Nilotinib in patients with GIST who failed imatinib and sunitinib: importance of prior surgery on drug bioavailability

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.

We analyzed the efficacy, tolerability and pharmacokinetic parameters of nilotinib (400 mg twice daily) in 17 GIST patients with histories of prior gastrointestinal surgery.

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).

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.