Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan.
Department of Clinical Trial Planning and Management, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
Clin Transl Sci. 2020 Nov;13(6):1150-1160. doi: 10.1111/cts.12796. Epub 2020 May 7.
The recommended daily dose of erlotinib was determined for patients with all types of non-small cell lung cancer (NSCLC). We determined the optimal dose (OD) in patients with NSCLC harboring only epidermal growth factor receptor (EGFR) sensitizing mutations. EGFR-tyrosine kinase inhibitor-naïve patients with sensitizing mutations were eligible. Clinical OD was determined in a phase I/II study based on the continual re-assessment method (CRM) of both disease control and dose-limiting toxicity, defined as any toxicity of grade 2 (G2) or higher within 8 weeks. We also determined the pharmacologic OD via a pharmacokinetic (PK) study. Thirty-eight patients were enrolled. Clinical OD was 25 mg/day by the CRM. Median progression-free survival (mPFS) was 9.3 months. In receiver operating characteristic (ROC) analysis of mPFS, the trough concentration ( ) was ≥ 0.30 μg/mL. The area under the curve (AUC) and were predicted via population PK (PopPK) or a bootstrap of 100 iterations (PopPK ). TOX20 was defined as < 20% duration of any toxicity ≥ G2 during the PFS period. In ROC analysis of mPFS and TOX20 in the PopPK study, was ≥ 0.17 and < 0.32 μg/mL, respectively. In ROC analysis of mPFS and TOX20 in the PopPK study, was ≥ 0.15 and < 0.31 μg/mL, AUC was ≥ 14.4 and < 14.5 μg/mL•hour, and the dosage was ≥ 58.4 and < 58.8 mg/day, respectively. Clinical and pharmacologic ODs were 25 by CRM and 50-60 mg/day by PK, respectively. The proposed starting OD is 50-60 mg/day, with personalized adjustment of 0.15-0.31 μg/mL based on as determined by PopPK monitoring.
厄洛替尼的推荐日剂量适用于所有类型的非小细胞肺癌（NSCLC）患者。我们确定了仅携带表皮生长因子受体（EGFR）敏感突变的 NSCLC 患者的最佳剂量（OD）。符合条件的是具有敏感突变的 EGFR 酪氨酸激酶抑制剂初治患者。临床 OD 是在一项基于疾病控制和剂量限制性毒性的连续再评估方法（CRM）的 I/II 期研究中确定的，定义为任何毒性≥2 级（G2）或更高在 8 周内。我们还通过药代动力学（PK）研究确定了药理 OD。共入组 38 例患者。根据 CRM，临床 OD 为 25mg/天。中位无进展生存期（mPFS）为 9.3 个月。在 mPFS 的接受者操作特征（ROC）分析中，谷浓度（ ）≥0.30μg/mL。通过群体 PK（PopPK）或 100 次迭代的引导（PopPK）预测 AUC 和 。TOX20 定义为在 PFS 期间任何毒性≥G2 的持续时间<20%。在 PopPK 研究中，mPFS 和 TOX20 的 ROC 分析中， 分别为≥0.17 和<0.32μg/mL。在 PopPK 研究中，mPFS 和 TOX20 的 ROC 分析中， 分别为≥0.15 和<0.31μg/mL，AUC 分别为≥14.4 和<14.5μg/mL•hour，剂量分别为≥58.4 和<58.8mg/天。临床和药理 OD 分别为 25 个由 CRM 和 50-60mg/天由 PK 确定。建议的起始 OD 为 50-60mg/天，根据 PopPK 监测确定的 作为个体化调整，范围为 0.15-0.31μg/mL。
