Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Cancer Chemother Pharmacol. 2011 Aug;68(2):285-91. doi: 10.1007/s00280-010-1479-6. Epub 2010 Oct 19.
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.
评估尼洛替尼在对伊马替尼和舒尼替尼均耐药或不耐受的晚期胃肠间质瘤（GIST）患者中的疗效，并探讨尼洛替尼药代动力学与临床结局之间的潜在关系。
我们分析了 17 例既往接受过胃肠手术的 GIST 患者应用尼洛替尼（每日 2 次，每次 400mg）的疗效、耐受性和药代动力学参数。
中位患者年龄为 59 岁（范围，35-71 岁），17 例患者中 14 例（82.4%）为男性，平均体重为 59.4kg。17 例患者中，2 例（11.8%）有部分缓解（PR），10 例（58.8%）有稳定疾病（SD），5 例（29.4%）有进展性疾病（PD），24 周时临床获益率（CR+PR+SD）为 47.0%。中位无进展生存期（PFS）和总生存期（OS）分别为 23.6 周（95%置信区间[CI]为 0.0-50.6 周）和 74.0 周（95%CI 为 27.4-120.6 周）。大多数观察到的不良事件为轻度（1 级，41.2%；2 级，52.9%），无 3/4 级事件。尼洛替尼的药代动力学参数如下：C(max)为 1754±970μg/L，T(1/2)为 13.4±8.94h，AUC(0-12h)为 14190±6853hμg/L。4 例有过主要（全胃或胃大部）胃切除术的患者（8526±7869hμg/L）与其余 13 例患者（15930±5759hμg/L）相比，尼洛替尼的 AUC(0-12h)明显降低（P=0.014）。在 4 例胃切除的患者中，有 2 例（50%）的尼洛替尼暴露量显著降低（AUC(0-12h)分别为 1914 和 3194hμg/L）且疾病快速进展（PFS 分别为 4.6 和 7.1 周）。
尼洛替尼在对伊马替尼和舒尼替尼均耐药或不耐受的晚期 GIST 患者中具有活性和安全性。胃大部切除术降低了尼洛替尼的生物利用度，并在某些患者中降低了其临床疗效。
