Optimizing Tyrosine Kinase Inhibitor Therapy in Gastrointestinal Stromal Tumors: Exploring the Benefits of Continuous Kinase Suppression

Abstract

Background. The oral tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of gastrointestinal stromal tumors (GISTs), most of which harbor oncogenic mutation in genes that encode the receptor tyrosine kinases KIT or PDGFA. Imatinib is the standard of care for patients with advanced GIST and for patients with primary GIST at significant risk of recurrence after surgery. Design. This review discusses data supporting continuous kinase suppression with imatinib and key issues, including response to imatinib reintroduction, effect of treatment interruption on secondary resistance to imatinib, and prognostic factors associated with sustained response to imatinib. Results. Long-term follow-up results of the B2222 study and updated results of the BFR14 trial demonstrate that continuous imatinib treatment in patients with advanced GIST is associated with reduced risk of progression. For patients progressing on or intolerant of imatinib, continuing therapy with TKIs sunitinib followed by regorafenib is recommended. In the adjuvant setting, final results of the trial by the Scandinavian Sarcoma Group and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie demonstrate that 3 years of adjuvant imatinib, compared with 1 year, significantly reduces the risk of recurrence and improves overall survival of patients with KIT-positive GIST at high risk of recurrence. Conclusions. Maintenance of therapy with TKIs is the key to successful treatment of GIST. Results from recent studies provide a strong rationale for continuous imatinib treatment for 3 years following surgical resection and long-term continuous administration in advanced or metastatic GIST. The Oncologist 2013;18:1192-1199 Implications for Practice: Imatinib interruption in advanced setting results in rapid progression in the vast majority of patients and should not be recommended outside clinical trials unless patients experienced significant toxicity. The results observed in advanced GIST need to be considered also for the use of imatinib in the adjuvant setting where the optimal duration of imatinib is unknown (at least three years) and where reintroduction of imatinib is the standard of care in case of disease recurrence.

Anti-angiogenesis target therapy for advanced osteosarcoma

“…However, for GIST, long-term follow-up results of the B2222 study and updated results of the BFR14 trial demonstrate that continuous imatinib treatment in patients with advanced GIST is associated with reduced risk of progression ( 118 ). For patients progressing on or intolerant of imatinib, continuing therapy with TKIs sunitinib followed by regorafenib is recommended ( 118 ), which seems to us a totally different strategy.…”

“…However, for GIST, long-term follow-up results of the B2222 study and updated results of the BFR14 trial demonstrate that continuous imatinib treatment in patients with advanced GIST is associated with reduced risk of progression ( 118 ). For patients progressing on or intolerant of imatinib, continuing therapy with TKIs sunitinib followed by regorafenib is recommended ( 118 ), which seems to us a totally different strategy. For non-small cell lung cancer (NSCLC) therapy, the reversible epidermal growth factor receptor (EGFR) TKIs gefitinib and erlotinib have been proven to be the first-line therapy for NSCLC harboring activating EGFR mutations ( 119 ).…”

PET-Based Molecular Imaging in Personalized Oncology: Potential of the Assessment of Therapeutic Outcome

“…Imatinib, an oral tyrosine kinase inhibitor, is an example of a targeted drug therapy, which may be given continuously as a maintenance therapy. Recent results support the hypothesis of a continuous imatinib treatment in patients with advanced gastrointestinal stromal tumors and demonstrate a reduced risk of progression [23]. Another example of a maintenance targeted therapy is the use of future science group www.futuremedicine.com the antibody rituximab, a monoclonal antibody against CD20 in patients with Hodgkin's disease.…”

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“…Based on pharmaco-economic studies recently published in Oncologist 15,16 it has been emphasized that adjuvant treatment with imatinib must not be neglected, based on mutational analysis and dose administration. This is justified by a significant economic impact on the national health system, and on the other hand, its adequate use concerning dosage and mutational status, allows a better approach to cost-benefit level for each patient.…”