Dose optimization of tyrosine kinase inhibitors to improve outcomes in GIST

Abstract

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.

Macroporous hydrogel micropillars for quantifying Met kinase activity in cancer cell lysates

“…In CML, patient sensitivity to imatinib varies significantly, partially based on factors such as cellular uptake and retention rates of imatinib, causing some patients to require higher doses to inhibit Bcr-Abl activity 43 . In gastrointestinal stromal tumors, when disease progression occurs during treatment with imatinib, clinicians must choose between increasing the dose of imatinib administered to patients or switching to sunitinib, another TKI 48 . To evaluate the ability of the Met kinase micropillar assay to identify Met activity inhibition by particular compounds, we quantified the dose-dependence of Met activity in the presence of known kinase inhibitors.…”

Multi-disciplinary management of recurrent gastrointestinal stromal tumor harboring KIT exon 11 mutation with the switch-control kinase inhibitor ripretinib and surgery`

“…For example, in patients treated with osimertinib for EGFR mutated non-small cell lung cancer (NSCLC), intracranial and leptomeningeal progression was controlled by increasing the dose from 80 mg to 160 mg QD in anecdotal studies [18][19][20]. In fact, dose escalation to overcome disease progression has been reported in GIST with other TKIs [21] and also with ripretinib [22,23].…”

Gastrointestinal Stromal Tumors Short Review on KIT/PDGFRA Gene Mutations and Molecular Therapy

“…Patients with WT GIST are typically less sensitive to tyrosine kinase inhibitors [26,27]. This group includes sporadic WT GIST, paediatric GIST and neurofibromatosis type-1(NF1)-related GIST [28][29][30][31][32][33][34][35][36][37][38][39][40].…”