Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which has shown improved clinical outcomes in the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions and exon 21 L858R mutations. Previous reports regarding the relationship between erlotinib pharmacokinetics and pharmacodynamics evaluated toxicities but not efficacy. Therefore, to evaluate the relationship between erlotinib exposure and efficacy, we conducted this prospective study.
Erlotinib was orally administered at a dose of 150 mg/body once daily to patients with NSCLC, who were not previously treated with EGFR-TKIs. A series of blood samples were taken at predetermined times on day 1 to calculate the area under the concentration-time curve (AUC). Erlotinib trough concentrartions (Ctrough) at each visit and the level of alpha1-acid glycoprotein (AAG), which is a binding protein of erlotinib in serum, were measured.
Of 70 patients enrolled, 61 had activating EGFR mutations (30 patients with exon 19 deletions and 31 with exon 21 L858R mutations). The AUC was 37.0 μg·h/mL in median (range; 9.7-63.3). Objective response rate and median progression-free survival (PFS) were 72% and 12.4 months in the patients with EGFR-activating mutations. Response was not associated with AUC. There was also no significant difference in PFS between patients with AUC > 37.0 μg·h/mL and ≤ 37.0 μg·h/mL. Ctrough was significantly correlated with the grade of skin rash (p 0.97 g/L, 7.9 months; AAG ≤ 0.97 g/L, 16.8 months, p
The lack of a relationship between erlotinib exposure and efficacy shows that the approved dose of erlotinib is sufficient to reach the therapeutic range in EGFR-activating mutant NSCLC, even with dose reduction due to toxicities. AAG level can be a prognostic factor for patients with NSCLC harboring EGFR-activating mutations treated with erlotinib.
Clinical trial identification
Legal entity responsible for the study
Shizuoka Cancer Center
JSPS KAKENHI Grant
H. Kenmotsu, N. Yamamoto, T. Takahashi: Grants and personal fees from Chugai Pharmaceutical Co, Ltd. C.K. Imamura, Y. Tanigawara: Honoraria from Chugai Pharmaceutical Co, Ltd. T. Kawamura, S. Omori, K. Wakuda, A. Ono, H. Murakami: Personal fees from Chugai Pharmaceutical Co, Ltd. All other authors have declared no conflicts of interest.