***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: 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 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 The BRAF inhibitor , vemurafenib , has demonstrated improved progression-free and overall survival compared with chemotherapy in a r and omized trial , and represents a new st and ard of care in patients with advanced melanoma harboring a BRAF-V600 mutation . A BRAF-V600 mutation is identified in approximately half of patients with cutaneous melanoma , and is unequivocally a biomarker predictive of profound clinical benefit for these patients . However , acquired vemurafenib resistance is a major clinical challenge and therapy is not yet curative . A substantial body of translational research has been performed alongside clinical trials of vemurafenib , providing key insights into the molecular basis of response and resistance . This review summarizes the development of vemurafenib for the treatment of BRAF-V600 mutant melanoma and discusses how knowledge of critical signaling pathways will be applied for its optimal clinical use in future BACKGROUND Previously , a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma . The study was continued to assess the secondary endpoint of overall survival , which we report in this Article . METHODS We did this double-blind phase 3 study at 113 sites in 14 countries . We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma . Participants were computer-r and omised ( 1:1 ) to receive a combination of dabrafenib ( 150 mg orally twice daily ) and trametinib ( 2 mg orally once daily ) , or dabrafenib and placebo . The primary endpoint was progression-free survival and overall survival was a secondary endpoint . This study is registered with Clinical Trials.gov , number NCT01584648 . FINDINGS Between May 4 , 2012 , and Nov 30 , 2012 , we screened 947 patients for eligibility , of whom 423 were r and omly assigned to receive dabrafenib and trametinib ( n=211 ) or dabrafenib only ( n=212 ) . The final data cutoff was Jan 12 , 2015 , at which time 222 patients had died . Median overall survival was 25·1 months ( 95 % CI 19·2-not reached ) in the dabrafenib and trametinib group versus 18·7 months ( 15·2 - 23·7 ) in the dabrafenib only group ( hazard ratio [ HR ] 0·71 , 95 % CI 0·55 - 0·92 ; p=0·0107 ) . Overall survival was 74 % at 1 year and 51 % at 2 years in the dabrafenib and trametinib group versus 68 % and 42 % , respectively , in the dabrafenib only group . Based on 301 events , median progression-free survival was 11·0 months ( 95 % CI 8·0 - 13·9 ) in the dabrafenib and trametinib group and 8·8 months ( 5·9 - 9·3 ) in the dabrafenib only group ( HR 0·67 , 95 % CI 0·53 - 0·84 ; p=0·0004 ; unadjusted for multiple testing ) . Treatment-related adverse events occurred in 181 ( 87 % ) of 209 patients in the dabrafenib and trametinib group and 189 ( 90 % ) of 211 patients in the dabrafenib only group ; the most common was pyrexia ( 108 patients , 52 % ) in the dabrafenib and trametinib group , and hyperkeratosis ( 70 patients , 33 % ) in the dabrafenib only group . Grade 3 or 4 adverse events occurred in 67 ( 32 % ) patients in the dabrafenib and trametinib group and 66 ( 31 % ) patients in the dabrafenib only group . INTERPRETATION The improvement in overall survival establishes the combination of dabrafenib and trametinib as the st and ard targeted treatment for BRAF Val600 mutation-positive melanoma . Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing . FUNDING GlaxoSmithKline BACKGROUND Resistance to therapy with B 
    Output:
    
Skin-related adverse events such as hyperkeratosis , cutaneous squamous-cell carcinoma were less compared with monotherapy .
However , gastrointestinal events like nausea , diarrhea , and vomiting were at a higher frequency .
CONCLUSION Doublet BRAF and MEK inhibition achieved better survival outcomes over single-agent BRAF inhibition and occurred less skin-related events , but gastrointestinal events were more in combination therapy