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

Purpose 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. Patients and Methods EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. Results Of the 70 enrolled patients, 61 had EGFR -activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683–63,257 ng·h/mL) and 2338 ng·h/mL (581–5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound AUC 0-24 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 (C trough,ss ) at each visit for 3 months after the initiation of erlotinib treatment ( P < 0.0001). Total and unbound C trough,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 unchanged for 3 months ( P = 0.0046, 0.0008). Conclusion The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR -activating mutations, despite wide inter-individual variability in exposure and dose reduction. Clinical trials registration number: UMIN000012862.