Cerebrospinal Fluid Penetration Rate and Efficacy of Afatinib in Patients with EGFR Mutation-positive Non-small Cell Lung Cancer with Leptomeningeal Carcinomatosis: A Multicenter Prospective Study.

Abstract

BACKGROUND:

Afatinib is an effective first-line treatment for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC). However, few reports have addressed the influence of cerebrospinal fluid (CSF) penetration rate on the efficacy of afatinib in patients with central nervous system metastases. Therefore, we conducted a prospective multicenter trial to evaluate the CSF penetration rate and efficacy of afatinib in patients with EGFR mutation-positive NSCLC with leptomeningeal carcinomatosis.

PATIENTS AND METHODS:

Eleven patients with histologically-proven EGFR mutation-positive NSCLC with leptomeningeal carcinomatosis were enrolled in the study between April 2014 and November 2015. They were treated with afatinib (40 mg/day), and blood and CSF levels of afatinib were analyzed on day 8. The primary endpoint was CSF penetration rate. Secondary endpoints included the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

RESULTS:

The median age of patients was 66 years. Five patients harbored an exon 19 deletion, three harbored a p.L858R point mutation, and three harbored an uncommon exon 18 mutation. The levels of afatinib in blood and CSF (mean±SD) were 233.26±195.40 nM and 3.16±1.95 nM, respectively. The CSF penetration rate was 2.45±2.91%. The ORR was 27.3% (three out of 11 patients), and two out of these three responders had uncommon EGFR mutations. The median PFS and OS were 2.0 and 3.8 months, respectively.

CONCLUSION:

The median CSF penetration rate of afatinib was higher than previously reported. Afatinib was effective against leptomeningeal carcinomatosis particularly in patients with NSCLC harboring uncommon EGFR mutations. The criteria for selecting a specific EGFR tyrosine kinase inhibitor for therapy of NSCLC should include its ability to penetrate CSF and its efficacy against specific mutation types.

• Authors: Akihiro Tamiya, Motohiro Tamiya, Takashi Nishihara, Takayuki Shiroyama, Keiko Nakao, Taisuke Tsuji, Naoko Takeuchi, Shun-Ichi Isa, Naoki Omachi, Norio Okamoto, Hidekazu Suzuki, Kyoichi Okishio, Ayano Iwazaki, Kimie Imai, Tomonori Hirashima, Shinji Atagi
• Journal: Anticancer research (Anticancer Res) Vol. 37 Issue 8 Pg. 4177-4182 (08 2017) ISSN: 1791-7530 [Electronic] Greece
• PMID: 28739703 (Publication Type: Clinical Trial, Journal Article, Multicenter Study)
• Copyright: Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Quinazolines
• Afatinib
• EGFR protein, human
• ErbB Receptors

Topics

• Afatinib
• Aged
• Carcinoma, Non-Small-Cell Lung (cerebrospinal fluid, drug therapy, genetics, pathology)
• Disease-Free Survival
• ErbB Receptors (genetics)
• Exons (genetics)
• Female
• Humans
• Male
• Meningeal Carcinomatosis (cerebrospinal fluid, drug therapy, genetics, pathology)
• Middle Aged
• Mutation
• Protein Kinase Inhibitors (administration & dosage)
• Quinazolines (administration & dosage)