Imatinib

Therapy with imatinib is the standard first-line treatment for most patients with metastatic or recurrent disease. The initial dose is 400 mg daily, except for patients with tumors containing KIT exon 9 variants, who may receive 800 mg daily.[1] The only exception is for patients with GISTs characterized by the PDGFRA D842V variant. In this subtype, avapritinib is used as first-line therapy given high clinical benefit and imatinib resistance.[2] Most patients can initiate imatinib empirically while awaiting confirmation of their tumor’s molecular profile. That profile may necessitate an imatinib dosing change (i.e., KIT exon 9), a change to avapritinib (i.e., PDGFRA D842V variant), or indicate likelihood for TKI resistance (i.e., SDH-deficient or neurofibromatosis type 1 [NF1]-related GISTs).

All patients receiving TKI therapy are closely monitored for tumor response and side effects, which may require dose reductions, interruptions, or cessation of TKI therapy in cases of persistent, excessive toxicity. In addition, dose modification of the TKI or substitution with medications that do not affect cytochrome P450 isoenzyme 3A4 (CYP450 3A4) levels may be necessary for patients taking drugs that affect CYP450 3A4 levels.[3]

Response is evaluated with computed tomography (CT), magnetic resonance imaging (MRI), or fluorine F 18-fludeoxyglucose positron emission tomography (18F-FDG PET).[3-7] Treatment is usually continued indefinitely in the absence of disease progression or unacceptable toxicity, with a median time to progression of 24 to 40 months and median survival approaching 45 to 60 months.[3,8-14] A cohort of patients from early imatinib trials have continued on therapy with long-term survival. In a multivariable analysis, age younger than 60 years, performance status 0, smaller size of the largest lesion, and exon 11 KIT variant were significant prognostic factors for the probability of surviving beyond 10 years.[10] A similar finding for exon 11 was seen in a phase II study.[9]

Evidence (imatinib therapy):

In the event of tumor progression in patients without KIT exon 9 variants on lower dose imatinib (i.e., 400 mg daily), the imatinib dosage may be increased to 800 mg daily (in split doses). Alternatively, in the management of imatinib resistance, the patient may be switched directly to sunitinib.[23]

The most common toxicities associated with imatinib therapy, all of which may improve with prolonged treatment, include:[6,11,24-26]

There are rare reports of heart failure related to imatinib use,[27] primarily in patients with preexisting heart disease. No excess cardiac toxicity was noted in either of the phase III trials of imatinib mentioned above for patients with advanced GISTs.[15,16] However, it is best to inform patients of this risk before starting imatinib and monitor clinically for signs of heart failure or left ventricular dysfunction.