lung adenocarcinoma patients with epidermal growth factor receptor ( egfr ) mutations generally respond well to egfr tyrosine kinase inhibitors ( tkis ) . a proportion of these patients are found to have brain metastases at the time of lung adenocarcinoma diagnosis . before the introduction of egfr tkis , only few cases of lung cancer were suitable for surgical resection and most patients needed brain radiotherapy before egfr tkis were used in lung cancer patients . early relapse or dementia happened in the patients who received local intent or whole - brain radiotherapy . in the past 10 years , the first - generation egfr tkis have demonstrated impressive efficacy in the treatment of brain metastases originating from lung adenocarcinomas with egfr mutations . egfr tkis can be used as first - line treatment without the need for immediate brain radiotherapy . afatinib , the second - generation egfr tki , is an irreversible pan - human epidermal growth receptor tki approved for the treatment of lung adenocarcinoma with egfr mutations . lux - lung 3 and lux - lung 6 studies demonstrated increased progression free survival ( pfs ) with afatinib treatment . hoffknecht et al , as part of the afatinib compassionate use consortium ( acuc ) , reported cerebral responses to afatinib treatment in 35% ( 11 of 31 ) of patients who were followed up with at least one cycle of chemotherapy and an egfr tki . to date , there have been no reports of clinical trials or case series demonstrating the efficacy of afatinib as a first - line treatment of lung adenocarcinoma with activating egfr mutations and active brain metastases . substantial disease control has been observing in this case series concerning patients with varying clinical presentations indicating that afatinib may have efficacy as a first - line treatment for brain metastases resulting from lung adenocarcinoma with egfr mutations . a 61-year - old female with pleural effusion underwent computed tomography ( ct ) on march 29 , 2015 . cellblock cytology confirmed the pulmonary lesions to be adenocarcinoma , and egfr l858r ( substitution at position 858 from a leucine to arginine ) mutation was identified . pet - mri ( positron emission tomography - magnetic resonance imaging ) revealed multiple lung , brain , bone , and liver metastases . the patient had no neurological symptoms despite multiple brain metastases observed on mri ( figure 1a  d ) . after discussions with the patient and family , treatment with afatinib , instead of erlotinib or gefitinib , was initiated . whole - brain radiotherapy was not performed because of the absence of neurological symptoms and its potential side effects . the patient received afatinib ( 40  mg / d ) from april 23 , 2015 . brain mri ( figure 1e  h ) and whole body ct showed marked regression of the brain metastatic lesions , metastatic liver nodules , and primary lung tumor on june 27 , 2015 , representing a partial response following afatinib treatment for 2 months . a good cerebral response to afatinib was observed in this case . brain mri showing multiple metastatic brain lesions in case a ( panels 1a to 1d ) . regression of multiple brain metastases was observed after treatment with afatinib for > 2 months ( panels 1e to 1h ) . the findings of this case indicate the efficacy of afatinib as a first - line treatment in selected lung adenocarcinoma patients with brain metastases and no neurological symptoms . a 52-year - old male was found to have a 2  cm nodule in the left upper lung and a brain lesion at the left periventricular region superior to left thalamus ( figure 2a and b ) . histological examination of a ct - guided biopsy of the left lung nodule showed adenocarcinoma in february 2015 . whole - brain radiotherapy was performed with a total 30 gray delivered in 10 fractions and afatinib 40  mg / d initiated following the diagnosis of lung adenocarcinoma with brain and mediastinal lymph node metastases . following treatment with afatinib for 3 months , chest ct on may 16 , 2015 , showed regression of the lung tumor and metastatic mediastinal lymph nodes . brain mri on june 24 , 2015 , showed regression of brain metastases following afatinib treatment and whole - brain radiotherapy ( figure 2c and d ) . a significant cerebral response to combined systemic treatment with afatinib and whole - brain radiotherapy was observed in this case . brain mri in case b showing brain metastases with mass effect ( panels 2a and 2b ) . marked regression of metastatic brain lesion on brain mri following brain radiotherapy and afatinib treatment for 4 months ( panels 2c and 2d ) . the findings of this case indicate the efficacy of afatinib treatment and brain radiotherapy in lung adenocarcinoma patients with brain metastases and neurological symptoms . a 55-year - old male smoker with no previous history of systemic disease was diagnosed with lung cancer . the patient reported back pain for several weeks before the development of strabismus in november 2014 . chest ct ( figure 3b and c ) and bone scanning showed the presence of a tumor in the left lower lung with multiple bone and lung - to - lung metastases . brain radiotherapy and afatinib therapy were arranged following discussions with the patient and his family . chest ct showed a partial response of the lung cancer to treatment on may 15 , 2015 ( figure 3e and f ) . brain mri found no evidence of brain metastasis recurrence on may 23 , 2015 ( figure 3d ) . the patient initially required bed rest , but was able to walk unaided following afatinib treatment for 3 months . chest ct revealed a tumor located in the left lower lung and multiple interstitial infiltrations ( panels 3b and 3c ) . the findings of this case indicate the efficacy of 6 months afatinib treatment in a lung adenocarcinoma patient with a single meningeal metastasis without the development of recurrence . patient information , including names and chart numbers , were deleted for de - identification before data analyses . the design of this study was approved by the institutional review board of the chang gung medical foundation ( irb no . a 61-year - old female with pleural effusion underwent computed tomography ( ct ) on march 29 , 2015 . cellblock cytology confirmed the pulmonary lesions to be adenocarcinoma , and egfr l858r ( substitution at position 858 from a leucine to arginine ) mutation was identified . pet - mri ( positron emission tomography - magnetic resonance imaging ) revealed multiple lung , brain , bone , and liver metastases . the patient had no neurological symptoms despite multiple brain metastases observed on mri ( figure 1a  d ) . after discussions with the patient and family , treatment with afatinib , instead of erlotinib or gefitinib , was initiated . whole - brain radiotherapy was not performed because of the absence of neurological symptoms and its potential side effects . the patient received afatinib ( 40  mg / d ) from april 23 , 2015 . brain mri ( figure 1e  h ) and whole body ct showed marked regression of the brain metastatic lesions , metastatic liver nodules , and primary lung tumor on june 27 , 2015 , representing a partial response following afatinib treatment for 2 months . a good cerebral response to afatinib was observed in this case . brain mri showing multiple metastatic brain lesions in case a ( panels 1a to 1d ) . regression of multiple brain metastases was observed after treatment with afatinib for > 2 months ( panels 1e to 1h ) . the findings of this case indicate the efficacy of afatinib as a first - line treatment in selected lung adenocarcinoma patients with brain metastases and no neurological symptoms . a 52-year - old male was found to have a 2  cm nodule in the left upper lung and a brain lesion at the left periventricular region superior to left thalamus ( figure 2a and b ) . histological examination of a ct - guided biopsy of the left lung nodule showed adenocarcinoma in february 2015 . whole - brain radiotherapy was performed with a total 30 gray delivered in 10 fractions and afatinib 40  mg / d initiated following the diagnosis of lung adenocarcinoma with brain and mediastinal lymph node metastases . following treatment with afatinib for 3 months , chest ct on may 16 , 2015 , showed regression of the lung tumor and metastatic mediastinal lymph nodes . brain mri on june 24 , 2015 , showed regression of brain metastases following afatinib treatment and whole - brain radiotherapy ( figure 2c and d ) . a significant cerebral response to combined systemic treatment with afatinib and whole - brain radiotherapy was observed in this case . brain mri in case b showing brain metastases with mass effect ( panels 2a and 2b ) . marked regression of metastatic brain lesion on brain mri following brain radiotherapy and afatinib treatment for 4 months ( panels 2c and 2d ) . the findings of this case indicate the efficacy of afatinib treatment and brain radiotherapy in lung adenocarcinoma patients with brain metastases and neurological symptoms . a 55-year - old male smoker with no previous history of systemic disease was diagnosed with lung cancer . the patient reported back pain for several weeks before the development of strabismus in november 2014 . chest ct ( figure 3b and c ) and bone scanning showed the presence of a tumor in the left lower lung with multiple bone and lung - to - lung metastases . brain radiotherapy and afatinib therapy were arranged following discussions with the patient and his family . chest ct showed a partial response of the lung cancer to treatment on may 15 , 2015 ( figure 3e and f ) . brain mri found no evidence of brain metastasis recurrence on may 23 , 2015 ( figure 3d ) . the patient initially required bed rest , but was able to walk unaided following afatinib treatment for 3 months . chest ct revealed a tumor located in the left lower lung and multiple interstitial infiltrations ( panels 3b and 3c ) . the findings of this case indicate the efficacy of 6 months afatinib treatment in a lung adenocarcinoma patient with a single meningeal metastasis without the development of recurrence . patient information , including names and chart numbers , were deleted for de - identification before data analyses . the design of this study was approved by the institutional review board of the chang gung medical foundation ( irb no . our case series provides information regarding the efficacy of afatinib as a first - line treatment for lung adenocarcinoma with brain metastases and egfr mutations . the 3 cases presented herein had different clinical presentations that were largely representative of the majority of lung adenocarcinoma patients with brain metastases . the first case of a patient having a lung adenocarcinoma with multiple brain metastases , but no neurological symptoms demonstrated an excellent response to first - line afatinib treatment . the second case demonstrated a good response of primary and metastatic lesions to combined systemic afatinib treatment and brain radiotherapy in a patient with neurological symptoms . the third case demonstrated the use of first - line afatinib treatment following surgical resection of meningeal metastasis . to date , there have been no reported retrospective studies or prospective clinical trials of first - line afatinib treatment in cases of lung adenocarcinoma with brain metastases . our case series provides information regarding the efficacy of first - line afatinib in selected cases of lung adenocarcinoma with brain metastases . herein , as we report only 3 cases , further studies are required to fully demonstrate the efficacy of first - line afatinib in achieving cerebral responses . hoffknecht et al from the acuc reported a 31% cerebral response rate in patients who had received at least one cycle of chemotherapy and at least one egfr tki , providing further evidence of the efficiency of afatinib treatment in patients with brain metastases . the cerebral response rate reported by hoffknecht et al may have been higher if afatinib had been used as the first - line treatment before the development of resistance to chemotherapy and prior egfr tki therapy . the acuc study reported good cerebral responses to afatinib , although the included patients had been treated with egfr tki and chemotherapybefore afatinib treatment . our case series provides evidence of the efficacy of first - line afatinib in lung adenocarcinoma patients with brain metastases . further studies including greater numbers of patients are required to confirm our findings and provide a rationale for future prospective studies . the low cerebrospinal fluid ( csf ) concentration of reversible first - generation egfr tkis may be responsible for the high rates or recurrence and progression observed with these pharmacological agents . the higher csf concentration obtained with erlotinib led to its consideration as a treatment for brain metastases in patients with egfr - mutated lung cancer . pulsed high doses of egfr tkis are recommended in lung adenocarcinoma patients with resistance to previous egfr tki therapy , although there is a lack of clinical trials providing evidence to support this recommendation . afatinib has been shown to have a lower ic50 than the reversible first - generation egfr tki in in vitro studies . a concentration of 1  nm is higher than the ic50 for lung cancer cell lines with egfr l858r mutation or deletion of egfr exon 19 . the second patient received afatinib 50  mg / d as a third - line treatment . the dose was increased to 60  mg / d at 9 months and then 70  mg / d at 12 months . the patient had rapid progression following 6 months of afatinib 70  mg / d and received afatinib treatment for a total of 16 months . the subgroup analyses of patients with brain metastases in the acuc study provided evidence of the efficacy of afatinib in the treatment of brain metastases from lung adenocarcinoma . the lux - lung 3 and lux - lung 6 studies reported increased pfs compared with previous clinical trials of first - generation reversible egfr tkis . a lack of studies of afatinib , a newly approved egfr tki for lung cancer , in lung cancer patient with brain metastases has limited the clinical application of afatinib in these patients . the acuc study and a small number of case reports have demonstrated the efficacy of afatinib in lung cancer patients with resistance to reversible egfr tkis . afatinib may have similar or greater efficacy in the treatment of metastatic brain lesions in patients with lung adenocarcinoma . the findings of the 3 clinical cases presented herein indicate afatinib may represent an efficacious first - line treatment for patients with brain metastases from lung adenocarcinoma . the combination of afatinib with radiotherapy or surgery may provide better control of brain metastases from lung adenocarcinoma . metastasectomy of solitary brain metastases resulted in better or the same survival in a number of studies of erlotinib . the third case in this series had no recurrence of meningeal metastasis following surgery and afatinib treatment . combination of surgery and afatinib may represent a valid option in select patients with solitary brain metastasis . the addition of erlotinib to whole - brain radiotherapy has been shown to result in similar response rates but reduced recurrence of brain metastases . a proportion of patients with brain metastases and no neurological symptoms receive egfr tki alone due to the side effects of whole - brain radiotherapy . the first case in this series had no neurological symptoms from multiple brain metastases and had a good cerebral response to afatinib alone . the second case in the present series had developed seizures and received whole - brain radiotherapy and afatinib treatment accordingly . brain mri in these cases showed a good response to combination of afatinib and radiotherapy . depending on the results of clinical trials or case reports of the use of erlotinib and afatinib , afatinib plus brain radiotherapy or surgery may represent a reasonable choice in the treatment of egfr - mutated lung cancer with brain metastases . afatinib has efficacy in the treatment of egfr - mutated lung adenocarcinoma with brain metastases . the acuc study proved a role for afatinib in the treatment of brain metastases from lung adenocarcinoma in patients with resistance to prior egfr tki therapy and chemotherapy . the findings of this case series indicate the use of afatinib alone or in combination with radiotherapy or surgery has efficacy in a range of clinical presentations of egfr - mutated lung adenocarcinoma with brain metastases .
abstracttyrosine kinase inhibitors ( tkis ) of epidermal growth factor receptor ( egfr ) were previously the standard first - line treatments for lung cancers with activating egfr mutations . 
 the first - generation reversible egfr tkis , gefitinib and erlotinib , demonstrated substantial efficacy in the treatment of brain metastases from egfr - mutated lung adenocarcinoma . 
 however , the efficacy of afatinib , the second - generation irreversible egfr tki , as the first - line treatment in lung adenocarcinoma patients with brain metastasis has yet to be evaluated.here , we report cases of 3 patients who received afatinib alone as the first - line treatment in combination with whole - brain radiotherapy or following surgical resection of brain metastases . 
 all 3 patients had egfr l858r mutation . the first patient had lung adenocarcinoma with brain metastasis and no neurologic symptoms . 
 after consultation , she received afatinib as a first - line treatment . 
 chest computed tomography and brain magnetic resonance imaging ( mri ) showed partial response . 
 the second patient had lung adenocarcinoma accompanied with a metastatic brain lesion associated with seizures . 
 this patient received whole - brain radiotherapy and afatinib treatment following brain mri and subsequently showed significant regression of the brain metastasis . 
 the third patient had strabismus of the right eye , and brain mri showed a single tumor at the cerebellar pontine angle . 
 this patient underwent surgical resection of the tumor followed by afatinib treatment . 
 he refused adjuvant radiotherapy after surgery for brain metastasis . 
 the brain mri showed no recurrent brain metastasis , and the patient had relatively less neurologic deficiency.this series of 3 cases indicate that afatinib may be an appropriate first - line treatment alternative in patients having lung adenocarcinoma with egfr mutations . 
 further retrospective analyses and prospective clinical trials are required to substantiate the efficacy of afatinib in the treatment of brain metastases of lung adenocarcinoma .