Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients.

Abstract

To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patientswith L858R). The median area under the concentration-time curve from 0 to 24h (AUC0-24) of total and unbound erlotinib on day 1 was 37,004ng·h/mL (range, 9683-63,257ng·h/mL) and 2338ng·h/mL (581-5904ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9months, and PFS did not differ between each tertile of total and unbound AUC0-24 on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state (Ctrough,ss) at each visit for 3months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound Ctrough,ss on day 7-15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchangedfor 3 months (P = 0.0046, 0.0008). The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. UMIN000012862.