). Majority (92%) of patients in the interrupted arm achieved tumor control once they recommenced imatinib after first progression. Ray-Coquard et al. reported that stopping imatinib after 5 years resulted in a higher rate of disease progression than imatinib maintenance in patients with advanced GIST responding to or stabilised by imatinib.~However, whether lifelong imatinib treatment duration is mandatory in metastatic GIST patients remains unclear. It is not known whether a cytostatic treatment of 10 years or longer is sufficient to inhibit definitively GIST cancer cells proliferation even after the interruption of the kinase inhibitor. This question has broad implications for all targeted therapies.~The aim of the present study is to address this question rigorously in a randomized setting. The investigators therefore want to determine whether prolonged use of imatinib beyond 10 years is needed to reduce the risk of GIST recurrence and to improve overall survival. For patients with imatinib interruption after at least 10 years of treatment, the investigators want to determine if imatinib rechallenge is efficient for treating recurrence. Therefore, the investigators design an open-label, randomized, multicenter phase II study to determine the clinical impact of maintaining imatinib treatment beyond 10 years in patients with locally advanced/metastatic GIST.
This is a 2 arms study concerning patients under imatinib treatment for at least 10 years of treatment with locally advanced/metastatic GIST.~In the first arm, patients will discontinue Imatinib treatment. This arm will allow to determine if the re-introduction of Imatinib at relapse is still an efficient treatment for the control of disease.~In the second arm, patients will continue Imatinib treatment, allowing to determine if the continuation of this treatment is efficient for disease control, by the rate of non-progression disease.