***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 Bevacizumab ( Avastin ; Genentech , South San Francisco , CA ) is a recombinant , humanized anti-vascular endothelial growth factor monoclonal antibody . Erlotinib HCl ( Tarceva , OSI-774 ; OSI Pharmaceuticals , New York , NY ) is a potent , reversible , highly selective and orally available HER-1/epidermal growth factor receptor tyrosine kinase inhibitor . Pre clinical data in various xenograft models produced greater growth inhibition than with either agent alone . Additionally , both agents have demonstrated benefit in patients with previously treated non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS A phase I/II study in two centers examined erlotinib and bevacizumab ( A+T ) in patients with nonsquamous stage IIIB/IV NSCLC with > or = one prior chemotherapy .  In phase I , erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days was established as the phase II dose , although no dose-limiting toxicities were observed . Phase II assessed the efficacy and tolerability of A+T at this dose . Pharmacokinetic parameters were evaluated . Results Forty patients were enrolled and treated in this study ( 34 patients at phase II dose ) ; the median age was 59 years ( range , 36 to 72 years ) , 21 were female , 30 had adenocarcinoma histology , nine were never-smokers , and 22 had > or = two prior regimens ( three patients had > or = four prior regimens ) . The most common adverse events were mild to moderate rash , diarrhea , and proteinuria . Preliminary data showed no pharmacokinetic interaction between A + T. Eight patients ( 20.0 % ; 95 % CI , 7.6 % to 32.4 % ) had partial responses and 26 ( 65.0 % ; 95 % CI , 50.2 % to 79.8 % ) had stable disease as their best response . The median overall survival for the 34 patients treated at the phase II dose was 12.6 months , with progression-free survival of 6.2 months . CONCLUSION Encouraging antitumor activity and safety of A + T support further development of this combination for patients with advanced NSCLC and other solid tumors 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 BACKGROUND With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) , median progression-free survival has been extended to about 12 months . Nevertheless , new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population . We aim ed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease . METHODS In this open-label , r and omised , multicentre , phase 2 study , patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations , Eastern Cooperative Oncology Group performance status 0 or 1 , and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity . The primary endpoint was progression-free survival , as determined by an independent review committee . R and omisation was done with a dynamic allocation method , and the analysis used a modified intention-to-treat approach , including all patients who received at least one dose of study treatment and had tumour assessment at least once after r and omisation . This study is registered with the Japan Pharmaceutical Information Center , number JapicCTI-111390 . FINDINGS Between Feb 21 , 2011 , and March 5 , 2012 , 154 patients were enrolled . 77 were r and omly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone , of whom 75 patients in the erlotinib plus bevacizumab  group and 77 in the erlotinib alone group were included in the efficacy analyses . Median progression-free survival was 16·0 months ( 95 % CI 13·9 - 18·1 ) with erlotinib plus bevacizumab and 9·7 months ( 5·7 - 11·1 ) with erlotinib alone ( hazard ratio 0·54 , 95 % CI 0·36 - 0·79 ; log-rank test p=0·0015 ) . The most common grade 3 or worse adverse events were rash ( 19 [ 25 % ] patients in the erlotinib plus bevacizumab group vs 15 [ 19 % ] patients in the erlotinib alone group ) , hypertension ( 45 [ 60 % ] vs eight [ 10 % ] ) , and proteinuria ( six [ 8 % ] vs none ) . Serious adverse events occurred at a similar frequency in both groups ( 18 [ 24 % ] patients in the erlotinib plus bevacizumab group and 19 [ 25 % ] patients in the erlotinib alone group ) . INTERPRETATION Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC . Further investigation of the regimen is warranted . FUNDING Chugai Pharmaceutical Co 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 Pre clinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor , EGFR antibody , and /or anti-angiogenic agent is synergistic in animal models . METHODS We conducted a dose-escalation , phase I study combining erlotinib , cetuximab , and bevacizumab . The subset of patients with non-small cell lung cancer ( NSCLC ) was analyzed for safety and response . RESULTS Thirty-four patients with NSCLC ( median four prior therapies ) received treatment on a range of dose levels . The most common treatment-related grade ≥2 adverse events were rash ( n=14 , 41 % ) , hypomagnesemia ( n=9 , 27 % ) , and fatigue ( n=5 , 15 % ) . Seven patients ( 21 % ) achieved stable disease ( SD ) ≥6 months , two achieved a partial response ( PR ) ( 6 % ) , and two achieved an unconfirmed partial response ( uPR ) ( 6 % ) ( total=32 % ) . We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and /or bevacizumab , those with brain metastases , smokers , and patients treated at lower dose levels . Five of 16 patients ( 31 % ) with wild-type EGFR experienced SD≥6 months or uPR . Correlation between grade of rash and rate of SD≥6 months/PR was observed ( p<0.01 ) . CONCLUSION The combination of erlotinib , cetuximab , and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with NSCLC 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 ) 
    Output:
    
The bevacizumab group showed increased ORR in both first- and second-line treatments .
The addition of bevacizumab to chemotherapy or erlotinib can significantly improve PFS and ORR both in first- and second-line treatments of advanced NSCLC , with an acceptable risk of bleeding events , hypertension , proteinuria , and rash .