Feasibility and clinical outcomes of imatinib personalized dosing in gastrointestinal stromal tumor patients.

Abstract

11521 Background: Imatinib treatment for metastatic gastrointestinal stromal tumors (GISTs) has substantial overall survival benefits compared to chemotherapy (56 vs 9 months) (Balachandran, 2014). Even better outcomes have been demonstrated for patients with imatinib minimal drug concentrations (C min ) ≥ 1100 ng/mL (Demetri, 2009). Drug concentration-guided dosing through therapeutic drug monitoring (TDM) of imatinib has previously been described as an option for personalized dosing, but there is no definite conclusion on efficacy results (IJzerman, 2020). The aim of the current study was to evaluate the feasibility and effect on clinical outcomes of imatinib personalized dosing through TDM for GIST patients. Methods: GIST patients starting with imatinib 400 mg once daily (QD) in both the (neo)adjuvant and metastatic setting were included. C min levels were measured during routine outpatient clinic visits, at 4, 8 and 12 weeks after start of treatment, and every 12 weeks thereafter. Dose increase to 600 mg QD and, if necessary, to 800 mg QD was advised when C min < 1100 ng/mL and treatment was well tolerated. Dose interventions were considered successful when median C min was ≥ 1100 ng/mL after intervention and no dose limiting toxicities (DLTs) occurred within the first month after dose intervention. Results: A total of 171 GIST patients were included, of which 61% (n = 104) were treated in the (neo)adjuvant setting and 39% (n = 67) in the palliative setting. Most patients (85.4%, n = 146) had a KIT exon 11 mutation. Median time on treatment was 30 months. A total of 1475 C min levels were measured (median of 8 levels per patient, IQR: 4−12), resulting in a median C min of 1111 ng/mL. Among all patients, 16% (n = 27) had all adequate C min levels, and 84% (n = 144) had ≥ 1 C min level below the target. Of these, 60% (n = 87) had a dose intervention, which was successful in 76% (n = 66) and unsuccessful in 24% (n = 21) of patients. When dose interventions were unsuccessful, this was primarily because C min levels were still below the target after the intervention (62%, n = 13). In the 40% of patients (n = 57) with ≥1 C min level below the target who had no dose intervention, this was mostly due to DLTs (51%, n = 29). Median C min before the dose intervention was 953 ng/mL, which increased to 1200 ng/mL (p < 0.001) after the intervention. DLTs were not correlated with dose interventions (p = 0.13; OR: 1.86, 95% CI: 0.83−4.16). Conclusions: This study confirms that personalized dosing of imatinib through TDM in GIST patients is feasible. Adequate drug concentrations improved from 16% to 54% of patients and interventions resulted in a clinically relevant drug concentration increase in patients who previously had C min levels below the target. Comparison of treatment efficacy and toxicity in our cohort with a standard-dose historical cohort will elucidate the effect of personalized dosing through TDM on clinical outcomes (analyses ready before ASCO). Clinical trial information: NTR6866 --- AND project number 11575 .