Afatinib for Advanced Non-small Cell Lung Cancer in a Case With an Uncommon Epidermal Growth Factor Receptor Mutation (G719A) Identified in the Cerebrospinal Fluid

Abstract

Few previous studies of patients with non-small cell lung cancer (NSCLC) and leptomeningeal metastases have used liquid biopsy of cerebrospinal fluid (CSF) to identify epidermal growth factor receptor (EGFR) mutations and guide therapy. A 34-year-old male patient with NSCLC and leptomeningeal metastases was admitted to the Interventional Radiology Department, Tianjin Huanhu Hospital on 18th April 2018 after showing no response to chemoradiotherapy. On admission, the patient was in critical condition with an estimated survival <1 month. A ventriculoperitoneal shunt was placed in the right lateral ventricle. The CSF level of carcinoembryonic antigen (CEA) was 9,869 ng/mL. Next-generation sequencing (NGS) of the CSF revealed an EGFR G719A mutation (frequency: 55.63%), whereas sequencing of circulating tumor DNA or cells in the peripheral blood identified no clinically significant mutations. Afatinib therapy was initiated based on the NGS results. During follow-up, the patient's symptoms improved, ventricular dilatation lessened, and pulmonary lesions decreased in size. At the last follow-up (7 months), the patient continued to show a good response to afatinib therapy with minimal adverse effects. This is the first clinical study to report the use of simultaneous genetic testing of CSF and peripheral blood to guide the successful implementation of afatinib therapy in a patient with NSCLC and leptomeningeal metastases. Notably, NGS of CSF was superior to genetic testing of peripheral blood at identifying an uncommon EGFR mutation (G719A) in a patient with NSCLC and leptomeningeal metastases.

Multiple intraventricular metastases from lung adenocarcinoma with EGFR G719X mutation: a case report

“…Afatinib, a second generation EGFR-TKI, was approved by the U.S. FDA for metastatic NSCLC with uncommon non-drugresistant EGFR mutations, such as L861Q, G719X, and S768I. Afatinib can achieve half maximal inhibitory concentration (IC50) against EGFR mutation in the cerebrospinal fluid [13] so that theoretically it can create an inhibitory effect on intraventricular metastases from lung cancer with minimal adverse effects. Molecular analysis indicated EGFR mutation (G719X) in this patient and both lesions in bilateral lungs and brain showed significant improvement after treatment with afatinib, which supported that the intraventricular lesions were metastatic disseminations of lung adenocarcinoma.…”

Efficacy of afatinib for pulmonary adenocarcinoma with leptomeningeal metastases harboring an epidermal growth factor receptor complex mutation (exon 19del+K754E)

“…Ma et al [ 13 ] reported on the efficacy of afatinib treatment in a patient with NSCLC and a non-classical EGFR mutation (G719A). Frega et al [ 8 ] have also reported on the response to afatinib treatment of a patient with NSCLC carrying 3 non-classical mutations: exon 18 E709K and an exon 21 L833V_H835L complex mutation.…”

Clinical applications of cerebrospinal fluid liquid biopsies in central nervous system tumors

“…As a result, there have been more studies investigating CSF ctDNA in LM than in BM, although patient numbers remain overall small, in part due to the rarity of this disease. Similarly to BM, some case reports detail successful treatment changes in response to mutations detected in CSF ctDNA [ 44 , 52 ], and a few studies report a similar correlation between CSF ctDNA levels and disease status, with increases at the time of progression and decreases in response to treatment [53] , [54] , [55] . Moreover, CSF ctDNA has been explored as a prognostic tool in LM, with a few studies in NSCLC showing a correlation between CSF ctDNA levels and presence of specific genomic alterations and survival [ 35 , 56 , 57 ].…”