erlotinib ( 150 mg , once daily ) was given to a 60-year - old non - smoking man who was diagnosed with stage iv lung adenocarcinoma with unknown status of egfr mutation after failing to respond to the first - line chemotherapy with pemetrexed 500 mg / m and cisplatin 75 mg / m ( every 3 weeks for 4 cycles ) in september 2009 ( fig . partial remission was revealed by a chest computed tomography ( ct ) in october 2009 ( fig . 1b ) with limited grade ii rash , and stable disease was confirmed by a follow - up chest ct until the progression of the disease shown in january 2010 with a ps score 1 ( fig . therefore , sorafenib ( 400 mg twice daily ) was added to his treatment with erlotinib as a salvage therapy after a complete informed consent had been obtained on january 29 , 2010 . gradual aggravation with symptoms of cough , dyspnea , fever and fatigue was observed 2 weeks after the initiation of the combination treatment ; however , the patient insisted and came back to the hospital until march 9 , 2010 . a chest ct scan the 2nd day after his hospitalization revealed a great mass in the lower lobe of the right lung with atelectasis , obstructive pneumonia and multiple patchy ground - glass opacities in the left lung ( fig . arterial blood gas measurements at a cardiac output of 8 l / min revealed a ph of 7.50 , paco2 of 32 mm hg , pao2 of 55 mm hg , hco3 of 25 mmol / l and base excess of 3.4 mmol / l . a clinical and radiological diagnosis of ild although treatment with supplemental oxygen , methylprednisolone , antibiotics ( meropenem ) and best supportive care was initiated immediately , the patient 's condition deteriorated and he died on march 25 , 2010 . . however , discontinuation of tkis after disease progression may result in a disease flare - up . unfortunately , he died 8 weeks after the initiation of the combination treatment due to a fatal ild . however , the pharmacokinetics of sorafenib may not be affected by the coadministration of erlotinib , while the clearance of erlotinib may be enhanced by concomitant sorafenib [ 2 , 8 ] . moreover , the median time to the onset of ild induced by erlotinib is 47 days ( range from 5 days to 9 months ) , while the overall peak time to onset of sorafenib - induced ild is 24 weeks . so , we conclude that ild occurred after the addition of sorafenib but not during the previous treatment course with erlotinib . to our knowledge , this is the first report on sorafenib - induced fatal ild in a patient with nsclc and living outside japan . there are no specific and effective treatments for ild except for immediate discontinuation of the suspected drug and empirical corticosteroid treatment with early recognition of the disease . without early awareness of ild , the clinical signs of ild are not observed until 7 weeks later , after a chest ct scan ; however , this was too late in our case to improve the syndrome of ild . we should be aware of this high - mortality ae and seek its early detection in order to avoid a severe course of ild leading to a decrease in the ild mortality rate . risk factors of developing egfr tki - induced ild include male sex , smoking , a poor ps and the existence of pulmonary fibrosis [ 4 , 5 ] . in our case , the patient had a good ps and no pulmonary fibrosis or smoking history , and grade ii rash was the only ae during the period of erlotinib administration . further investigation of the exact mechanism and the risk factors of developing sorafenib - induced ild is warranted .
interstitial lung disease ( ild ) induced by epidermal growth factor receptor tyrosine kinase inhibitors has been extensively documented with decreasing incidence after appropriate patient selection due to increasing awareness over the years . 
 however , ild induced by sorafenib was mentioned with lower frequency only in patients with hepatocellular and renal cell carcinoma living in japan but not in patients with other carcinomas or living outside japan , and it has been overlooked in clinical practice . in the present case , sorafenib was added to the treatment of a 60-year - old non - smoking patient with non - small cell lung cancer ( nsclc ) . 
 after his failing to improve with erlotinib alone , erlotinib was continued to be given in combination with sorafenib as a salvage therapy . 
 although clinical signs of ild were observed 2 weeks after the addition of sorafenib , the radiological diagnosis of ild was only made 41 days after the initiation of the combination treatment , and the patient died 56 days after treatment onset . 
 it was concluded that ild was indeed induced by sorafenib . 
 this is the first report of ild induced by sorafenib in a patient with nsclc living outside japan . 
 oncologists should be aware of this fatal complication for its early detection in order to avoid a severe course of ild leading to a decrease in the ild mortality rate .