***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 
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    Input: Background Combination of erlotinib and bevacizumab is a promising regimen in advanced non-squamous non-small-cell lung cancer ( NSCLC ) . We are conducting a single arm phase II trial which aims to evaluate the efficacy and safety of this regime as a second- or third-line chemotherapy . Methods Key eligibility criteria were histologically or cytologically confirmed non-squamous NSCLC , stage III/IV or recurrent NSCLC not indicated radical chemoradiation , prior one or two regimen of chemotherapy , age 20 years or more , and performance status of two or less . The primary endpoint is objective response rate . The secondary endpoints include overall survival , progression-free survival , disease control rate and incidence of adverse events . This trial plans to accrue 80 patients based on a two-stage design employing a binomial distribution with an alternative hypothesis response rate of 35 % and a null hypothesis threshold response rate of 20 % . A subset analysis according to EGFR mutation status is planned . Discussion We have presented the design of a single arm phase II trial to evaluate the efficacy and safety of combination of bevacizumab and erlotinib in advanced non-squamous NSCLC patients . In particular we are interested in determining the merit of further development of this regimen and whether prospect i ve patient selection using EGFR gene is necessary in future trials . Trial registration This trial was registered at the UMIN Clinical Trials Registry as UMIN000004255 ( http://www.umin.ac.jp/ctr/index.htm ) 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 We conducted a r and omized , placebo-controlled , double-blind trial to determine whether the epidermal growth factor receptor inhibitor erlotinib prolongs survival in non-small-cell lung cancer after the failure of first-line or second-line chemotherapy . METHODS Patients with stage IIIB or IV non-small-cell lung cancer , with performance status from 0 to 3 , were eligible if they had received one or two prior chemotherapy regimens .  The patients were stratified according to center , performance status , response to prior chemotherapy , number of prior regimens , and prior platinum-based therapy and were r and omly assigned in a 2:1 ratio to receive oral erlotinib , at a dose of 150 mg daily , or placebo . RESULTS The median age of the 731 patients who underwent r and omization was 61.4 years ; 49 percent had received two prior chemotherapy regimens , and 93 percent had received platinum-based chemotherapy .  The response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group ( P<0.001 ) ; the median duration of the response was 7.9 months and 3.7 months , respectively . Progression-free survival was 2.2 months and 1.8 months , respectively ( hazard ratio , 0.61 , adjusted for stratification categories ; P<0.001 ) . Overall survival was 6.7 months and 4.7 months , respectively ( hazard ratio , 0.70 ; P<0.001 ) , in favor of erlotinib . Five percent of patients discontinued erlotinib because of toxic effects . CONCLUSIONS Erlotinib can prolong survival in patients with non-small-cell lung cancer after first-line or second-line chemotherapy PURPOSE The phase III , r and omized , placebo-controlled Sequential Tarceva in Unresectable NSCLC ( SATURN ; BO18192 ) study found that erlotinib maintenance therapy extended progression-free survival ( PFS ) and overall survival in patients with advanced non-small-cell lung cancer ( NSCLC ) who had nonprogressive disease following first-line platinum-doublet chemotherapy .  This study included prospect i ve analysis of the prognostic and predictive value of several biomarkers . PATIENTS AND METHODS M and atory diagnostic tumor specimens were collected before initiating first-line chemotherapy and were tested for epidermal growth factor receptor ( EGFR ) protein expression by using immunohistochemistry ( IHC ) , EGFR gene copy number by using fluorescent in situ hybridization ( FISH ) , and EGFR and KRAS mutations by using DNA sequencing . An EGFR CA simple sequence repeat in intron 1 ( CA-SSR1 ) polymorphism was evaluated in blood . RESULTS All 889 r and omly assigned patients provided tumor sample s.  EGFR IHC , EGFR FISH , KRAS mutation , and EGFR CA-SSR1 repeat length status were not predictive for erlotinib efficacy . A profound predictive effect on PFS of erlotinib relative to placebo was observed in the EGFR mutation-positive subgroup ( hazard ratio [ HR ] , 0.10 ; P < .001 ) . Significant PFS benefits were also observed with erlotinib in the wild-type EGFR subgroup ( HR , 0.78 ; P = .0185 ) . KRAS mutation status was a significant negative prognostic factor for PFS . CONCLUSION This large prospect i ve biomarker study found that patients with activating EGFR mutations derive the greatest PFS benefit from erlotinib maintenance therapy . No other biomarkers were predictive for outcomes with erlotinib , although the study was not powered for clinical outcomes in biomarker subgroups other than EGFR IHC-positive [ corrected ] . KRAS mutations were prognostic for reduced PFS . The study demonstrated the feasibility of prospect i ve tissue collection for biomarker analyses in NSCLC BACKGROUND Poor PS is a negative prognostic factor for survival and a risk factor for treatment-related toxicity with st and ard platinum-doublet chemotherapy for advanced NSCLC . A phase II study combining erlotinib and bevacizumab for treatment of recurrent NSCLC showed encouraging efficacy and acceptable toxicity . PATIENTS AND METHODS This single-arm phase II study evaluated erlotinib and bevacizumab as first-line therapy for newly diagnosed nonsquamous advanced NSCLC patients with Eastern Cooperative Oncology Group PS ≥ 2 or age 70 or older . Only patients eligible for bevacizumab per label were enrolled . Patients received erlotinib 150 mg orally daily and bevacizumab 15 mg/kg intravenously on day 1 every 21 days for up to 6 cycles . The primary end point was the rate of nonprogressive disease at 4 months ( alternative hypothesis > 60 % ) . RESULTS Twenty-five patients were enrolled , with median age 77 years ( range , 52 - 90 years ) , 44 % female , 20 % never- or remote-smokers . Ninety-two percent of patients enrolled had PS of 2 per investigator assessment . The rate of nonprogressive disease at 4 months was 28 % . There were no complete responses , 1 patient achieved a partial response , and 11 patients ( 44 % ) experienced stable disease as best response . Rash , fatigue , and diarrhea were the most common toxicities . CONCLUSION The combination of erlotinib and bevacizumab had insufficient activity in the absence of known activating epidermal growth factor receptor gene mutations to warrant study in newly diagnosed elderly or poor PS patients with nonsquamous 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 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 
    Output:
    
The addition of bevacizumab to erlotinib can significantly improve PFS and the ORR in  the second-line treatment of NSCLC with an acceptable and manageable risk of rash and diarrhoea .