Open AccessPhase I/II Study of Erlotinib to Determine the Optimal Dose in Patients With Non‐Small Cell Lung Cancer Harboring Only EGFR Mutations
Author(s) -
Takeda Yuichiro,
Ishizuka Naoki,
Sano Kazumi,
Hirano Satoshi,
Suzuki Manabu,
Naka Go,
Sugiyama Haruhito
Publication year - 2020
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12796
Subject(s) - erlotinib , lung cancer , medicine , oncology , maximum tolerated dose , mutation , erlotinib hydrochloride , epidermal growth factor receptor , pharmacology , cancer , bioinformatics , cancer research , biology , genetics , gene
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 ( C min ss ) was ≥ 0.30 μg/mL. The area under the curve (AUC) and C min ss were predicted via population PK (PopPK) or a bootstrap of 100 iterations (PopPK 100 ). TOX20 was defined as < 20% duration of any toxicity ≥ G2 during the PFS period. In ROC analysis of mPFS and TOX20 in the PopPK 100 study, C min ss was ≥ 0.17 and < 0.32 μg/mL, respectively. In ROC analysis of mPFS and TOX20 in the PopPK 100 study, C min ss 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 C min ss as determined by PopPK monitoring.