Afatinib active against NSCLC nervous system metastases

Oct 22 2014

By Laura Cowen, medwireNews Reporter

Heavily pretreated patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) and central nervous system (CNS) metastases may benefit from treatment with afatinib, say German researchers.

The team, led by Petra Hoffknecht, from Mathias Spital Rheine, explains that although EGFR-tyrosine kinase inhibitors (TKIs) such as afatinib are now recommended as a first-line treatment for patients with EGFR mutation-positive NSCLC, data on their efficacy in patients with CNS metastases remain limited.

To address this, the researchers studied 541 patients with NSCLC who received afatinib as part of a compassionate use programme, initiated to provide access to the drug for patients who experienced disease progression during treatment with erlotinib or gefitinib.

Of the 541 patients treated with afatinib at a starting dose of 50 mg daily, 100 had brain metastases and/or leptomeningeal disease, 74% of whom had a confirmed EGFR mutation. The efficacy of afatinib in these patients was compared with that in 100 patients from the compassionate use programme who did not have CNS metastases. The two groups were matched for age, gender, histology, mutational subgroup, median treatment duration with reversible EGFR-TKI and treatment line.

As reported in the Journal of Thoracic Oncology, the median time to treatment failure for the patients with CNS metastases was 3.6 months, and did not differ from that of the matched patients without CNS metastases, at a hazard ratio of 1.16.

The majority of patients with CNS metastases benefitted from afatinib treatment, with 42% of those evaluable (n=31) experiencing partial remission and a further 39% having stable disease. The median response duration was 4 months.

The cerebral response rate was 35%, with the response of half of these patients occurring exclusively in the brain. Two-thirds (66%) had cerebral disease control during afatinib treatment.

In their report, Hoffknecht and co-authors highlight the “impressive response” by one patient who received afatinib as fourth-line therapy. This patient had leptomeningeosis carcinomatosa and was hospitalised with an Eastern Cooperative Oncology Group (ECOG) performance status of 3/4. After a few days of afatinib treatment, the patient’s neurological symptoms regressed and the ECOG status improved to 1/2.

Further testing showed a cerebrospinal fluid afatinib concentration of nearly 1 nmol/L 3 hours after administration, and a month after initiation of afatinib therapy there were no detectable tumour cells in the spinal fluid.

This indicates that “[a]fatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases”, the researchers remark.

They conclude that their results “are encouraging” because “CNS metastases negatively impact the quality of life and [overall survival] of many patients with NSCLC and continue to present a therapeutic challenge.”

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