***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: AIM Underst and ing predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments . A prior pooled analysis of dabrafenib plus trametinib ( D + T)-r and omised trials ( median follow-up , 20.0 months ) identified baseline lactate dehydrogenase ( LDH ) and number of organ sites with metastasis as predictive factors for progression-free ( PFS ) and overall ( OS ) survival . However , longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit . METHODS Three-year l and mark data were retrospectively pooled for D + T patients in phase 3 trials ( COMBI-d [ NCT01584648 ] ; COMBI-v [ NCT01597908 ] ) . Univariate and multivariate analyses assessed prognostic values of predefined baseline factors ; regression tree analysis determined hierarchy and interactions between variables . RESULTS Long-term pooled outcomes were consistent with individual trial results ( N = 563 ; 3-year PFS , 23 % ; 3-year OS , 44 % ) . Baseline LDH level and number of organ sites remained strongly associated with and /or predictive of PFS and OS . In addition , baseline sum of lesion diameters ( SLD ) was identified as a predictor for progression . In the most favourable prognostic group ( normal LDH , SLD < 66 mm , <3 organ sites ; n = 183/563 [ 33 % ] ) , 3-year PFS was 42 % . Baseline number of organ sites was also predictive of outcomes in patients with PFS ≥ 6 months . CONCLUSION Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma , these results demonstrate that durable responses lasting ≥3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow-up , factors predicting clinical outcomes with the combination remained consistent with previous analyses BACKGROUND The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma , as previously reported in the coBRIM study . In this Article , we report up date d efficacy results , including overall survival and safety after longer follow-up , and selected biomarker correlative studies . METHODS In this double-blind , r and omised , placebo-controlled , multicentre study , adult patients ( aged ≥18 years ) with histologically confirmed BRAF(V600 ) mutation-positive unresectable stage IIIC or stage IV melanoma were r and omly assigned ( 1:1 ) using an interactive response system to receive cobimetinib ( 60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle ) or placebo , in combination with oral vemurafenib ( 960 mg twice daily ) . Progression-free and overall survival were primary and secondary endpoints , respectively ; all analyses were done on the intention-to-treat population . This study is registered with Clinical Trials.gov , number NCT01689519 , and is ongoing but no longer recruiting participants . FINDINGS Between Jan 8 , 2013 , and Jan 31 , 2014 , 495 eligible adult patients were enrolled and r and omly assigned to the cobimetinib plus vemurafenib group ( n=247 ) or placebo plus vemurafenib group ( n=248 ) . At a median follow-up of 14·2 months ( IQR 8·5 - 17·3 ) , the up date d investigator-assessed median progression-free survival was 12·3 months ( 95 % CI 9·5 - 13·4 ) for cobimetinib and vemurafenib versus 7·2 months ( 5·6 - 7·5 ) for placebo and vemurafenib ( HR 0·58 [ 95 % CI 0·46 - 0·72 ] , p<0·0001 ) . The final analysis for overall survival occurred when 255 ( 52 % ) patients had died ( Aug 28 , 2015 ) . Median overall survival was 22·3 months ( 95 % CI 20·3-not estimable ) for cobimetinib and vemurafenib versus 17·4 months ( 95 % CI 15·0 - 19·8 ) for placebo and vemurafenib ( HR 0·70 , 95 % CI 0·55 - 0·90 ; p=0·005 ) . The safety profile for cobimetinib and vemurafenib was tolerable and manageable , and no new safety signals were observed with longer follow-up . The most common grade 3 - 4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase ( 36 [ 15 % ] in the cobimetinib and vemurafenib group vs 25 [ 10 % ] in the placebo and vemurafenib  group ) , blood creatine phosphokinase increase ( 30 [ 12 % ] vs one [ < 1 % ] ) , and alanine transaminase increase ( 28 [ 11 % ] vs 15 [ 6 % ] ) . Serious adverse events occurred in 92 patients ( 37 % ) in the cobimetinib and vemurafenib group and 69 patients ( 28 % ) in the vemurafenib group . Pyrexia ( six patients [ 2 % ] ) and dehydration ( five patients [ 2 % ] ) were the most common serious adverse events reported in the cobimetinib and vemurafenib group . A total of 259 patients have died : 117 ( 47 % ) in the cobimetinib and vemurafenib group and 142 ( 58 % ) in the vemurafenib group . The primary cause of death was disease progression in most patients : 109 ( 93 % ) of 117 in the cobimetinib and vemurafenib group and 133 ( 94 % ) of 142 in the vemurafenib group . INTERPRETATION These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a st and ard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma . FUNDING F Hoffmann-La Roche-Genentech BACKGROUND Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib ( PLX4032 ) have shown response rates of more than 50 % in patients with metastatic melanoma with the BRAF V600E mutation . METHODS We conducted a phase 3 r and omized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated , metastatic melanoma with the BRAF V600E mutation . Patients were r and omly assigned to receive either vemurafenib ( 960 mg orally twice daily ) or dacarbazine ( 1000 mg per square meter of body-surface area intravenously every 3 weeks ) . Co primary end points were rates of overall and progression-free survival . Secondary end points included the response rate , response duration , and safety . A final analysis was planned after 196 deaths and an interim analysis after 98 deaths . RESULTS At 6 months , overall survival was 84 % ( 95 % confidence interval [ CI ] , 78 to 89 ) in the vemurafenib group and 64 % ( 95 % CI , 56 to 73 ) in the dacarbazine group . In the interim analysis for overall survival and final analysis for progression-free survival , vemurafenib was associated with a relative reduction of 63 % in the risk of death and of 74 % in the risk of either death or disease progression , as compared with dacarbazine ( P<0.001 for both comparisons ) . After review of the interim analysis by an independent data and safety monitoring board , crossover from dacarbazine to vemurafenib was recommended . Response rates were 48 % for vemurafenib and 5 % for dacarbazine . Common adverse events associated with vemurafenib were arthralgia , rash , fatigue , alopecia , keratoacanthoma or squamous-cell carcinoma , photosensitivity , nausea , and diarrhea ; 38 % of patients required dose modification because of toxic effects . CONCLUSIONS Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation . ( Funded by Hoffmann-La Roche ; BRIM-3 Clinical Trials.gov number , NCT01006980 . ) BACKGROUND Combined BRAF-MEK inhibitor therapy is the st and ard of care for BRAFV600-mutant advanced melanoma . We investigated encorafenib , a BRAF inhibitor with unique target-binding properties , alone or in combination with the MEK inhibitor binimetinib , versus vemurafenib in patients with advanced BRAFV600-mutant melanoma . METHODS COLUMBUS was conducted as a two-part , r and omised , open-label phase 3 study at 162 hospitals in 28 countries . Eligible patients were aged 18 years or older and had histologically confirmed locally advanced ( American Joint Committee on Cancer [ AJCC ] stage IIIB , IIIC , or IV ) , unresectable or metastatic cutaneous melanoma , or unknown primary melanoma ; a BRAFV600E or BRAFV600 K mutation ; an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 or 1 ; and were treatment naive or had progressed on or after previous first-line immunotherapy . In part 1 of the study , patients were r and omly assigned ( 1:1:1 ) via interactive response technology to receive either oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily ( encorafenib plus binimetinib group ) , oral encorafenib 300 mg once daily ( encorafenib group ) , or oral vemurafenib 960 mg twice daily ( vemurafenib group ) . The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib . Efficacy analyses were by intention-to-treat . Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment . The results of part 2 will be published separately . This study is registered with Clinical Trials.gov , number NCT01909453 , and EudraCT , number 2013 - 001176 - 38 . FINDINGS Between Dec 30 , 2013 , and April 10 , 2015 , 577 of 1345 screened patients were r and omly assigned to either the encorafenib plus binimetinib group ( n=192 ) , the encorafenib group ( n=194 ) , or the vemurafenib group ( n=191 ) . With a median follow-up of 16·6 months ( 95 % CI 14·8 - 16·9 ) , median progression-free survival was 14·9 months ( 95 % CI 11·0 - 18·5 ) in the encorafenib plus binimetinib group and 7·3 months ( 5·6 - 8·2 ) in the vemurafenib group ( hazard ratio [ HR ] 0·54 , 95 % CI 0·41 - 0·71 ; two-sided p<0·0001 ) . The most common grade 3 - 4 adverse events seen in more than 5 % of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase ( 18 [ 9 % ] of 192 patients ) , increased creatine phosphokinase ( 13 [ 7 % ] ) , and hypertension ( 11 [ 6 % ] ) ; in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome ( 26 [ 14 % ] of 192 patients ) , myalgia ( 19 [ 10 % ] ) , and arthralgia ( 18 [ 9 % ] ) ; and in the vemurafenib group it was arthralgia ( 11 [ 6 % ] of 186 patients ) . There were no treatment-related deaths except for one death in the combination group , which was considered possibly related to treatment by the investigator . INTERPRETATION Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib . Overall , encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib . Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma . FUNDING Array BioPharma , Novartis BACKGROUND Combined BRAF and MEK inhibition , as compared with BRAF inhibition alone , delays the emergence of resistance and reduces toxic effects in patients who have 
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The indirect comparison revealed no statistically differences for OS , PFS and ORR across trials , while safety profile differed between the three couples of agents .
This indirect adjusted meta- analysis suggests a similar efficacy and a slightly different safety profile , related to specific molecular properties of the three different BRAF and MEK inhibitors currently approved in the management of advanced MM