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Kim, Kyu-pyo; Ryu, Min-Hee; Yoo, Changhoon; Ryoo, Baek-Yeol; Choi, Dae Ro; Chang, Heung Moon; Lee, Jae-Lyun; Beck, Mo Youl; Kim, Tae Won; Kang, Yoon-Koo
Cancer chemotherapy and pharmacology, 08/2011, Volume: 68, Issue: 2Journal Article
Purpose To evaluate the efficacy of nilotinib in patients with advanced gastrointestinal stromal tumors (GISTs) resistant or intolerant to both imatinib and sunitinib and to explore the potential relationship between nilotinib pharmacokinetics and clinical outcomes. Patients and methods We analyzed the efficacy, tolerability and pharmacokinetic parameters of nilotinib (400 mg twice daily) in 17 GIST patients with histories of prior gastrointestinal surgery. Results Median patient age was 59 years (range, 35–71 years), 14 of 17 patients (82.4%) were male, and mean body weight was 59.4 kg. Of the 17 patients, 2 (11.8%) had partial responses (PR), 10 (58.8%) had stable disease (SD), and 5 (29.4%) had progressive disease (PD), with a clinical benefit rate (CR + PR + SD) at 24 weeks of 47.0%. Median progression-free survival (PFS) and overall survival (OS) were 23.6 weeks (95% confidence interval CI 0.0–50.6 weeks) and 74.0 weeks (95% CI 27.4–120.6 weeks), respectively. Most observed adverse events were mild (grade 1, 41.2%; grade 2, 52.9%), with no grade 3/4 events. Pharmacokinetic parameters of nilotinib were as follows: C max of 1,754 ± 970 μg/L, T 1/2 of 13.4 ± 8.94 h and AUC 0–12 h of 14,190 ± 6,853 h μg/L. The AUC 0–12 h of nilotinib was significantly lower in the 4 patients with prior major (total or subtotal) gastrectomy than in the other 13 patients (8,526 ± 7,869 h μg/L vs. 15,930 ± 5,759 h μg/L, P = 0.014). Of the 4 gastrectomized patients, two (50%) showed markedly decreased nilotinib exposure ( AUC 0–12 h of 1,914 and 3,194 h μg/L) and rapid disease progression (PFS of 4.6 and 7.1 weeks). Conclusion Nilotinib was active and safe in patients with advanced GIST resistant to both imatinib and sunitinib. Major gastrectomy decreased the bioavailability of nilotinib and, in some patients, lowered its clinical activity.
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