***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 Nivolumab ( a programmed death 1 [ PD-1 ] checkpoint inhibitor ) and ipilimumab ( a cytotoxic T-lymphocyte-associated antigen 4 [ CTLA-4 ] checkpoint inhibitor ) have been shown to have complementary activity in metastatic melanoma . In this r and omized , double-blind , phase 3 study , nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma . METHODS We assigned , in a 1:1:1 ratio , 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone , nivolumab plus ipilimumab , or ipilimumab alone  . Progression-free survival and overall survival were co primary end points . Results regarding progression-free survival are presented here . RESULTS The median progression-free survival was 11.5 months ( 95 % confidence interval [ CI ] , 8.9 to 16.7 ) with nivolumab plus ipilimumab , as compared with 2.9 months ( 95 % CI , 2.8 to 3.4 ) with ipilimumab ( hazard ratio for death or disease progression , 0.42 ; 99.5 % CI , 0.31 to 0.57 ; P<0.001 ) , and 6.9 months ( 95 % CI , 4.3 to 9.5 ) with nivolumab ( hazard ratio for the comparison with ipilimumab , 0.57 ; 99.5 % CI , 0.43 to 0.76 ; P<0.001 ) . In patients with tumors positive for the PD-1 lig and ( PD-L1 ) , the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group , but in patients with PD-L1-negative tumors , progression-free survival was longer with the combination therapy than with nivolumab alone ( 11.2 months [ 95 % CI , 8.0 to not reached ] vs. 5.3 months [ 95 % CI , 2.8 to 7.1 ] ) . Treatment-related adverse events of grade 3 or 4 occurred in 16.3 % of the patients in the nivolumab group , 55.0 % of those in the nivolumab-plus-ipilimumab group , and 27.3 % of those in the ipilimumab group . CONCLUSIONS Among previously untreated patients with metastatic melanoma , nivolumab alone or combined with ipilimumab result ed in significantly longer progression-free survival than ipilimumab alone . In patients with PD-L1-negative tumors , the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone . ( Funded by Bristol-Myers Squibb ; CheckMate 067 Clinical Trials.gov number , NCT01844505 . ) BACKGROUND In the NIBIT-M1 study , we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma ( MM ) patients with or without brain metastases . To corroborate these initial findings , we now investigated the long-term efficacy of this combination . PATIENTS AND METHODS This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment .  Median overall survival ( OS ) , 3-year survival rates , immune-related ( ir ) progression-free survival ( irPFS ) , brain PFS , and ir duration of response ( irDOR ) for the entire population and for patients with brain metastases were assessed . Clinical results were correlated with circulating CD3(+)CD4(+)ICOS(+)CD45RO(+ ) or CD45RA(+ ) T cells , neutrophil/lymphocyte ( N/L ) ratios , and tumorBRAF-V600 mutational status . RESULTS Eighty-six MM patients , including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects , were enrolled in the study . With a median follow-up of 39.9 months , median OS and 3-year survival rates were 12.9 months [ 95 % confidence interval ( CI ) 7.1 - 18.7 months ] and 28.5 % for the whole study population , and 12.7 months ( 95 % CI 2.7 - 22.7 months ) and 27.8 % for patients with brain metastases , respectively . Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21 % of patients . The absolute increase from baseline to week 12 in ' memory ' but not in ' naïve ' T cells identified patients with a better survival ( P = 0.002 ) . The N/L ratio correlated with a significantly better survival at early time points . BRAF status did not correlate with clinical outcome . CONCLUSIONS Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients . Fotemustine does not seem to impair the immunologic activity of ipilimumab . EUDRACT NUMBER 2010 - 019356 - 50 . CINICALTRIALSGOV NCT01654692 Background Patients with advanced melanoma are faced with a poor prognosis and , until recently , limited treatment options . Ipilimumab , a novel immunotherapy that blocks cytotoxic T-lymphocyte-associated antigen-4 , was the first agent to improve survival of patients with advanced melanoma in a r and omised , controlled phase 3 trial . We used data from an exp and ed access programme ( EAP ) at Italian centres to evaluate the clinical activity and safety profile of ipilimumab 10 mg/kg in patients with advanced melanoma in a setting more similar to that of daily practice . Methods Data were collected from patients enrolled in an ipilimumab EAP across eight participating Italian centres . As per the EAP protocol , patients had life-threatening , unresectable stage III/IV melanoma , had failed or did not tolerate previous treatments and had no other therapeutic option available . Treatment comprised ipilimumab 10 mg/kg every 3 weeks for a total of four doses . If physicians believed patients would continue to derive benefit from ipilimumab treatment , maintenance therapy with ipilimumab 10 mg/kg was provided every 12 weeks . Tumour responses were assessed every 12 weeks using modified World Health Organization criteria and safety continuously monitored . Results Seventy-four pretreated patients with advanced melanoma were treated with ipilimumab 10 mg/kg . Of these , 9 ( 13.0 % ) had an objective response , comprising 3 patients with a complete response and 6 with a partial response . Median overall survival was 7.0 months ( 95 % confidence interval , 5.3–8.7 ) and 16.6 % of patients were alive after 3 years . Forty-five patients ( 60.8 % ) reported treatment-related adverse events of any grade , which were most commonly low- grade pruritus , pain , fever and diarrhoea . Grade 3 or 4 treatment-related AEs were reported in 8 patients ( 10.8 % ) . Conclusions The clinical activity and safety profile of ipilimumab 10 mg/kg in the EAP was similar to that seen in previous clinical trials of ipilimumab in pretreated patient population 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 Combined BRAF and MEK inhibition , as compared with BRAF inhibition alone , delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600 K mutations . METHODS In this phase 3 trial , we r and omly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600 K mutation to receive a combination of dabrafenib ( 150 mg orally twice daily ) and trametinib ( 2 mg orally once daily ) or dabrafenib and placebo . The primary end point was progression-free survival . Secondary end points included overall survival , response rate , response duration , and safety . A preplanned interim overall survival analysis was conducted . RESULTS The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group ( hazard ratio for progression or death in the dabrafenib-trametinib group , 0.75 ; 95 % confidence interval [ CI ] , 0.57 to 0.99 ; P=0.03 ) . The overall response rate was 67 % in the dabrafenib-trametinib group and 51 % in the dabrafenib-only group ( P=0.002 ) . At 6 months , the interim overall survival rate was 93 % with dabrafenib-trametinib and 85 % with dabrafenib alone ( hazard ratio for death , 0.63 ; 95 % CI , 0.42 to 0.94 ; P=0.02 ) . However , a specified efficacy-stopping boundary ( two-sided P=0.00028 ) was not crossed . Rates of adverse events were similar in the two groups , although more dose modifications occurred in the dabrafenib-trametinib group . The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group ( 2 % vs. 9 % ) , whereas pyrexia occurred in more patients ( 51 % vs. 28 % ) and was more often severe ( grade 3 , 6 % vs. 2 % ) in the dab 
    Output:
    
Evidence of clinical activity exists for both immunotherapy and MAP-kinase inhibitors .
CONCLUSIONS MAP-kinase inhibitors and immunologic checkpoint blockade antibodies have clinical activity and may achieve improved OS in patients with metastatic melanoma and BM .
These results support the inclusion of patients with BM in investigations of new agents and new treatment regimens for metastatic melanoma