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Imatinib (Gleevec®, Glivec®) is a small molecule inhibitor of tyrosine kinase that has been evaluated for efficacy in patients with gastrointestinal stromal tumours (GIST). The drug is approved for the treatment of unresectable and/or metastatic, KIT-positive GIST in the US, Europe and many other countries.
Imatinib has had a significant impact on the management of advanced GIST, which has traditionally had a poor prognosis, and has quickly become the first choice of treatment in the medical therapy of unresectable and/or metastatic, KIT-positive GIST. In randomised, nonblind trials, imatinib 400–800 mg/day produced complete or partial responses in up to two-thirds of patients, with long-term efficacy, and substantially prolonged progression-free and overall survival. The drug was generally well tolerated in GIST patients, including during long-term treatment. Imatinib dosages higher than 400 mg/day (up to 800 mg/day) may improve progression-free survival, with an increase in dosage benefiting some patients who show disease progression at the lower dosage, particularly in those with exon 9 mutation; however, there is also a dose-related increase in imatinib toxicity. Mutational genotype and other, nonbiomolecular factors may aid in guiding imatinib therapy and predicting prognosis in GIST patients. Further data are required to evaluate the use of imatinib in adjuvant and neoadjuvant settings. Nevertheless, imatinib currently provides the most effective treatment option in the management of advanced GIST.
Imatinib acts by selectively and competitively inhibiting the protein-tyrosine kinase activity associated with KIT receptors and platelet-derived growth factor receptor-α. Inhibition of constitutively active KIT signalling by imatinib resulted in inhibition of cell proliferation and apoptosis induction in vitro in GIST cell lines, and arrest of tumour cell proliferation and decrease in tumour volume in vivo in a mouse model. Several pharmacodynamic and pharmacokinetic mechanisms of resistance, among the most common being secondary kinase mutations and constitutive KIT reactivation, have been proposed for the initial and late resistance to imatinib observed in clinical trials.
Imatinib is rapidly absorbed after oral administration with almost complete bioavailability. It is highly plasma protein bound and extensively distributed into body tissues. Cytochrome P450 (CYP) 3A4 is the main enzyme involved in imatinib metabolism, resulting in the formation of its major, active metabolite CGP 74588. The drug is eliminated mostly as metabolites, mainly via the faeces. Imatinib may interact with drugs that are inhibitors or inducers of, or substrate for, CYP3A4.
In randomised, nonblind, multicentre trials, imatinib 400–800 mg/day was associated with a complete or partial response in 48–58% of patients with advanced, unresectable and/or metastatic, KIT-positive GIST, with response rates in imatinib 400 mg/day recipients being similar to those in patients receiving imatinib 600 or 800 mg/day. Response rates were even higher (67%) during long-term follow-up in a phase II trial, most of them durable for >1 year. In a phase III trial, the median time to onset of response was 30 weeks, but occasional best responses required as long as 2 years of treatment.
The estimated progression-free and overall survival rates at 2 years were 44–52% and 69–76%. Imatinib 400mg twice daily appeared to provide greater benefit than imatinib 400mg once daily in terms of progression-free survival in one trial, but not in the other. During a 52-month follow-up in a phase II trial, the estimated median overall survival for all patients was 248 weeks.
Exploratory analyses of data from phase II/III trials showed that dosage escalation could be beneficial in some patients, particularly those harboring an exon 9 mutation, who had disease progression despite treatment with imatinib 400 mg/day; compared with continuous therapy, imatinib interruption was associated with a significant reduction in progression-free survival; dosage reductions did not appear to have an adverse impact on outcomes; and mutational genotype was the major predictor of clinical response to imatinib.
Imatinib was generally well tolerated in patients with GIST in clinical trials, including the 52-month follow-up of a phase II trial; most of the adverse events were mild to moderate in severity. Anaemia and fatigue were the most common haematological and nonhaematological grade 3/4 adverse events. Overall, grade 3/4 adverse events were more common with imatinib 800 than 400 mg/day, although the incidence of serious adverse events was similar.