Efficacy, safety, and pharmacokinetics of imatinib dose escalation to 800 mg/day in patients with advanced gastrointestinal stromal tumors

Imatinib dose escalation has been suggested as an effective therapy for advanced gastrointestinal stromal tumors (GIST) after progression on the standard dose. We evaluated the efficacy, tolerability, and pharmacokinetics of imatinib dose escalation. Eighty-four patients with GIST who received imatinib 800 mg/day as second-line therapy were reviewed. In 66 patients, imatinib plasma trough level (C_min) at 800 mg/day was measured. The relationships between imatinib exposure and therapeutic efficacy or toxicity were examined by grouping patients into quartiles according to C_min and its percent change after dose escalation. Disease control was achieved in 56 % of patients. The median progression-free survival (PFS) was 5.1 months. There was a strong tendency for better PFS in patients with KIT exon 9 mutations compared to patients with other genotypes (median PFS 11 vs 4 months, p = 0.051). The common grade 3–4 toxicities were anemia (26 %), neutropenia (11 %), and hemorrhage (5 %). Mean ± standard deviation imatinib C_min at 800 mg/day and percent C_min change was 3,552 ± 1,540 ng/mL and 160 ± 101 %, respectively. Body surface area, hemoglobin, and absolute neutrophil count were independent covariates of C_min at 800 mg/day. Neither C_min nor its percent change associated with efficacy. The upper three quartiles of percent C_min change associated with more frequent severe toxicities (56 %) than the lowest quartile (10 %; p = 0.01). Dose escalation to 800 mg/day was active and feasible in GIST after progression on the standard dose. Imatinib C_min monitoring may help to manage the patients with standard dose-resistant GIST that may require dose escalation.