***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: PURPOSE In non-small-cell lung cancer ( NSCLC ) , clinical and biologic predictors for epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor sensitivity have been identified in retrospective studies , and there is urgent need to vali date these results in prospect i ve trials . The ONCOBELL trial is a prospect i ve phase II study evaluating gefitinib sensitivity in NSCLC patients who never smoked or have increased EGFR gene copy number or activation of the antiapoptotic protein Akt . PATIENTS AND METHODS EGFR gene copy number was evaluated using fluorescence in situ hybridization ( FISH ) , and presence of phospho-Akt was evaluated using immunohistochemistry . Additional tests included immunohistochemistry analysis of EGFR , FISH analysis of HER2 , and mutation analysis of EGFR , HER2 , and K-ras . RESULTS From November 2004 to February 2006 , 183 patients were screened , and 42 patients were enrolled onto the trial . We observed one complete and 19 partial responses , for an overall response rate ( RR ) of 47.6 % ( 95 % CI , 32.5 % to 62.7 % ) . Median duration of response was 6.1 months , median time to progression ( TTP ) was 6.4 months , 1-year survival rate was 64.3 % , and median survival time was not reached . EGFR FISH-positive patients , compared with negative patients , had higher RR ( 68.0 % v 9.1 % , respectively ; P < .001 ) , longer TTP ( 7.6 v 2.7 months , respectively ; P = .02 ) , and a trend for longer survival ( median survival not reached v 7.4 months , respectively ; P = .3 ) . Therapy was well tolerated , and there were no drug-related deaths . Median follow-up time was too short for significance tests of differences in survival outcomes . CONCLUSION Gefitinib is active and well tolerated in patients with trial characteristics , and EGFR FISH analysis is an accurate predictor for such therapy Lung adenocarcinomas responsive to epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors  possess EGFR mutations and often increased EGFR copy number . We prospect ively studied 334 clinical cases using polymerase chain reaction-based assays to detect deletions within exon 19 and the L858R mutation in exon 21 , which together account for approximately 90 % of EGFR mutations . Seventy-eight ( 23 % ) of these tumors had an EGFR mutation , with 55 ( 71 % ) exon 19 deletions and 23 ( 29 % ) exon 21 L858R mutations . We were able to compare mutant and normal EGFR alleles and found a preferential amplification of the mutant allele . The association of mutations with EGFR amplification ( determined by chromogenic in situ hybridization ) and EGFR expression ( determined by immunohistochemistry ) was further examined in a subset of 60 tumors .  EGFR amplification ( > or = 5 EGFR signals per nucleus ) was seen in 15 of 29 ( 52 % ) EGFR-mutated tumors but in only five of 31 ( 6 % ) non-mutated tumors ( P = 0.006 ) . EGFR overexpression was strongly associated with amplification but was statistically independent of EGFR mutation .  Most patients with EGFR mutations ( 17 of 29 , 59 % ) never smoked compared with 13 % ( four of 31 ) of patients lacking such mutations ( P = 0.0003 ) . The association of amplification with smoking status was marginal and was nonexistent with EGFR expression . Thus , these results indicate that EGFR amplification , preferentially of the mutant allele , often accompanies EGFR mutation , whereas EGFR immunohistochemical staining associates with amplification but can not predict EGFR mutation status 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 September 27 , 2006 , the U.S. Food and Drug Administration granted approval to panitumumab ( Vectibix , Amgen , Inc. , Thous and Oaks , CA ) for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing , metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine- , oxaliplatin- , and irinotecan-containing chemotherapy regimens . Panitumumab approval is based on the results of a single , open-label , r and omized , multinational study that enrolled 463 patients with EGFR-expressing ( at least 1 + membrane staining in > or = 1 % of tumor cells ) metastatic colorectal cancer . Patients were r and omized to either best supportive care ( BSC ) alone or BSC plus panitumumab  , 6 mg/kg i.v . , every other week . The primary study endpoint was progression-free survival ( PFS ) , determined by an independent review committee that was blinded as to treatment assignment . BSC patients who progressed were eligible to receive panitumumab .  The study patients ' median age was 62 years , with 40 % aged > or = 65 ; 63 % were male , 99 % were white , 86 % had a baseline Eastern Cooperative Oncology Group performance status score of 0 or 1 , and 67 % had colon cancer . The median time from diagnosis of metastases was approximately 19 months and the median number of prior therapies was 2.4 . The PFS duration was significantly longer among patients r and omized to receive panitumumab in addition to BSC ( n = 231 ) compared with BSC alone ( n = 232 ) . The median and mean PFS times were 56 and 96.4 days , respectively , for patients receiving panitumumab and 51 and 59.7 days , respectively , for patients receiving BSC alone . Nineteen partial responses ( 8 % , 95 % confidence interval [ CI ] , 5.3%-12.5 % ) were observed in panitumumab treated patients . The median duration of response was 17 weeks ( 95 % CI , 16 - 25 weeks ) . Approximately 75 % of patients in the BSC alone arm crossed over to receive panitumumab after disease progression . There was no difference in overall survival between the two study arms . The most common adverse events were skin rash , hypomagnesemia , paronychia , fatigue , abdominal pain , nausea , and diarrhea . The most serious adverse events were pulmonary fibrosis , severe dermatologic toxicity complicated by infectious sequelae and septic death , infusion reactions , abdominal pain , hypomagnesemia , nausea , vomiting , diarrhea , and constipation 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  
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EGFR gene gain was also associated with response to TKIs , albeit with lower sensitivity and specificity .
In subgroup analysis , the only recognized trend was for a higher predictive value in Whites compared with East Asians for both mutation and gene copy number .
CONCLUSION This analysis provides empirical evidence that EGFR mutations are sensitive and specific predictors of response to single-agent epidermal growth factor receptor TKIs in advanced NSCLC .
The diagnostic performance of mutations seems better than that of EGFR gene gain