***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 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 Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma . The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study . METHODS We r and omly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab ( at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks ) or dacarbazine ( at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks ) . The primary end point was overall survival . RESULTS At 1 year , the overall rate of survival was 72.9 % ( 95 % confidence interval [ CI ] , 65.5 to 78.9 ) in the nivolumab group , as compared with 42.1 % ( 95 % CI , 33.0 to 50.9 ) in the dacarbazine group ( hazard ratio for death , 0.42 ; 99.79 % CI , 0.25 to 0.73 ; P<0.001 ) . The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group ( hazard ratio for death or progression of disease , 0.43 ; 95 % CI , 0.34 to 0.56 ; P<0.001 ) . The objective response rate was 40.0 % ( 95 % CI , 33.3 to 47.0 ) in the nivolumab group versus 13.9 % ( 95 % CI , 9.5 to 19.4 ) in the dacarbazine group ( odds ratio , 4.06 ; P<0.001 ) . The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups , including subgroups defined by status regarding the programmed death lig and 1 ( PD-L1 ) . Common adverse events associated with nivolumab included fatigue , pruritus , and nausea . Drug-related adverse events of grade 3 or 4 occurred in 11.7 % of the patients treated with nivolumab and 17.6 % of those treated with dacarbazine . CONCLUSIONS Nivolumab was associated with significant improvements in overall survival and progression-free survival , as compared with dacarbazine , among previously untreated patients who had metastatic melanoma without a BRAF mutation . ( Funded by Bristol-Myers Squibb ; CheckMate 066 Clinical Trials.gov number , NCT01721772 . ) Metastatic melanoma is a highly aggressive disease . Recent progress in immunotherapy ( IT ) and targeted therapy ( TT ) has led to significant improvements in response and survival rates in metastatic melanoma patients . The current project aims to determine the benefit of the introduction of these new therapies in advanced melanoma across several regions of Switzerl and . This is a retrospective multicenter analysis of 395 advanced melanoma patients treated with st and ard chemotherapy , checkpoint inhibitors , and kinase inhibitors from January 2008 until December 2014 . The 1-year survival was 69 % ( n=121 ) in patients treated with checkpoint inhibitors ( IT ) , 50 % in patients treated with TTs ( n=113 ) , 85 % in the IT+TT group ( n=66 ) , and 38 % in patients treated with st and ard chemotherapy ( n=95 ) . The median overall survival ( mOS ) from first systemic treatment in the entire study cohort was 16.9 months . mOS of patients treated either with checkpoint or kinase inhibitors ( n=300 , 14.6 months ) between 2008 and 2014 was significantly improved ( P<0.0001 ) compared with patients treated with st and ard chemotherapy in 2008–2009 ( n=95 , 7.4 months ) . mOS of 61 patients with brain metastases at stage IV was 8.1 versus 12.5 months for patients without at stage IV ( n=334 ) , therefore being significantly different ( P=0.00065 ) . Furthermore , a significant reduction in hospitalization duration compared with chemotherapy was noted . Treatment with checkpoint and kinase inhibitors beyond clinical trials significantly improves the mOS in real life and the results are consistent with published prospect i ve trial data 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 Ipilimumab improves survival of patients with metastatic melanoma , many of whom develop brain metastases . Chemotherapy-induced release of tumour antigens might amplify ipilimumab 's antitumour activity . We aim ed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases . METHODS In our open-label , single-arm phase 2 trial , we enrolled patients 18 years or older with measurable , locally advanced , unresectable stage III or stage IV melanoma between July 6 , 2010 , and April 14 , 2011 . Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less , and could have received a maximum of one previous line of chemotherapy . Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses , and 100 mg/m(2 ) intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24 . Patients with a confirmed clinical response were eligible for maintenance treatment from week 24 , with ipilimumab every 12 weeks and fotemustine every 3 weeks . The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria . Analyses were done per protocol . This trial is registered with EudraCT , number 2010 - 019356 - 50 , and with Clinical Trials.gov , number NCT01654692 . FINDINGS 86 patients were eligible for treatment , of whom 20 had asymptomatic brain metastases at baseline . 40 patients in the study population achieved disease control ( 46·5 % , 95 % CI 35·7 - 57·6 ) , as did ten with brain metastases ( 50·0 % , 27·2 - 72·8 ) . 47 patients ( 55 % ) had grade 3 or 4 treatment-related adverse events , of which the most common was myelotoxicity ( thrombocytopenia in 21 [ 24 % ] patients and neutropenia in 16 [ 19 % ] ) . The most common grade 3 or 4 immune-related adverse events were hepatic : 21 patients ( 24 % ) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase . INTERPRETATION The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma , including those with brain metastases . FUNDING Bristol-Myers Squibb BACKGROUND The immune checkpoint inhibitor ipilimumab is the st and ard-of-care treatment for patients with advanced melanoma .  Pembrolizumab inhibits the programmed cell death 1 ( PD-1 ) immune checkpoint and has antitumor activity in patients with advanced melanoma . METHODS In this r and omized , controlled , phase 3 study , we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab ( at a dose of 10 mg per kilogram of body weight ) every 2 weeks or every 3 weeks or four doses of ipilimumab ( at 3 mg per kilogram ) every 3 weeks . Primary end points were progression-free and overall survival . RESULTS The estimated 6-month progression-free-survival rates were 47.3 % for pembrolizumab every 2 weeks , 46.4 % for pembrolizumab every 3 weeks , and 26.5 % for ipilimumab ( hazard ratio for disease progression , 0.58 ; P<0.001 for both pembrolizumab regimens versus ipilimumab ; 95 % confidence intervals [ CIs ] , 0.46 to 0.72 and 0.47 to 0.72 , respectively ) . Estimated 12-month survival rates were 74.1 % , 68.4 % , and 5 
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Combined modality therapy was investigated in 71 % of the studies and result ed in increased survival and better distant/local control than monotherapy , especially with targeted therapy or immunotherapy .
However , neurotoxic side-effects also occurred more frequently .
Timing appeared to be an important determinant , with the best results when radiotherapy was given before or during systemic therapy .
Improved tumor control and prolonged survival can be achieved by combining radiotherapy with immunotherapy or targeted therapy .