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


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).


CONCLUSIONS
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.
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Kyu-pyo
KP
Kim
Min-Hee
MH
Ryu
Changhoon
C
Yoo
Baek-Yeol
BY
Ryoo
Dae Ro
DR
Choi
Heung Moon
HM
Chang
Jae-Lyun
JL
Lee
Mo Youl
MY
Beck
Tae Won
TW
Kim
Yoon-Koo
YK
Kang
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001549:Benzamides; D001682:Biological Availability; D057176:Compassionate Use Trials; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D005743:Gastrectomy / Q000009:adverse effects*; D046152:Gastrointestinal Stromal Tumors / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D006207:Half-Life; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use; D000077210:Sunitinib; D016019:Survival Analysis
D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D011480:Protease Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; C498826:nilotinib; D000077210:Sunitinib