***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: MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors . We demonstrate that MET activation by its lig and , HGF , also induces drug resistance , but through GAB1 signaling . Using high-throughput FISH analyses in both cell lines and in patients with lung cancer , we identify sub population s of cells with MET amplification prior to drug exposure . Surprisingly , HGF accelerates the development of MET amplification both in vitro and in vivo . EGFR kinase inhibitor resistance , due to either MET amplification or autocrine HGF production , was cured in vivo by combined EGFR and MET inhibition . These findings highlight the potential to prospect ively identify treatment naive , patients with EGFR-mutant lung cancer who will benefit from initial combination therapy PURPOSE V and etanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor ( VEGFR ) and epidermal growth factor receptor ( EGFR ) signaling . In this two-part phase II study , the efficacy and safety of v and etanib was compared with that of gefitinib , an inhibitor of EGFR signaling . PATIENTS AND METHODS Patients ( N = 168 ) with locally advanced or metastatic ( stage IIIB/IV ) non-small-cell lung cancer ( NSCLC ) , after failure of first-line with or without second-line platinum-based chemotherapy  , received once-daily v and etanib 300 mg ( n = 83 ) or gefitinib 250 mg ( n = 85 ) until disease progression or evidence of toxicity ( part A ) . After a 4-week washout period , eligible patients had the option to switch to the alternative treatment ( part B ) . Progression-free survival ( PFS ) was the primary efficacy assessment in part A , which was design ed to have a higher than 75 % power to detect a 33 % prolongation of PFS at a one-sided significance level of .2 . RESULTS In part A , v and etanib  prolonged PFS compared with gefitinib ( hazard ratio = 0.69 ; 95 % CI , 0.50 to 0.96 ; one-sided P = .013 ) . Patients receiving v and etanib experienced adverse events that were manageable and generally consistent with inhibition of EGFR and VEGFR signaling , including diarrhea , rash , and hypertension . There were no unexpected safety findings with gefitinib . Overall survival , a secondary assessment , was not significantly different between patients initially r and omly assigned to either v and etanib or gefitinib . CONCLUSION The primary efficacy objective was achieved , with v and etanib demonstrating a significant prolongation of PFS versus gefitinib . V and etanib 300 mg/d is currently being evaluated as a monotherapy in two r and omized phase III studies in advanced NSCLC BACKGROUND Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles . On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer ( NSCLC ) , we aim ed to assess efficacy and safety of this combination in a phase 3 trial . METHODS In our double-blind , placebo-controlled , r and omised phase 3 trial ( BeTa ) , we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment . Patients were r and omly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab ( bevacizumab group ) or erlotinib plus placebo ( control group ) according to a computer-generated r and omisation sequence by use of an interactive voice response system . The primary endpoint was overall survival in all enrolled patients . Patients , study staff , and investigators were masked to treatment assignment . We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses . This trial is registered with Clinical Trials.gov , number NCT00130728 . FINDINGS Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group ( hazard ratio [ HR ] 0·97 , 95 % CI 0·80 - 1·18 , p=0·7583 ) . Median overall survival was 9·3 months ( IQR 4·1 - 21·6 ) for patients in the bevacizumab group compared with 9·2 months ( 3·8 - 20·2 ) for controls . Progression-free survival seemed to be longer in the bevacizumab group ( 3·4 months [ 1·4 - 8·4 ] ) than in the control group ( 1·7 months [ 1·3 - 4·1 ] ; HR 0·62 , 95 % CI 0·52 - 0·75 ) and objective response rate suggested some clinical activity of bevacizumab and erlotinib . However , these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done , to control type I error rate . In the bevacizumab group , 130 ( 42 % ) of 313 patients with safety  data had a serious adverse event , compared with 114 ( 36 % ) controls . There were 20 ( 6 % ) grade 5 adverse events , including two arterial thromboembolic events , in the bevacizumab group , and 14 ( 4 % ) in the control group . INTERPRETATION Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC . FUNDING Genentech PURPOSE Bevacizumab , a humanized anti-vascular endothelial growth factor monoclonal antibody , and erlotinib , a reversible , orally available epidermal growth factor receptor tyrosine kinase inhibitor , have demonstrated evidence of a survival benefit in the treatment of non-small-cell lung cancer ( NSCLC ) . A single-arm phase I and II study of bevacizumab plus erlotinib demonstrated encouraging efficacy , with a favorable safety profile . PATIENTS AND METHODS A multicenter , r and omized phase II trial evaluated the safety of combining bevacizumab with either chemotherapy ( docetaxel or pemetrexed ) or erlotinib and preliminarily assessed these combinations versus chemotherapy alone , as measured by progression-free survival ( PFS ) .  All patients had histologically confirmed nonsquamous NSCLC that had progressed during or after one platinum-based regimen . RESULTS One hundred twenty patients were r and omly assigned and treated . No unexpected adverse events were noted . Fewer patients ( 13 % ) in the bevacizumab-erlotinib arm discontinued treatment as a result of adverse events than in the chemotherapy alone ( 24 % ) or bevacizumab-chemotherapy ( 28 % ) arms . The incidence of grade 5 hemorrhage in patients receiving bevacizumab was 5.1 % . Although not statistically significant , relative to chemotherapy alone , the risk of disease progression or death was 0.66 ( 95 % CI , 0.38 to 1.16 ) among patients treated with bevacizumab-chemotherapy and 0.72 ( 95 % CI , 0.42 to 1.23 ) among patients treated with bevacizumab-erlotinib .  One-year survival rate was 57.4 % for bevacizumab-erlotinib and 53.8 % for bevacizumab-chemotherapy compared with 33.1 % for chemotherapy alone . CONCLUSION Results for PFS and overall survival favor combination of bevacizumab with either chemotherapy or erlotinib over chemotherapy alone in the second-line setting . No unexpected safety signals were noted . The rate of fatal pulmonary hemorrhage was consistent with previous bevacizumab trials . The toxicity profile of the bevacizumab-erlotinib combination is favorable compared with either chemotherapy-containing group BACKGROUND Bevacizumab , a monoclonal antibody against vascular endothelial growth factor , has been shown to benefit patients with a variety of cancers . METHODS Between July 2001 and April 2004 , the Eastern Cooperative Oncology Group ( ECOG ) conducted a r and omized study in which 878 patients with recurrent or advanced non-small-cell lung cancer ( stage IIIB or IV ) were assigned to chemotherapy with paclitaxel and carboplatin alone ( 444 ) or paclitaxel and carboplatin plus bevacizumab ( 434 ) . Chemotherapy was administered every 3 weeks for six cycles , and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable . Patients with squamous-cell tumors , brain metastases , clinical ly significant hemoptysis , or inadequate organ function or performance status ( ECOG performance status , > 1 ) were excluded . The primary end point was overall survival . RESULTS The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab , as compared with 10.3 months in the chemotherapy-alone group ( hazard ratio for death , 0.79 ; P=0.003 ) . The median progression-free survival in the two groups was 6.2 and 4.5 months , respectively ( hazard ratio for disease progression , 0.66 ; P<0.001 ) , with corresponding response rates of 35 % and 15 % ( P<0.001 ) . Rates of clinical ly significant bleeding were 4.4 % and 0.7 % , respectively ( P<0.001 ) . There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group , including 5 from pulmonary hemorrhage . CONCLUSIONS The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths . ( Clinical Trials.gov number , NCT00021060 . Background : Sunitinib malate ( SUTENT ) has promising single-agent activity given on Schedule 4/2 ( 4 weeks on treatment followed by 2 weeks off treatment ) in advanced non-small cell lung cancer ( NSCLC ) . Methods : We examined the activity of sunitinib on a continuous daily dosing ( CDD ) schedule in an open-label , multicentre phase II study in patients with previously treated , advanced NSCLC . Patients ⩾18 years with stage IIIB/IV NSCLC after failure with platinum-based chemotherapy , received sunitinib 37.5 mg per day . The primary end point was objective response rate ( ORR ) . Secondary end points included progression-free survival ( PFS ) , overall survival ( OS ) , 1-year survival rate , and safety . Results : Of 47 patients receiving sunitinib , one patient achieved a confirmed partial response ( ORR 2.1 % ( 95 % confidence interval ( CI ) 0.1 , 11.3 ) ) and 11 ( 23.4 % ) had stable disease ( SD ) ⩾8 weeks . Five patients had SD>6 months . Median PFS was 11.9 weeks ( 95 % CI 8.6 , 14.1 ) and median OS was 37.1 weeks ( 95 % CI 31.1 , 69.7 ) . The 1-year survival probability was 38.4 % ( 95 % CI 24.2 , 52.5 ) . Treatment was generally well tolerated . Conclusions : The safety profile and time-to-event analyses , albeit relatively low response rate of 2 % , suggest single-agent sunitinib on a CDD schedule may be a potential therapeutic agent for patients with advanced , refractory NSCLC 3549 Background : ARQ197 ( A ) is a selective , non-ATP competitive inhibitor of c-Met , a receptor tyrosine kinase implicated in tumor cell migration , invasion , and proliferation . Phase I data for ARQ 197 monotherapy is previously reported . Recent evidence suggests c-Met promotes resistance to EGFR-inhibition by driving ERBB3 (HER3)-dependent PI3 K activation . Dual EGFR-Met inhibition is now proposed as a strategy for overcoming resistance to EGFR-inhibition . METHODS Patients ( pts ) were enrolled in a sequential-cohort dose-escalation trial seeking to define safety , tolerability , pharmacokinetics ( PK ) , and preliminary anti-tumor activity of A in combination with 150 mg daily oral erlotinib ( E ) . Oral A was administered at escalating doses of 120 , 240 , and 360 mg bid . Intra-patient dose escalation was allowed in the absence of dose-limiting toxicity ( DLT ) through 1 cycle of therapy ( 21 days ) . RESULTS 25 pts ( 10 F/15 M ; mean 60.5 yrs ) received EA combination with starting A dose of 120 ( 8 pts ) , 240 ( 4 pts ) , and 360 ( 13 pts ) mg bid . PK data reveal linear kinetics through 360 bid and no evidence of drug-drug 
    Output:
    
Compared with single-agent erlotinib , doublets ( erlotinib plus another targeted agent ) significantly improve ORR and DCR , but not OS , and induce no significance of more frequent and serious AEs .
The benefit-to-risk ratio of doublets in advanced NSCLC may be more favorable than that of single-agent .
The results of this systematic review suggest that patients with advanced NSCLC might benefit from doublet-targeted therapy based on erlotinib compared to erlotinib alone .