Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall‐cell lung cancer

Abstract

BACKGROUND:We investigated the risk of central nervous system (CNS) failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in Korean patients with nonsmall-cell lung cancer (NSCLC) METHODS: We retrospectively evaluated the pattern of disease progression of 287 advanced NSCLC patients who were treated with gefitinib or erlotinib. Patients whose best tumor response was complete response, partial response, or stable disease (90 days) were classified into the group receiving clinical benefit with these drugs. RESULTS: The clinical benefit group had a higher incidence of CNS failure as an initial progression, compared with the non-clinical benefit group (26% vs 4%; P < .001). Isolated CNS failure was also more frequent in the clinical benefit group than in the non-clinical benefit group (13% vs 1%; P < .001). In a multivariate analysis, clinical benefit with EGFR-TKIs significantly increased the risk of isolated CNS failure, with an adjusted hazard ratio of 10.9 (95% confidence interval [CI], 1.4-29.1, P ¼ .01). In patients with isolated CNS failure, the median time from initial intracranial failure to extracranial failure was 9.9 months (95% CI, 1.9-21.9 months) and to death was 12.9 months (95% CI, 3.3-22.5 months). CONCLUSIONS: The CNS was frequently the initial failure site after clinical benefit with EGFR-TKIs in Korean NSCLC patients. Patients with isolated CNS failure showed durable extracranial control after cranial progression. A role for close surveillance of the CNS during EGFR-TKI treatment or prophylactic measures appears worthy of further study in these patients. Cancer 2010;116:1336-43.

Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers

“…Patients with EGFR-mutant cancers may be at greater risk for CNS involvement with the cumulative incidence of CNS metastases approaching 60% [20][21][22][36][37][38]. New EGFR TKIs such as AZD3759 are being developed specifically for their superior CNS penetration and activity, but robust efficacy data is not yet available [39].…”

“…Although a benefit is commonly seen with EGFR TKIs when CNS disease is already present, duration of CNS control is less well-described. Up to 33% of patients with EGFR-mutant lung cancers have CNS progression during initial EGFR TKI therapy and in many patients, the CNS progression occurs in the setting of continued systemic control [20][21][22]. CNS-only progression may be a result of low drug concentrations, with CSF concentrations of erlotinib 3-5% of that in plasma [23].…”

Non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases: role of tyrosine kinase inhibitors (TKIs) and evidence in favor or against their use with concurrent cranial radiotherapy

“…Most importantly, EGFR mutant tumors are more likely to develop BM during the course of the disease mainly due to longer life expectancy. On the other hand, it has been postulated that approximately 14-17% of patients with EGFR mutant NSCLC present with isolated CNS progression after front line treatment with EGFR TKIs (34)(35)(36)(37). However, others have demonstrated a lower incidence of BM in the same population (38).…”

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future

“…Its higher binding affinity and broader target could enhance therapeutic efficacy and delay the development of resistance mutations in EGFR-mutated pts (112). Despite the effectiveness in NSCLC with BM, there are evidences that pts treated with first generation EGFR-TKIs over a period of many months may have an increased risk of developing BM (113). In fact the concentration of TKIs in the CSF seems sufficient to inhibit treatment naive but non-TKIsresistant cells.…”

“…In fact the concentration of TKIs in the CSF seems sufficient to inhibit treatment naive but non-TKIsresistant cells. Moreover the lower drug concentration could select for resistant clones over time (112,113).…”