***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 Blockade of programmed death 1 ( PD-1 ) , an inhibitory receptor expressed by T cells , can overcome immune resistance . We assessed the antitumor activity and safety of BMS-936558 , an antibody that specifically blocks PD-1 . METHODS We enrolled patients with advanced melanoma , non-small-cell lung cancer , castration-resistant prostate cancer , or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks . Response was assessed after each 8-week treatment cycle . Patients received up to 12 cycles until disease progression or a complete response occurred . RESULTS A total of 296 patients received treatment through February 24 , 2012 .  Grade 3 or 4 drug-related adverse events occurred in 14 % of patients ; there were three deaths from pulmonary toxicity . No maximum tolerated dose was defined . Adverse events consistent with immune-related causes were observed . Among 236 patients in whom response could be evaluated , objective responses ( complete or partial responses ) were observed in those with non-small-cell lung cancer , melanoma , or renal-cell cancer .  Cumulative response rates ( all doses ) were 18 % among patients with non-small-cell lung cancer ( 14 of 76 patients ) , 28 % among patients with melanoma ( 26 of 94 patients ) , and 27 % among patients with renal-cell cancer ( 9 of 33 patients ) . Responses were durable ; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up . To assess the role of intratumoral PD-1 lig and ( PD-L1 ) expression in the modulation of the PD-1-PD-L1 pathway , immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients . Of 17 patients with PD-L1-negative tumors , none had an objective response ; 9 of 25 patients ( 36 % ) with PD-L1-positive tumors had an objective response ( P=0.006 ) . CONCLUSIONS Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer , melanoma , or renal-cell cancer ; the adverse-event profile does not appear to preclude its use . Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response . ( Funded by Bristol-Myers Squibb and others ; Clinical Trials.gov number , NCT00730639 . ) 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 , a fully human IgG4 PD-1 immune checkpoint inhibitor antibody , can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors . We assessed the efficacy and safety of nivolumab compared with investigator 's choice of chemotherapy ( ICC ) as a second-line or later-line treatment in patients with advanced melanoma . METHODS In this r and omised , controlled , open-label , phase 3 trial , we recruited patients at 90 sites in 14 countries . Eligible patients were 18 years or older , had unresectable or metastatic melanoma , and progressed after ipilimumab , or ipilimumab and a BRAF inhibitor if they were BRAF(V 600 ) mutation-positive . Participating investigators r and omly assigned ( with an interactive voice response system ) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC ( dacarbazine 1000 mg/m(2 ) every 3 weeks or paclitaxel 175 mg/m(2 ) combined with carboplatin area under the curve 6 every 3 weeks ) until progression or unacceptable toxic effects . We stratified r and omisation by BRAF mutation status , tumour expression of PD-L1 , and previous best overall response to ipilimumab . We used permuted blocks ( block size of six ) within each stratum . Primary endpoints were the proportion of patients who had an objective response and overall survival . Treatment was given open-label , but those doing tumour assessment s were masked to treatment assignment . We assessed objective responses per- protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks , and safety in all patients who had had at least one dose of treatment . The trial is closed and this is the first interim analysis , reporting the objective response primary endpoint . This study is registered with Clinical Trials.gov , number NCT01721746 . FINDINGS Between Dec 21 , 2012 , and Jan 10 , 2014 , we screened 631 patients , r and omly allocating 272 patients to nivolumab and 133 to ICC . Confirmed objective responses were reported in 38 ( 31·7 % , 95 % CI 23·5 - 40·8 ) of the first 120 patients in the nivolumab group versus five ( 10·6 % , 3·5 - 23·1 ) of 47 patients in the ICC group . Grade 3 - 4 adverse events related to nivolumab included increased lipase ( three [ 1 % ] of 268 patients ) , increased alanine aminotransferase , anaemia , and fatigue ( two [ 1 % ] each ) ; for ICC , these included neutropenia ( 14 [ 14 % ] of 102 ) , thrombocytopenia ( six [ 6 % ] ) , and anaemia ( five [ 5 % ] ) . We noted grade 3 - 4 drug-related serious adverse events in 12 ( 5 % ) nivolumab-treated patients and nine ( 9 % ) patients in the ICC group . No treatment-related deaths occurred . INTERPRETATION Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor . Nivolumab represents a new treatment option with clinical ly meaningful durable objective responses in a population of high unmet need . FUNDING Bristol-Myers Squibb Purpose : Diarrhea ( with or without colitis ) is an immune-related adverse event ( irAE ) associated with ipilimumab . A r and omized , double-blind , placebo-controlled , multicenter , multinational phase II trial was conducted to determine whether prophylactic budesonide ( Entocort EC ) , a nonabsorbed oral steroid , reduced the rate of grade ≥2 diarrhea in ipilimumab-treated patients with advanced melanoma . Experimental Design : Previously treated and treatment-naïve patients ( N = 115 ) with unresectable stage III or IV melanoma received open-label ipilimumab  ( 10 mg/kg every 3 weeks for four doses ) with daily blinded budesonide ( group A ) or placebo ( group B ) through week 16 . The first scheduled tumor evaluation was at week 12 ; eligible patients received maintenance treatment starting at week 24 . Diarrhea was assessed using Common Terminology Criteria for Adverse Events ( CTCAE ) 3.0 . Patients kept a diary describing their bowel habits . Results : Budesonide did not affect the rate of grade ≥2 diarrhea , which occurred in 32.7 % and 35.0 % of patients in groups A and B , respectively . There were no bowel perforations or treatment-related deaths . Best overall response rates were 12.1 % in group A and 15.8 % in group B , with a median overall survival of 17.7 and 19.3 months , respectively . Within each group , the disease control rate was higher in patients with grade 3 to 4 irAEs than in patients with grade 0 to 2 irAEs , although many patients with grade 1 to 2 irAEs experienced clinical benefit . Novel patterns of response to ipilimumab were observed . Conclusions : Ipilimumab shows activity in advanced melanoma , with encouraging survival and manageable adverse events . Budesonide should not be used prophylactically for grade ≥2 diarrhea associated with ipilimumab therapy . ( Clin Cancer Res 2009;15(17):5591–8 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 , 
    Output:
    
Results Monotherapies with a programmed cell death 1 ( PD-1 ) immune-checkpoint-inhibitor had a higher probability of good performance for overall survival than monotherapies with ipilimumab or BRAF/MEK inhibitors .
The combination treatments had all similar levels of effectiveness to the PD-1 immune-checkpoint-inhibitors .
PD-1 immune-checkpoint-inhibitors are more effective and more costly compared with ipilimumab in monotherapy .
Nivolumab in combination with ipilimumab had higher costs and the same level of effectiveness as the PD-1 immune-checkpoint-inhibitors in monotherapy .
BRAF/MEK inhibitor combinations ( dabrafenib and trametinib or vemurafenib and cobimetinib ) had both similar effectiveness and cost-effectiveness ; however , the combination therapies are more likely to give higher quality adjusted life year gains than BRAF or MEK inhibitor monotherapies , but to a higher cost .
Conclusions None of the drugs investigated can be considered cost-effective at what has normally been considered a reasonable willingness-to-pay ( WTP ) in Norway .
Price reductions ( from the official list prices ) in the region of 63%–84 % would be necessary for these drugs to be cost-effective at a WTP of € 55 850 per QALY