***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Previous , uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer . METHODS In this phase 3 , open-label study , we r and omly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib ( 250 mg per day ) ( 609 patients ) or carboplatin ( at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute ) plus paclitaxel ( 200 mg per square meter of body-surface area ) ( 608 patients ) . The primary end point was progression-free survival . RESULTS The 12-month rates of progression-free survival were 24.9 % with gefitinib and 6.7 % with carboplatin-paclitaxel . The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority , as compared with carboplatin-paclitaxel , with respect to progression-free survival in the intention-to-treat population ( hazard ratio for progression or death , 0.74 ; 95 % confidence interval [ CI ] , 0.65 to 0.85 ; P<0.001 ) . In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene ( EGFR ) mutation , progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel ( hazard ratio for progression or death , 0.48 ; 95 % CI , 0.36 to 0.64 ; P<0.001 ) , whereas in the subgroup of 176 patients who were negative for the mutation , progression-free survival was significantly longer among those who received carboplatin-paclitaxel ( hazard ratio for progression or death with gefitinib , 2.85 ; 95 % CI , 2.05 to 3.98 ; P<0.001 ) . The most common adverse events were rash or acne ( in 66.2 % of patients ) and diarrhea ( 46.6 % ) in the gefitinib group and neurotoxic effects ( 69.9 % ) , neutropenia ( 67.1 % ) , and alopecia ( 58.4 % ) in the carboplatin-paclitaxel group . CONCLUSIONS Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia . The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib . ( Clinical Trials.gov number , NCT00322452 . Purpose : The ISTANA ( IRESSA as Second-line Therapy in Advanced NSCLC — KoreA ) study compared gefitinib with docetaxel in patients with advanced or metastatic non – small cell lung carcinoma ( NSCLC ) pretreated with platinum-based chemotherapy . Experimental Design : We conducted a multicenter , r and omized , open-label phase III trial of gefitinib ( 250 mg/d ) versus docetaxel ( 75 mg/m2 day 1 every 3 weeks ) in patients with advanced or metastatic NSCLC treated with one previous platinum-based chemotherapy . The primary endpoint was progression-free survival . Results : A total of 161 patients ( male , 62 % ; never smoker , 41 % ; adenocarcinoma , 68 % ) were enrolled .  Progression-free survival was longer for gefitinib compared with docetaxel ( hazard ratio , 0.729 ; 90 % confidence interval , 0.533 - 0.998 ; one-sided P = 0.0441 ) . Gefitinib significantly improved objective response rate ( 28.1 % versus 7.6 % ; two-sided P = 0.0007 ) . In the final analysis of overall survival , the hazard ratio was 0.870 ( 95 % confidence interval , 0.613 - 1.236 ; two-sided P = 0.4370 ) . No significant differences were seen in the quality of life or symptom improvement rates between the two treatment groups . Gefitinib was well tolerated , was consistent with previous data and disease , and had fewer serious adverse events and fewer Common Terminology Criteria for Adverse Events grade 3 or 4 adverse events than docetaxel . The incidence of interstitial lung disease – type events was 3.7 % ( n = 3 ) with gefitinib and 3.9 % ( n = 3 ) with docetaxel . Conclusions : The primary endpoint of progression-free survival was longer with gefitinib than docetaxel , and the secondary endpoints showed superior objective response rate , good tolerability , and similar quality of life improvement rates for gefitinib than docetaxel . Therefore , gefitinib is an important valid treatment option for second-line therapy for Korean NSCLC patients . Clin Cancer Res ; 16(4 ) ; PURPOSE To evaluate the efficacy and tolerability of two doses of gefitinib ( Iressa [ ZD1839 ] ; AstraZeneca , Wilmington , DE ) , a novel epidermal growth factor receptor tyrosine kinase inhibitor , in patients with pretreated advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS This was a r and omized , double-blind , parallel-group , multicenter phase II trial . Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens ( at least one containing platinum )  were r and omly assigned to receive either 250-mg or 500-mg oral doses of gefitinib once daily . RESULTS Efficacy was similar for the 250- and 500-mg/d groups . Objective tumor response rates were 18.4 % ( 95 % confidence interval [ CI ] , 11.5 to 27.3 ) and 19.0 % ( 95 % CI , 12.1 to 27.9 ) ; among evaluable patients , symptom improvement rates were 40.3 % ( 95 % CI , 28.5 to 53.0 ) and 37.0 % ( 95 % CI , 26.0 to 49.1 ) ; median progression-free survival times were 2.7 and 2.8 months ; and median overall survival times were 7.6 and 8.0 months , respectively . Symptom improvements were recorded for 69.2 % ( 250 mg/d ) and 85.7 % ( 500 mg/d ) of patients with a tumor response . Adverse events ( AEs ) at both dose levels were generally mild ( grade 1 or 2 ) and consisted mainly of skin reactions and diarrhea . Drug-related toxicities were more frequent in the higher-dose group . Withdrawal due to drug-related AEs was 1.9 % and 9.4 % for patients receiving gefitinib 250 and 500 mg/d , respectively . CONCLUSION Gefitinib showed clinical ly meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients . At 250 mg/d , gefitinib had a favorable AE profile . Gefitinib 250 mg/d is an important , novel treatment option for patients with pretreated advanced NSCLC [ corrected PURPOSE The purpose of this study was to determine whether the addition of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ( Iressa , ZD1839 ; AstraZeneca , Wilmington , DE ) to st and ard first-line gemcitabine and cisplatin provides clinical benefit over gemcitabine and cisplatin alone in patients with advanced or metastatic non-small-cell lung cancer ( NSCLC ) .  Gefitinib has demonstrated encouraging efficacy in advanced NSCLC in phase II trials in pretreated patients , and a phase I trial of gefitinib in combination with gemcitabine and cisplatin showed favorable tolerability . PATIENTS AND METHODS This was a phase III r and omized , double-blind , placebo-controlled , multicenter trial in chemotherapy-naive patients with unresectable stage III or IV NSCLC . All patients received up to six cycles of chemotherapy ( cisplatin 80 mg/m(2 ) on day 1 and gemcitabine 1,250 mg/m(2 ) on days 1 and 8 of the 3-week cycle ) plus either gefitinib 500 mg/d , gefitinib 250 mg/d , or placebo . Daily gefitinib or placebo was continued until disease progression . End points included overall survival ( primary ) , time to progression , response rates , and safety evaluation . RESULTS A total of 1,093 patients were enrolled . There was no difference in efficacy end points between the treatment groups : for the gefitinib 500 mg/d , gefitinib 250 mg/d , and placebo groups , respectively , median survival times were 9.9 , 9.9 , and 10.9 months ( global ordered log-rank [ GOLrank ] P = .4560 ) , median times to progression were 5.5 , 5.8 , and 6.0 months ( GOLrank ; P = .7633 ) , and response rates were 49.7 % , 50.3 % , and 44.8 % . No significant unexpected adverse events were seen . CONCLUSION Gefitinib in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced NSCLC did not have improved efficacy over gemcitabine and cisplatin alone . The reasons for this remain obscure and require further pre clinical testing On November 18 , 2004 , erlotinib ( Tarceva ) ; OSI Pharmaceuticals , Inc. , Melville , NY , http://www.osip.com , and Genentech , Inc. , South San Francisco , CA , http://www.gene.com ) received regular approval as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer ( NSCLC ) after failure of at least one prior chemotherapy regimen .  Survival of erlotinib-treated  patients was superior to that of placebo-treated patients . The median survival duration of erlotinib-treated patients was 6.67 months , compared with 4.70 months for placebo-treated patients . Exploratory univariate analyses showed a larger survival prolongation in two subsets of patients : those who never smoked and those with epidermal growth factor receptor (EGFR)-positive tumors . Patients who never smoked and were EGFR-positive had a large erlotinib survival benefit . Erlotinib was also superior to placebo for progression-free survival and a response rate of 8.9 % versus 0.9 % . Skin rash and diarrhea were the most common erlotinib adverse events . Severe rash occurred in 8 % , and severe diarrhea occurred in 6 % of erlotinib-treated patients . In the first-line treatment of NSCLC , two large , controlled , r and omized trials showed no benefit from adding erlotinib to doublet , platinum-based chemotherapy . Therefore , erlotinib is not indicated for use in this setting CONTEXT More persons in the United States die from non-small cell lung cancer ( NSCLC ) than from breast , colorectal , and prostate cancer combined . In pre clinical testing , oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor ( EGFR ) , a mediator of cell signaling , and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib . OBJECTIVE To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib .  DESIGN , SETTING , AND PATIENTS Double-blind , r and omized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers . Patients ( N = 221 ) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens . INTERVENTION Daily oral gefitinib , either 500 mg ( administered as two 250-mg gefitinib tablets ) or 250 mg ( administered as one 250-mg gefitinib tablet and 1 matching placebo ) . MAIN OUTCOME MEASURES Improvement of NSCLC symptoms ( 2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [ FACT-L ] instrument ) and tumor regression ( > 50 % decrease in lesion size on imaging studies ) . RESULTS Of 221 patients enrolled , 216 received gefitinib as r and omized . Symptoms of NSCLC improved in 43 % ( 95 % confidence interval [ CI ] , 33%-53 % ) of patients receiving 250 mg of gefitinib and in 35 % ( 95 % CI , 26%-45 % ) of patients receiving 500 mg . These benefits were observed within 3 weeks in 75 % of patients . Partial radiographic responses occurred in 12 % ( 9 
    Output:
    
Treatment with EGFR TKIs gefitinib and erlotinib is associated with a significant increase in the risk of developing both all- grade and fatal ILD events in advanced NSCLC