human
***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: Cetuximab tumor-specific monotherapy for head and neck cancers is effective in less than 20 % of cases . Cytolytic T cells were found to be increased , yet expressed PD-1 and TIM-3 . Addition of checkpoint blockade could potentially improve clinical outcomes . Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells , it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy . We examined the expression patterns of immune checkpoint receptors ( including PD-1 , CTLA-4 , and TIM-3 ) and cytolytic molecules ( including granzyme B and perforin ) of CD8 + tumor-infiltrating lymphocytes ( TIL ) and compared them with those of peripheral blood T lymphocytes ( PBL ) in patients with head and neck cancer ( HNSCC ) during cetuximab therapy .  The frequency of PD-1 and TIM-3 expression was significantly increased in CD8 + TILs compared with CD8 + PBLs ( P = 0.008 and P = 0.02 , respectively ) . This increased CD8 + TIL population coexpressed granzyme B/perforin and PD-1/TIM-3 , which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8 + TILs . Indeed , the increased frequency of PD-1 + and TIM-3 + CD8 + TILs was inversely correlated with clinical outcome of cetuximab therapy . These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8 + T cells in the tumor microenvironment during cetuximab therapy . Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8 + TIL dysfunction , thus potentially improving clinical outcomes of HNSCC patients . Cancer Immunol Res ; 5(5 ) ; 408–16 . © 2017 AACR 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 more clinical ly beneficial option compared with the reverse sequence , albeit with a higher frequency of adverse events . FUNDING Bristol-Myers Squibb One hundred eligible patients with inoperable , locally advanced or metastatic squamous cell carcinoma of the head and neck region following prior therapy were r and omized to receive i m methotrexate ( 50 patients ) or iv cisplatin ( 50 patients ) . Methotrexate produced a complete plus partial response rate of 16.0 % and cisplatin produced a partial response rate of 8.0 % , with median duration s of response of 18 and 8 weeks , respectively . The corresponding median survival times were 20 and 18 weeks . Methotrexate responders survived 60 weeks , versus 17 weeks for nonresponders . The corresponding survival times for cisplatin-treated patients were 38 and 18 weeks . Good pretreatment performance status had a significantly positive effect on survival ( P = 0.04 ) , but prior therapy did not . Toxicity secondary to either agent occurred with the expected frequency . The two agents examined showed comparable antitumor activity in patients with squamous cell carcinoma of the head and neck who had not previously received chemotherapy 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 . ) A number of single agents have been tested in patients with carcinoma of the head and neck receiving palliative treatment . In general , 15‐30 % of patients achieve a partial response lasting 3‐4 months . Treatment has not been shown to alter survival rates . It is clear that new drugs with potentially greater activity need to be identified . For this purpose , the Eastern Cooperative Oncology Group conducted a Phase II evaluation of paclitaxel Summary A phase III 2x2 factorial trial of cisplatinum and bleomycin in 116 patients with recurrent or advanced squamous cell carcinoma of the head and neck is reported . Thirty percent of patients proved to be unfit for chemotherapy , and of those treated progression of tumour was the commonest “ response ” . However , 25 % of patients achieved a partial or complete response , with no significant difference in response rates between the treated arms . The median number of courses received was 1 ( range 0–6 ) and the commonest causes for discontinuation of treatment were renal toxicity and death .  Bleomycin  reduced survival , but not significantly so , whereas cisplatinum  prolonged median survival significantly by 10 weeks . Significant predictors of survival , in addition to treatment by cisplatinum , were age , performance status , N status , number of courses and response of the tumor We describe a phase III trial on 200 patients with end stage squamous cell carcinoma of the head and neck . The patients were r and omised to one of four treatment arms : cisplatinum alone , methotrexate alone , cisplatinum + 5-FU and cisplatinum + methotrexate . There was no significant difference in the response rates , but the survival of the cisplatinum arm was significantly better than that of the methotrexate arm . The survival of patients receiving cisplatinum as a single agent was longer than that of patients receiving cisplatinum in combination with methotrexate or 5-FU , but not significantly so . Nausea/vomiting and anaemia were significantly more common in the cisplatinum arms than in the methotrexate arm , but the toxicity of combination regimens was not significantly greater than that of cisplatinum used as a single agent Seventy-two patients with advanced squamous-cell carcinomas of the head and neck were r and omised to receive weekly intravenous methotrexate at doses of either 50 mg/m2 ( low dose ) , 500 mg/m2 ( medium dose ) , or 5 g/m2 
    Output:
    
agent
***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: Cetuximab tumor-specific monotherapy for head and neck cancers is effective in less than 20 % of cases . Cytolytic T cells were found to be increased , yet expressed PD-1 and TIM-3 . Addition of checkpoint blockade could potentially improve clinical outcomes . Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells , it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy . We examined the expression patterns of immune checkpoint receptors ( including PD-1 , CTLA-4 , and TIM-3 ) and cytolytic molecules ( including granzyme B and perforin ) of CD8 + tumor-infiltrating lymphocytes ( TIL ) and compared them with those of peripheral blood T lymphocytes ( PBL ) in patients with head and neck cancer ( HNSCC ) during cetuximab therapy .  The frequency of PD-1 and TIM-3 expression was significantly increased in CD8 + TILs compared with CD8 + PBLs ( P = 0.008 and P = 0.02 , respectively ) . This increased CD8 + TIL population coexpressed granzyme B/perforin and PD-1/TIM-3 , which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8 + TILs . Indeed , the increased frequency of PD-1 + and TIM-3 + CD8 + TILs was inversely correlated with clinical outcome of cetuximab therapy . These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8 + T cells in the tumor microenvironment during cetuximab therapy . Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8 + TIL dysfunction , thus potentially improving clinical outcomes of HNSCC patients . Cancer Immunol Res ; 5(5 ) ; 408–16 . © 2017 AACR 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 more clinical ly beneficial option compared with the reverse sequence , albeit with a higher frequency of adverse events . FUNDING Bristol-Myers Squibb One hundred eligible patients with inoperable , locally advanced or metastatic squamous cell carcinoma of the head and neck region following prior therapy were r and omized to receive i m methotrexate ( 50 patients ) or iv cisplatin ( 50 patients ) . Methotrexate produced a complete plus partial response rate of 16.0 % and cisplatin produced a partial response rate of 8.0 % , with median duration s of response of 18 and 8 weeks , respectively . The corresponding median survival times were 20 and 18 weeks . Methotrexate responders survived 60 weeks , versus 17 weeks for nonresponders . The corresponding survival times for cisplatin-treated patients were 38 and 18 weeks . Good pretreatment performance status had a significantly positive effect on survival ( P = 0.04 ) , but prior therapy did not . Toxicity secondary to either agent occurred with the expected frequency . The two agents examined showed comparable antitumor activity in patients with squamous cell carcinoma of the head and neck who had not previously received chemotherapy 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 . ) A number of single agents have been tested in patients with carcinoma of the head and neck receiving palliative treatment . In general , 15‐30 % of patients achieve a partial response lasting 3‐4 months . Treatment has not been shown to alter survival rates . It is clear that new drugs with potentially greater activity need to be identified . For this purpose , the Eastern Cooperative Oncology Group conducted a Phase II evaluation of paclitaxel Summary A phase III 2x2 factorial trial of cisplatinum and bleomycin in 116 patients with recurrent or advanced squamous cell carcinoma of the head and neck is reported . Thirty percent of patients proved to be unfit for chemotherapy , and of those treated progression of tumour was the commonest “ response ” . However , 25 % of patients achieved a partial or complete response , with no significant difference in response rates between the treated arms . The median number of courses received was 1 ( range 0–6 ) and the commonest causes for discontinuation of treatment were renal toxicity and death .  Bleomycin  reduced survival , but not significantly so , whereas cisplatinum  prolonged median survival significantly by 10 weeks . Significant predictors of survival , in addition to treatment by cisplatinum , were age , performance status , N status , number of courses and response of the tumor We describe a phase III trial on 200 patients with end stage squamous cell carcinoma of the head and neck . The patients were r and omised to one of four treatment arms : cisplatinum alone , methotrexate alone , cisplatinum + 5-FU and cisplatinum + methotrexate . There was no significant difference in the response rates , but the survival of the cisplatinum arm was significantly better than that of the methotrexate arm . The survival of patients receiving cisplatinum as a single agent was longer than that of patients receiving cisplatinum in combination with methotrexate or 5-FU , but not significantly so . Nausea/vomiting and anaemia were significantly more common in the cisplatinum arms than in the methotrexate arm , but the toxicity of combination regimens was not significantly greater than that of cisplatinum used as a single agent Seventy-two patients with advanced squamous-cell carcinomas of the head and neck were r and omised to receive weekly intravenous methotrexate at doses of either 50 mg/m2 ( low dose ) , 500 mg/m2 ( medium dose ) , or 5 g/m2 
    Output:
    