Sunnybrook Odette Cancer Centre, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada.
Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada.
Eur J Cancer. 2019 Feb;108:69-77. doi: 10.1016/j.ejca.2018.12.006. Epub 2019 Jan 14.
Sunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient.
In a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria.
The null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6-16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18-20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration.
Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. CLINICALTRIALS.
NCT01499121.
舒尼替尼的给药方案是严格规定的，但并非对所有患者都最佳。我们假设毒性驱动的剂量和方案调整将为每个患者优化药物暴露和结果。
在一项 2 期试验中，117 例转移性透明细胞肾细胞癌患者开始接受舒尼替尼 50mg/天治疗，目标是治疗 28 天。治疗休息时间减少至 7 天。根据毒性情况个体化调整舒尼替尼剂量和治疗天数，旨在使毒性最小的患者达到≤2 级毒性。主要终点的无效假设是无进展生存期（PFS）为 8.5 个月，该假设基于具有相似入选标准的研究。
无效假设被拒绝（p<0.001），中位 PFS 为 12.5 个月（95%置信区间 [CI]：9.6-16.5）。中位总生存期为 38.5 个月（95%CI：28.3-未达到）。客观缓解率（46.1%）和疾病稳定率（38.5%）使 84.6%的患者受益，治疗期间生活质量评分没有下降。与标准舒尼替尼剂量相比，剂量减少（26.5%比 50%）或因毒性而停药（7.7%比 18-20%）的患者更少，并且 20 名（18.4%）患者的剂量增加至 62.5mg（12 名）和 75mg（8 名），最佳剂量和治疗持续时间存在广泛的个体差异。
个体化舒尼替尼治疗是可行的、安全的，并且是管理毒性的有效方法，在转移性肾细胞癌中，口服血管内皮生长因子抑制剂的疗效最佳之一。临床试验。
NCT01499121。
