Efficacy of the Irreversible ErbB Family Blocker Afatinib in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI)–Pretreated Non–Small-Cell Lung Cancer Patients with Brain Metastases or Leptomeningeal Disease

Abstract

Introduction:Afatinib is an effective first-line treatment in patients with epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC) and has shown activity in patients progressing on EGFR-tyrosine kinase inhibitors (TKIs). First-line afatinib is also effective in patients with central nervous system (CNS) metastasis. Here we report on outcomes of pretreated NSCLC patients with CNS metastasis who received afatinib within a compassionate use program.Methods:Patients with NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment received afatinib. Medical history, patient demographics, EGFR mutational status, and adverse events including tumor progression were documented.Results:From 2010 to 2013, 573 patients were enrolled and 541 treated with afatinib. One hundred patients (66% female; median age, 60 years) had brain metastases and/or leptomeningeal disease with 74% having documented EGFR mutation. Median time to treatment failure for patients with CNS metastasis was 3.6 months, and did not differ from a matched group of 100 patients without CNS metastasis. Thirty-five percent (11 of 31) of evaluable patients had a cerebral response, five (16%) responded exclusively in brain. Response duration (range) was 120 (21–395) days. Sixty-six percent (21 of 32) of patients had cerebral disease control on afatinib. Data from one patient with an impressive response showed an afatinib concentration in the cerebrospinal fluid of nearly 1 nMol.Conclusion:Afatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases. Afatinib may therefore be an effective treatment for heavily pretreated patients with EGFR-mutated or EGFR–TKI-sensitive NSCLC and CNS metastasis.

Promising Effects of Afatinib on Leptomeningeal Carcinomatosis Derived from Erlotinib-resistant Lung Adenocarcinoma

“…Recently, the T790M mutation was reported to occur more frequently in extracranial lesions than CNS lesions (1, 13, 14), indicating that the presence of the T790M mutation in the extracranial lesion does not always correspond to the positivity of the T790M mutation in the CNS lesion. In addition, the superior effect of afatinib over first-generation EGFR-TKIs on CNS lesions has also been demonstrated in the following two reports: Hata et al reported a case of T790M-negative NSCLC with BM, which developed during erlotinib treatment but responded to afatinib immediately after erlotinib therapy (15); and Hoffknecht et al reported that CNS metastases were controlled by afatinib in 66% of patients heavily treated with first-generation EGFR-TKIs (16). In the report by Hoffknecht et al, a case of T790M-positive adenocarcinoma with LMC was successfully treated with afatinib, which reached an effective concentration in the cerebral spinal fluid (CSF), although the penetration rate remained less than 1% (16).…”

“…In addition, the superior effect of afatinib over first-generation EGFR-TKIs on CNS lesions has also been demonstrated in the following two reports: Hata et al reported a case of T790M-negative NSCLC with BM, which developed during erlotinib treatment but responded to afatinib immediately after erlotinib therapy (15); and Hoffknecht et al reported that CNS metastases were controlled by afatinib in 66% of patients heavily treated with first-generation EGFR-TKIs (16). In the report by Hoffknecht et al, a case of T790M-positive adenocarcinoma with LMC was successfully treated with afatinib, which reached an effective concentration in the cerebral spinal fluid (CSF), although the penetration rate remained less than 1% (16). Taking those reports into consideration together with the present case, afatinib treatment should be considered for CNS metastases, regardless of the presence of the T790M mutation in the extracranial lesion.…”

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

“…Thirty-five percent of evaluable patients developed a CNS response with median duration response of 120 days. One patient who developed a response on 40 mg of oral afatinib, achieved a CSF afatinib concentration of about 1 nM [86].…”

Successful afatinib treatment through nasogastric tube in a ventilated patient with non-small cell lung cancer

“…indicated superior clinical effect of afatinib on the central nervous system metastasis [16] . Afatinib has toxicities that are similar to gefitinib or erlotinib, such as diarrhea, skin rash, stomatitis and interstitial pneumonia.…”