***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: Treating advanced or recurrent melanoma remains a challenge . Cancer cells can evade the immune system by blocking T‐cell activation through overexpression of the inhibitory receptor programmed death 1 ( PD‐1 ) lig and s. The PD‐1 inhibitor nivolumab blocks the inhibitory signal in T cells , thus overcoming the immune resistance of cancer cells . Nivolumab has shown promising anticancer activity in various cancers . We carried out a single‐arm , open‐label , multicenter , phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma . Twenty‐four patients with stage III/IV or recurrent melanoma were enrolled and received i.v . nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity . The primary endpoint was overall response rate evaluated by an independent radiology review committee . The independent radiology review committee‐assessed overall response rate was 34.8 % ( 90 % confidence interval , 20.8–51.9 ) , and the overall survival rate at 18 months was 56.5 % ( 90 % confidence interval , 38.0–71.4 ) . Treatment‐related adverse events ( AEs ) of grade 3 or 4 only occurred in three patients ( 12.5 % ) . Two patients discontinued nivolumab because of AEs , but all AEs were considered manageable by early diagnosis and appropriate treatment . Subgroup analyses showed that nivolumab was clinical ly beneficial and tolerable regardless of BRAF genotype , and that patients with treatment‐related select AEs and with vitiligo showed tendency for better survival . In conclusion , nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma , with or without BRAF mutations . ( Trial registration no. JapicCTI‐142533 . 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 Purpose Expression of programmed death-lig and 1 ( PD-L1 ) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 ( PD-1 ) . This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study ( clinical trial information : NCT01295827 ) . Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks , or 2 mg/kg once every 3 weeks .  Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors ( RECIST ) v1.1 by independent central review . Primary outcome was objective response rate . Secondary outcomes included progression-free survival ( PFS ) and overall survival ( OS ) . Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay ( 22C3 antibody ) and scored on a unique melanoma ( MEL ) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome ; a score ≥ 2 ( membranous staining in ≥ 1 % of cells ) was considered positive . Results Of 451 patients with evaluable PD-L1 expression , 344 ( 76 % ) had PD-L1-positive tumors . Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients . An association between higher MEL score and higher response rate and longer PFS ( hazard ratio , 0.76 ; 95 % CI , 0.71 to 0.82 ) and OS ( hazard ratio , 0.76 ; 95 % CI , 0.69 to 0.83 ) was observed ( P < .001 for each ) . Objective response rate was 8 % , 12 % , 22 % , 43 % , 57 % , and 53 % for MEL 0 , 1 , 2 , 3 , 4 , and 5 , respectively . Conclusion PD-L1 expression in pretreatment tumor biopsy sample s was correlated with response rate , PFS , and OS ; however , patients with PD-L1-negative tumors may also achieve durable responses There is an unmet need to identify markers predictive of response to ipilimumab in patients with melanoma because the number of responders to ipilimumab is low and its cost is very high . An increase in absolute lymphocyte count ( ALC ) or low neutrophil/lymphocyte ratio ( NLR ) just before the third infusion has been reported to be associated with better overall survival ( OS ) Ipilimumab , a fully human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 ( CTLA-4 ) , is the first immune checkpoint inhibitor approved for the treatment of unresectable melanoma on the basis of its overall survival ( OS ) benefit . However , ipilimumab is associated with significant immune-related adverse events . We hypothesized that biomarker exploration of pretreatment tumor sample s and correlation with clinical outcome would enable patient selection with an increased benefit/risk ratio for ipilimumab therapy .  At the University of Texas MD And erson Cancer Center , a total of 81 advanced melanoma patients were treated on the Ipilimumab Exp and ed Access Program from 2007 to 2008 . Using immunohistochemistry , we analyzed the expression of immune checkpoint ( CTLA-4 , PD-1 , PD-L1 ) and Akt-pathway proteins in formalin-fixed tumor tissue . Associations between these biomarkers and progression-free survival ( PFS ) and OS were analyzed with univariate and multivariate Cox proportional-hazards models . There was a significant correlation between high CTLA-4 protein expression levels in tumor cells and risk of death ( P=0.02 ) and decreased PFS ( P=0.023 ) . In addition , high expression of CTLA-4 in peritumoral lymphocytes correlated with poor OS ( P=0.023 ) . In multivariate analysis , patients with high CTLA-4 and phospho-Akt ( p-Akt ) expression correlated with poor OS ( log-rank test , P=0.039 ) and PFS ( log-rank test , P=0.014 ) . High levels of CTLA-4 and p-Akt expression in pretreatment tumor cells in melanoma patients were associated with poor clinical outcomes . Immunohistochemistry analysis of CTLA-4 and p-Akt in pretreatment tumor sample s provides useful biomarkers that may enable improved patient selection for ipilimumab therapy . Prospect i ve clinical studies are warranted to investigate the predictive value of these biomarkers BACKGROUND Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma , albeit with more high- grade adverse events . We assessed whether sequential administration of nivolumab followed by ipilimumab , or the reverse sequence , could improve safety without compromising efficacy . METHODS We did this r and omised , open-label , phase 2 study at nine academic medical centres in the USA . Eligible patients ( aged ≥18 years ) with unresectable stage III or IV melanoma ( treatment-naive or who had progressed after no more than one previous systemic therapy , with an Eastern Cooperative Oncology Group performance status of 0 or 1 ) were r and omly assigned ( 1:1 ) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses , or the reverse sequence . R and omisation was done by an independent interactive voice response system with a permuted block schedule ( block size four ) without stratification factors . After induction , both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity . The primary endpoint was treatment-related grade 3 - 5 adverse events until the end of the induction period ( week 25 ) , analysed in the as-treated population . Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25 . Overall survival was a prespecified exploratory endpoint . This study is registered with Clinical Trials.gov , number NCT01783938 , and is ongoing but no longer enrolling patients . FINDINGS Between April 30 , 2013 , and July 21 , 2014 , 140 patients were enrolled and r and omly assigned to nivolumab followed by ipilimumab ( n=70 ) or to the reverse sequence of ipilimumab followed by nivolumab ( n=70 ) , of whom 68 and 70 patients , respectively , received at least one dose of study drug and were included in the analyses . The frequencies of treatment-related grade 3 - 5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group ( 34 [ 50 % ; 95 % CI 37·6 - 62·4 ] of 68 patients ) and in the ipilimumab followed by nivolumab group ( 30 [ 43 % ; 31·1 - 55·3 ] of 70 patients ) . The most common treatment-related grade 3 - 4 adverse events during the whole study period were colitis ( ten [ 15 % ] ) in the nivolumab followed by ipilimumab group vs 14 [ 20 % ] in the reverse sequence group ) , increased lipase ( ten [ 15 % ] vs 12 [ 17 % ] ) , and diarrhoea ( eight [ 12 % ] vs five [ 7 % ] ) . No treatment-related deaths occurred . The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence ( 28 [ 41 % ; 95 % CI 29·4 - 53·8 ] vs 14 [ 20 % ; 11·4 - 31·3 ] ) . Progression was reported in 26 ( 38 % ; 95 % CI 26·7 - 50·8 ) patients in the nivolumab followed by ipilimumab group and 43 ( 61 % ; 49·0 - 72·8 ) patients in the reverse sequence group at week 13 and in 26 ( 38 % ; 26·7 - 50·8 ) and 42 ( 60 % ; 47·6 - 71·5 ) patients at week 25 , respectively . After a median follow-up of 19·8 months ( IQR 12·8 - 25·7 ) , median overall survival was not reached in the nivolumab followed by ipilimumab group ( 95 % CI 23·7-not reached ) , whereas over a median follow-up of 14·7 months ( IQR 5·6 - 23·9 ) in the ipilimumab followed by nivolumab group , median overall survival was 16·9 months ( 95 % CI 9·2 - 26·5 ; HR 0·48 [ 95 % CI 0·29 - 0·80 ] ) . A higher proportion of patients in the nivolumab followed by ipilimumab  group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group ( 76 % ; 95 % CI 64 - 85 vs 54 % ; 42 - 65 ) . INTERPRETATION Nivolumab followed by ipilimumab appears to be a 
    Output:
    
In advanced MM treated with IT or BRAFi±MEKi , elevated LDH level at baseline represents a poor prognostic factor .
However , patients with increased LDH levels and treated with these drugs gain significant benefits in terms of PFS and OS