Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan.
Faculty of Pharmacy, Kindai University, Higashiosaka, Osaka, Japan.
J Clin Pharmacol. 2020 Feb;60(2):256-263. doi: 10.1002/jcph.1521. Epub 2019 Sep 19.
Although axitinib shows a good objective response rate and acceptable tolerability for advanced renal cell carcinoma, substantial differences in drug concentrations among individuals have hampered the reliable administration of the drug in a neoadjuvant setting. This study aimed to evaluate the relationship between axitinib pharmacokinetics and clinical efficacy in patients with advanced renal cell carcinoma treated in a neoadjuvant setting. We retrospectively reviewed 16 patients who underwent neoadjuvant axitinib treatment from prospective phase 2 study cohorts treated with axitinib and assessed whether the drug concentration was associated with clinical efficacy for primary tumors of advanced metastatic/oligometastatic clear cell renal cell carcinoma. Axitinib was administered orally at a starting dose of 5 mg twice daily for 2 months in principle before the operation, and the axitinib pharmacokinetics were examined. Best response, reduction rate, adverse events (AEs), and surgical complication were assessed. Four patients (25.0%) showed a partial response, and 12 (75.0%) had stable disease, with a mean reduction rate of 22.8%. No progressive disease was noted, and 9 of the 16 patinets (56.3%) showed downstaging. The trough level of axitinib significantly correlated with the objective response rate (P = .0052) and best tumor reduction (P = .0128). All AEs could be safely managed until termination of the dosing period. With respect to perioperative complications, grade 2 anemia was observed. Neoadjuvant axitinib treatment showed acceptable antitumor activity and safety profile for advanced renal cell carcinoma. The pharmacokinetics of neoadjuvant axitinib influenced the efficacy in patients with advanced renal cell carcinoma.
尽管阿昔替尼显示出对晚期肾细胞癌的良好客观缓解率和可接受的耐受性，但个体之间药物浓度的显著差异妨碍了在新辅助治疗环境中可靠地给药。本研究旨在评估新辅助治疗中晚期肾细胞癌患者阿昔替尼药代动力学与临床疗效之间的关系。我们回顾性分析了 16 例接受新辅助阿昔替尼治疗的患者，这些患者来自前瞻性 2 期研究队列，接受阿昔替尼治疗，并评估了药物浓度是否与晚期转移性/寡转移透明细胞肾细胞癌的原发肿瘤的临床疗效相关。阿昔替尼在手术前原则上以 5 mg 每日两次的起始剂量口服给药 2 个月，并检查阿昔替尼的药代动力学。评估最佳反应、缓解率、不良反应 (AE) 和手术并发症。4 例（25.0%）患者出现部分缓解，12 例（75.0%）患者疾病稳定，平均缓解率为 22.8%。未观察到疾病进展，16 例患者中有 9 例（56.3%）降期。阿昔替尼的谷浓度与客观缓解率显著相关（P = 0.0052）和最佳肿瘤缓解（P = 0.0128）。所有 AE 都可以在停药期间安全处理。关于围手术期并发症，观察到 2 级贫血。新辅助阿昔替尼治疗显示出对晚期肾细胞癌的可接受的抗肿瘤活性和安全性。新辅助阿昔替尼的药代动力学影响晚期肾细胞癌患者的疗效。
