***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: Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background Nintedanib is a potent , oral angiokinase inhibitor that targets VEGF , PDGF and FGF signalling , as well as RET and Flt3 . The maximum tolerated dose of nintedanib was evaluated in a phase I study of treatment-refractory patients with advanced solid tumours . In this preplanned sub analysis , the effect of nintedanib on the tumour vasculature , along with efficacy and safety , was assessed in 30 patients with colorectal cancer ( CRC ) . Methods Patients with advanced CRC who had failed conventional treatment , or for whom no therapy of proven efficacy existed , were treated with nintedanib ranging from 50–450 mg once-daily ( n = 14 ) or 150–250 mg twice-daily ( n = 16 ) for 28 days . After a 1-week rest , further courses were permitted in the absence of progression or undue toxicity . The primary objective was the effect on the tumour vasculature using dynamic contrast-enhanced magnetic resonance imaging ( DCE-MRI ) and expressed as the initial area under the DCE-MRI contrast agent concentration – time curve after 60 seconds ( iAUC60 ) or the volume transfer constant between blood plasma and extravascular extracellular space ( Ktrans ) . Results Patients received a median of 4.0 courses ( range : 1–13 ) . Among 21 evaluable patients , 14 ( 67 % ) had a ≥40 % reduction from baseline in Ktrans and 13 ( 62 % ) had a ≥40 % decrease from baseline in iAUC60 , representing clinical ly relevant effects on tumour blood flow and permeability , respectively . A ≥40 % reduction from baseline in Ktrans was positively associated with non-progressive tumour status ( Fisher ’s exact : p = 0.0032 ) . One patient achieved a partial response at 250 mg twice-daily and 24 ( 80 % ) achieved stable disease lasting ≥8 weeks . Time to tumour progression ( TTP ) at 4 months was 26 % and median TTP was 72.5 days ( 95 % confidence interval : 65–114 ) . Common drug-related adverse events ( AEs ) included nausea ( 67 % ) , vomiting ( 53 % ) and diarrhoea ( 40 % ) ; three patients experienced drug-related AEs ≥ grade 3 . Four patients treated with nintedanib once-daily had an alanine aminotransferase and /or aspartate aminotransferase increase ≥ grade 3 . No increases > grade 2 were seen in the twice-daily group . Conclusions Nintedanib modulates tumour blood flow and permeability in patients with advanced , refractory CRC , while achieving antitumour activity and maintaining an acceptable safety profile BACKGROUND The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer ( NSCLC ) . METHODS Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy , stratified by ECOG performance status , previous bevacizumab treatment , histology , and presence of brain metastases , were allocated ( by computer-generated sequence through an interactive third-party system , in 1:1 ratio ) , to receive docetaxel 75 mg/m(2 ) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2 - 21 , every 3 weeks until unacceptable adverse events or disease progression . Investigators and patients were masked to assignment . The primary endpoint was progression-free survival ( PFS ) by independent central review , analysed by intention to treat after 714 events in all patients . The key secondary endpoint was overall survival , analysed by intention to treat after 1121 events had occurred , in a prespecified stepwise order : first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy , then in all patients with adenocarcinoma , then in all patients . This trial is registered with Clinical Trials.gov , number NCT00805194 . FINDINGS Between Dec 23 , 2008 , and Feb 9 , 2011 , 655 patients were r and omly assigned to  receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo . The primary analysis was done after a median follow-up of 7·1 months ( IQR 3·8 - 11·0 ) . PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group ( median 3·4 months [ 95 % CI 2·9 - 3·9 ] vs 2·7 months [ 2·6 - 2·8 ] ; hazard ratio [ HR ] 0·79 [ 95 % CI 0·68 - 0·92 ] , p=0·0019 ) . After a median follow-up of 31·7 months ( IQR 27·8 - 36·1 ) , overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group ( 206 patients ) compared with those in the docetaxel plus placebo group ( 199 patients ; median 10·9 months [ 95 % CI 8·5 - 12·6 ] vs 7·9 months [ 6·7 - 9·1 ] ; HR 0·75 [ 95 % CI 0·60 - 0·92 ] , p=0·0073 ) . Similar results were noted for all patients with adenocarcinoma histology ( 322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group ; median overall survival 12·6 months [ 95 % CI 10·6 - 15·1 ] vs 10·3 months [ 95 % CI 8·6 - 12·2 ] ; HR 0·83 [ 95 % CI 0·70 - 0·99 ] , p=0·0359 ) , but not in the total study population ( median 10·1 months [ 95 % CI 8·8 - 11·2 ] vs 9·1 months [ 8·4 - 10·4 ] ; HR 0·94 , 95 % CI 0·83 - 1·05 , p=0·2720 ) . Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea ( 43 [ 6·6 % ] of 652 vs 17 [ 2·6 % ] of 655 ) , reversible increases in alanine aminotransferase ( 51 [ 7·8 % ] vs six [ 0·9 % ] ) , and reversible increases in aspartate aminotransferase ( 22 [ 3·4 % ] vs three [ 0·5 % ] ) . 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression ; the most common of these events were sepsis ( five with docetaxel plus nintedanib vs one with docetaxel plus  placebo ) , pneumonia ( two vs seven ) , respiratory failure ( four vs none ) , and pulmonary embolism ( none vs three ) . INTERPRETATION Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy , especially for patients with adenocarcinoma . FUNDING Boehringer Ingelheim 
    Output:
    
No heterogeneity was observed despite different drugs .
Protracted inhibition of the VEGF pathway is associated with a significant improvement of both PFS and OS , independently from the antiangiogenic agent used