Definition of an imatinib trough concentration threshold in the treatment of advanced gastrointestinal stromal tumors (GIST).

Molimard, Mathiéu; Bouchet, Stéphane; Poulette, S.; Chauzit, Emmanuelle; Titier, Karine; Moore, Nicholas; Lassalle, R.; Abouelfath, Abdelilah; Italiano, Antoîne; Chevreau, Christine; Duffaud, F.; Rios, M.; Cupissol, Didier; Adenis, Antoine; Ray-Coquard, I. L.; Bouché, Olivier; Cesne, Axel Le; Blay, Jean‐Yves; Nguyen, Binh Bui

doi:10.1200/jco.2011.29.15_suppl.10013

Cited by 3 publications

(2 citation statements)

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“…This approach is supported by results from a study conducted by Demetri et al who found that patients with steadystate imatinib trough levels below 1100 ng/mL displayed a lower rate of clinical benefit (67 vs 82%) and a shorter TTP (11.3 vs > 30.5 months) compared with patients above this threshold. 44 Further studies are under way to explore the variability of blood-level testing in the longer term, 45,46 given limited earlier data suggesting that imatinib clearance may increase over time. 47 Ideally, a prospective, randomized trial examining the impact of imatinib dose adjustments to suboptimal blood levels is needed, as has been done in chronic myelogenous leukemia.…”

Section: The Potential Role Of Drug Blood-level Testingmentioning

confidence: 99%

Dose optimization of tyrosine kinase inhibitors to improve outcomes in GIST

Zalcberg¹,

Desai²

2012

Asia-Pac J Clncl Oncology

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Tyrosine kinase inhibitors such as imatinib and sunitinib have greatly improved clinical outcomes for patients with gastrointestinal stromal tumors (GIST). Dose optimization of these agents is critical and involves multiple considerations, including ensuring a durable response, monitoring drug blood levels to confirm adequate dosing, deciding whether to use high-dose imatinib or switch to second-line sunitinib in the event of disease progression and appropriately managing treatment-associated side effects. Imatinib is the standard first-line therapy for unresectable or metastatic GIST and is also an option for the adjuvant treatment of resected disease. Despite the efficacy and safety of imatinib in patients with advanced GIST, some individuals develop primary or secondary resistance or intolerance to the drug. For patients with advanced disease, imatinib dose escalation to 800 mg/day is warranted in cases of disease progression on imatinib 400 mg/day. In addition, patients with documented KIT exon 9 mutations are likely to derive benefit from initial treatment with high-dose imatinib to improve clinical outcomes. For patients who fail imatinib, sunitinib is an effective treatment option. However, the decision to use either high-dose imatinib or sunitinib should be based on the underlying cause of failure on imatinib, KIT mutational status and on whether the patient is intolerant of or has developed a resistance to imatinib. In this article we review the existing literature supporting the use of imatinib and sunitinib in GIST to provide a current clinical perspective on how best to use these agents in the management of GIST to optimize patient outcomes.

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Section: The Potential Role Of Drug Blood-level Testingmentioning

confidence: 99%

Dose optimization of tyrosine kinase inhibitors to improve outcomes in GIST

Zalcberg¹,

Desai²

2012

Asia-Pac J Clncl Oncology

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“…In a recent retrospective analysis from the B2222 study, patients in the lowest quartile of imatinib trough levels (Ͻ1,100 ng/mL) demonstrated a shorter TTP (11.3 months) than patients in all other quartiles (Ͼ1,100 ng/mL; TTP: 30 months; p ϭ .0029) [37]. More recent prospective evaluation of imatinib trough levels and PFS in patients with advanced GIST suggest that an even lower imatinib trough level threshold of 780 ng/mL may be sufficient to achieve extended PFS [38]. Notably, patients who have undergone major gastrectomy frequently have low imatinib trough plasma levels [39].…”

Section: Prognostic Factors Associated With Long-term Responsementioning

confidence: 99%

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

et al. 2013

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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.

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