Increased PD-1+ and TIM-3+ TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Comparison of methotrexate and cisplatin for patients with advanced squamous cell carcinoma of the head and neck region: a Southwest Oncology Group Study. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck Cisplatinum and Bleomycin for advanced or recurrent squamous cell carcinoma of the head and neck: a randomised factorial phase III controlled trial A phase III randomised trial of cisplatinum, methotrextate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Liverpool Head and Neck Oncology Group. Methotrexate treatment of squamous-cell head and neck cancers: dose-response evaluation. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. A randomized comparison of high-dose infusion methotrexate versus standard-dose weekly therapy in head and neck squamous cancer. A phase II trial of paclitaxel in squamous cell carcinoma of the head and neck with correlative laboratory studies. Docetaxel: an active drug for squamous cell carcinoma of the head and neck. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. Phase III comparison of high-dose paclitaxel + cisplatin + granulocyte colony-stimulating factor versus low-dose paclitaxel + cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group Study E1393. Platinum-based chemotherapy plus cetuximab in head and neck cancer. Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. Ipilimumab for Patients with Relapse after Allogeneic Transplantation. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected].
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 ( high dose ) . Patients who failed to respond after four treatments at their initial dose were given four further treatments at the next higher dose . There were two complete responses and 21 partial responses to the initial dose -- in 10 out of 22 patients given the high dose , seven out of 27 given the medium dose , six out of 23 given the low dose . A further five out of 16 patients responded after crossing over to a higher dose . Toxicity was more severe with the high-dose regimen . Responders survived significantly longer than non-responders ( p less than 0.05 ) , but there was no significant difference in duration s of survival among the three treatment groups . Analysis of patients who completed the first four treatments indicated an improved response rate and duration of survival for the high-dose group . Because of toxicity associated with high-dose methotrexate this treatment produces no overall greater benefit than low-dose regimens PURPOSE To determine whether combination chemotherapy is superior to single agents for recurrent/metastatic head and neck cancer , we compared the efficacy and toxicity of cisplatin ( CP ) and fluorouracil ( 5-FU ) , alone and in combination in a phase III trial . PATIENTS AND METHODS Two hundred forty-nine patients with recurrent head and neck cancer were r and omized to one of three treatments :  CP ( 100 mg/m2 ) and 5-FU ( 1 g/m2 x 4 ) , CP , or 5-FU every 3 weeks . RESULTS The overall response rate to the combination ( 32 % ) was superior to that of CP ( 17 % ) or 5-FU ( 13 % ) ( P = .035 ) . Response was associated with good performance status ( PS ) but not with primary site , site of recurrence , histology , prior irradiation , or relative dose intensity . Median time to progression was less than 2.5 months , and there was no significant difference in median survival ( 5.7 months ) among the groups . By multivariate analysis , patients with better PS and poorly differentiated tumors had superior survival . Hematologic toxicity and alopecia were worse in the combination arm . CONCLUSION Although the response rate to the combination of CP plus 5-FU was superior to that achieved with single agents , survival did not improve Forty-seven patients with recurrent or metastatic head and neck squamous cancer were entered into a prospect ively controlled study comparing high-dose infusion methotrexate with leucovorin against st and ard-dose methotrexate without leucovorin .  Patients were stratified for prior treatment and hematogenous metastases prior to r and omization . Patients received either methotrexate ( 1,500 mg/m2 ) infused over 24 hours with leucovorin or 40 mg/m2 intramuscularly . Each treatment was given weekly for the first six weeks and followed a dose escalation schedule to toxicity . After six weeks patients received the high-dose regimen every two weeks and the low-dose schedule continued weekly . One patient was ineligible and four had inadequate follow-up to assess response ( less than two weeks ) . Forty-two patients were evaluable for survival and 37 for response .  Six of 19 patients ( 32 % ) treated with high-dose infusion responded ( one complete response ) and four of 18 patients ( 22 % ) receiving st and ard dosage responded ( P = .52 ) . Treatment with high-dose methotrexate result ed in an improved duration of disease control over st and ard dosage with the respective median times to progression of 11 weeks and five weeks ( P = .04 ) . These differences were most marked in good performance status patients ( P = .007 ) and those without hematogenous dissemination ( P = .02 ) . Toxicity , however , was also significantly worse in the high-dose treatment group ( P = .01 ) and survival was identical between treatments ( 4.2 months ) . The authors conclude that any treatment advantage to high-dose methotrexate may be attributable to its greater toxicity rather than to a selective therapeutic effect and this regimen does not result in improved patient survival . Good performance status patients may benefit from more aggressive therapy Head and neck cancer is a major cause of cancer-related deaths . In general , early stage head and neck cancers are effectively treated with either radiation or surgery . More advanced tumors often require combined-modality therapy with both radiation therapy and surgery . Recent investigations indicate that the addition of chemotherapy may be helpful . One of the newer chemotherapy agents that appears to have significant activity against head and neck cancer is paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) . Paclitaxel , originally derived from the western yew Taxus brevifolia , acts by increasing the stability of microtubules and preventing mitosis . Recent evidence indicates that the microtubule system is vital to the release of various cytokines and that modulation of cytokine release may play a major role in the drug 's antitumor activity . We report a phase II trial of paclitaxel in patients with head and neck cancer , not only to evaluate its clinical effects , but also to study its effect on cytokine release . We assessed interleukin-1 beta ( IL-1 beta ) and tumor necrosis factor-alpha production by using a sensitive enzyme-linked immunosorbent assay to assess the serum of patients receiving paclitaxel  and to detect cytokine release in vitro . The objective response rate was 36 % , with 12 % complete responses and 24 % partial responses . No IL-1 beta or tumor necrosis factor-alpha was detected in patient serum at any time during the infusion of paclitaxel or after overnight incubation with patient monocytes . No proIL-1 beta was detected in in vitro cultures of paclitaxel-treated patient monocytes . When monocytes were stimulated with endotoxin , IL-1 beta production was greatest at 48 hours , suggesting that paclitaxel can prime cells to produce greater quantities of cytokines after a second stimulus PURPOSE We conducted a phase II study design ed to evaluate the activity , safety , and tolerability of docetaxel ( Taxotere : Rhône-Poulenc Rorer Pharmaceuticals Inc , Collegeville , PA ) in patients with advanced , incurable , or recurrent squamous cell carcinoma of the head and neck ( SCCHN ) who had not received prior palliative chemotherapy . PATIENTS AND METHODS Thirty-one patients with measurable , locoregional , or metastatic SCCHN were treated with docetaxel , administered at a dose of 100 mg/m2 as a 1-hour intravenous ( i.v . ) infusion once every 21 days on an outpatient basis . All patients were premedicated with dexamethasone , diphenhydramine , and cimetidine . Prophylactic administration of growth factors or antiemetics was not permitted . RESULTS Thirty-one patients were treated . Twenty-nine patients were assessable for  response  and 30 for toxicity .  Four of 31 patients ( 13 % ) achieved complete response ( CR ) , nine ( 29 % ) achieved partial response had stable disease ( SD ) and seven ( 23 % ) experienced progression of disease ( PD ) . The major response rate was 42 % ( 95 % confidence interval [ CI ] , 24 % to 60 % ) . The median duration of responses was 5 months ( range , 2 to 14 ) . The principal toxicity was leukopenia , which occurred with rapid onset and brief duration . Sixteen patients ( 53 % ) experienced nadir fever , and 13 required dose reduction . Hypersensitivity reactions occurred in four patients . Grade 3 peripheral neuropathy occurred in two patients ; grade 2 or 3 fatigue occurred in six ( 20 % ) and 10 ( 33 % ) , respectively . Minimal edema ( grade 1 ) occurred in five patients ( 17 % ) . Clinical ly significant mucositis , diarrhea , or dermatitis were not observed . CONCLUSION Docetaxel has major activity against SCCHN . It appears to be well tolerated in this group of patients and can be safely administered on an outpatient basis . Premedication with dexamethasone , cimetidine , and diphenhydramine is associated with a reduced incidence of significant edema , hypersensitivity reactions , and dermatologic toxicities PURPOSE The Southwest Oncology Group ( SWOG ) conducted a r and omized comparison of cisplatin plus fluorouracil ( 5-FU ) and carboplatin plus 5-FU versus single-agent methotrexate ( MTX ) in patients with recurrent and metastatic squamous-cell carcinoma ( SCC ) of the head and neck . The primary objective was to compare separately the response rates of each combination regimen to st and ard weekly MTX . PATIENTS AND METHODS Two hundred seventy-seven patients diagnosed with SCC of the head and neck were r and omized to one of three treatments : ( 1 ) cisplatin 100 mg/m2 intravenously ( IV ) on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 21 days ; ( 2 ) carboplatin 300 mg/m2 IV on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 28 days ; and ( 3 ) MTX 40 mg/m2 IV given weekly . RESULTS All three treatment regimens were well tolerated . However , both hematologic and nonhematologic toxicities were significantly greater with cisplatin plus 5-FU compared with MTX ( P = .001 ) . Toxicity from carboplatin plus 5-FU was intermediate compared with the other regimens . The complete and partial response rates were 32 % for cisplatin plus 5-FU , 21 % for carboplatin plus 5-FU , and 10 % for MTX . The comparison of cisplatin plus 5-FU to MTX was statistically significant ( P less than .001 ) , and the comparison of carboplatin plus 5-FU to MTX was of borderline statistical significance ( P = .05 ) . Median response duration s and median survival times were similar for all three treatment groups . Logistic regression models showed that only treatment assigned was associated significantly with response ( P = .001 ) . Cox proportional hazards models indicated that only performance status was associated significantly with survival ( P less than .01 ) . CONCLUSIONS We conclude that combination chemotherapy result ed in improved response rates but was associated with an increased toxicity and no improvement in overall survival . Therefore , new treatments that may alter the course of disease in recurrent head and neck cancer patients still need to be identified BACKGROUND The anti-programmed-death-receptor-1 ( PD-1 ) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma . We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma . METHODS In an open-label , international , multicentre expansion cohort of a phase 1 trial , patients ( aged ≥18 years ) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were r and omly assigned with a computer-generated allocation schedule ( 1:1 final ratio ) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression , intolerable toxicity , or consent withdrawal . Primary endpoint was overall response rate ( ORR ) assessed with the Response Evaluation Criteria In Solid Tumors ( RECIST , version 1.1 ) by independent central review . Analysis was done on the full- analysis set ( all treated patients with measurable disease at baseline ) . This study is registered with Clinical Trials.gov , number NCT01295827 . FINDINGS 173 patients received pembrolizumab 2 mg/kg ( n=89 ) or 10 mg/kg ( n=84 ) . Median follow-up duration was 8 months . ORR was 26 % at both doses--21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group ( difference 0 % , 95 % CI -14 to 13 ; p=0·96 ) . Treatment was well tolerated , with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths . The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue ( 29 [ 33 % ] vs 31 [ 37 % ] ) , pruritus ( 23 [ 26 % ] vs 16 [ 19 % ] ) , and rash ( 16 [ 18 % ] vs 15 [ 18 % ] ) . Grade 3 fatigue , reported in five ( 3 % ) patients in the 2 mg/kg pembrolizumab group , was the only drug-related grade 3 to 4 adverse event reported in more than one patient . INTERPRETATION The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options . FUNDING Merck Sharp and Dohme PURPOSE To determine the response rate , survival and toxicity of infusional cisplatin plus fluorouracil ( CF ) versus cisplatin plus paclitaxel ( CP ) in patients with incurable squamous cell cancer of the head and neck , with the hypothesis that CP is superior . PATIENTS AND METHODS Two hundred eighteen patients with locally advanced , recurrent , or metastatic disease were r and omly assigned to CF ( cisplatin 100 mg/m2 day 1 and fluorouracil 1,000 mg/m2/24 hours by continuous intravenous infusion day 1 through 4 ) or CP ( cisplatin 75 mg/m2 day 1 and paclitaxel 175 mg/m2 over 3 hours on day 1 ) . Cycles were repeated every 3 weeks until progression or a minimum of 6 cycles with complete response or stable disease . The primary outcome was overall survival . Secondary outcomes included response rate and toxicity . RESULTS No significant difference in overall survival or response rate was seen . Estimated median survival was 8.7 months in the CF group and 8.1 month in the CP group . Objective response rate ( complete response plus partial response ) was 27 % in the CF group and 26 % in the CP group . Toxicity was similar between groups , with the most frequent including myelosuppression , thrombocytopenia , anemia , nausea , vomiting , and stomatitis . A total of 12 deaths occurred ( CF , seven ; CP , five ) during treatment ; eight from infection , two from hemorrhage , one from cardiac causes and one from unknown causes . Gastrointestinal and hematologic toxicities were more common in the CF group , whereas neurotoxicity was equivalent between groups . CONCLUSION This phase III , r and omized , multicenter trial showed no difference in survival between patients treated with CF or CP PURPOSE To determine dose-response effects and the activity of paclitaxel combined with cisplatin in patients with incurable squamous cell carcinoma of the head and neck . PATIENTS AND METHODS Two hundred ten patients with locally advanced , recurrent , or metastatic disease were r and omly placed in either Arm A , paclitaxel 200 mg/m(2 ) ( 24-hour infusion ) + cisplatin 75mg/m(2 ) + granulocyte colony-stimulating factor , or Arm B , paclitaxel 135 mg/m(2 ) ( 24-hour infusion ) + cisplatin 75 mg/m(2 ) . Cycles were repeated every 3 weeks until progression or a total of 12 cycles for complete responses . Primary outcomes were event-free and overall survival . RESULTS No significant differences in outcomes were observed between the high- and low-dose paclitaxel regimens . The estimated median survival was 7.3 months ( 95 % confidence interval , 6.0 to 8.6 ) . The 1-year survival rate was 29 % , and event-free survival was 4.0 months . The objective response rate ( complete response plus partial response ) was 35 % for the high-dose patients and 36 % for the low-dose patients . Myelosuppression was the most frequent toxicity : grade 3 or 4 granulocytopenia , 70 % of patients in Arm A and 78 % in Arm B ; febrile neutropenia , 27 % of patients in Arm A and 39 % in Arm B. Grade 5 toxicities occurred in 22 patients ( 10.5 % ) . Treatment was terminated early in 31 % because of excessive toxicity or patient refusal . CONCLUSION This phase III multicenter trial showed ( 1 ) no advantage for high-dose paclitaxel and ( 2 ) excessive hematologic toxicity associated with both regimens . Therefore , neither of the paclitaxel regimens evaluated in this trial can be recommended BACKGROUND Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck . We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck . METHODS We r and omly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin ( at a dose of 100 mg per square meter of body-surface area on day 1 ) or carboplatin ( at an area under the curve of 5 mg per milliliter per minute , as a 1-hour intravenous infusion on day 1 ) plus fluorouracil ( at a dose of 1000 mg per square meter per day for 4 days ) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab ( at a dose of 400 mg per square meter initially , as a 2-hour intravenous infusion , then 250 mg per square meter , as a 1-hour intravenous infusion per week ) for a maximum of 6 cycles . Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects , whichever occurred first . RESULTS Adding cetuximab to platinum-based chemotherapy with fluorouracil ( platinum-fluorouracil ) significantly prolonged the median overall survival from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab ( hazard ratio for death , 0.80 ; 95 % confidence interval , 0.64 to 0.99 ; P=0.04 ) . The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months ( hazard ratio for progression , 0.54 ; P<0.001 ) and increased the response rate from 20 % to 36 % ( P<0.001 ) . The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia ( 19 % and 13 % , respectively ) , neutropenia ( 23 % and 22 % ) , and thrombocytopenia ( 11 % in both groups ) . Sepsis occurred in 9 patients in the cetuximab group and in 1 patient in the chemotherapy-alone group ( P=0.02 ) . Of 219 patients receiving cetuximab , 9 % had grade 3 skin reactions and 3 % had grade 3 or 4 infusion-related reactions . There were no cetuximab-related deaths . CONCLUSIONS As compared with platinum-based chemotherapy plus fluorouracil alone , cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck . ( Clinical Trials.gov number , NCT00122460 . BACKGROUND Docetaxel ( Taxotere ) is a new cytotoxic agent acting as a promoter of tubulin polymerisation with broad spectrum antitumor activity in pre clinical testing . Phase I clinical trials have shown promising activity of docetaxel in patients with breast , ovarian and lung carcinomas . The objective of this open multicentre phase II study was to determine the efficacy and tolerability of this agent in patients with head and neck cancer . PATIENTS AND METHODS Patients with proven advanced and /or recurrent squamous cell carcinoma of the head and neck without prior chemotherapy for advanced disease were eligible for this trial . Docetaxel was given at a dose of 100 mg/m2 as a 1 hour infusion every 3 weeks . Dose reductions were performed according to hematological and non-hematological toxicities . No pre-medication was given to prevent hypersensitivity reactions . RESULTS Fourty-three patients entered this trial : 39 patients were evaluable for toxicity and 37 patients were evaluable for response . Sixty-five percent of the patients had locoregional disease , 28 % had metastatic disease , and 7 % had both . Twenty-five percent of the patients had previously received neo-adjuvant cisplatin-based chemotherapy . A total of 166 docetaxel courses were administered . The most frequent side-effects associated with docetaxel were alopecia ( 90 % of the patients ) , asthenia ( 69 % of the patients ) and short lasting neutropenia ( grade 3 - 4 neutropenia in 61 % of the courses ) . Fifty-four percent of the patients experienced skin toxicity , 23 % experienced hypersensitivity reaction , and 31 % developed peripheral edema . Ten partial and 2 complete responses were observed , yielding a response rate of 32 % ( 95 % confidence interval 17%-47 % ) . CONCLUSION Docetaxel is an active drug in patients with advanced squamous cell carcinoma of the head and neck BACKGROUND In a phase 1 dose-escalation study , combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response , including complete responses , among patients with advanced melanoma . METHODS In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment , we r and omly assigned patients in a 2:1 ratio to receive ipilimumab ( 3 mg per kilogram of body weight ) combined with either nivolumab ( 1 mg per kilogram ) or placebo once every 3 weeks for four doses , followed by nivolumab ( 3 mg per kilogram ) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects . The primary end point was the rate of investigator-assessed , confirmed objective response among patients with BRAF V600 wild-type tumors . RESULTS Among patients with BRAF wild-type tumors , the rate of confirmed objective response was 61 % ( 44 of 72 patients ) in the group that received both ipilimumab and nivolumab ( combination group ) versus 11 % ( 4 of 37 patients ) in the group that received ipilimumab and placebo ( ipilimumab-monotherapy group ) ( P<0.001 ) , with complete responses reported in 16 patients ( 22 % ) in the combination group and no patients in the ipilimumab-monotherapy group . The median duration of response was not reached in either group . The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy ( hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death , 0.40 ; 95 % confidence interval , 0.23 to 0.68 ; P<0.001 ) . Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors .  Drug-related adverse events of grade 3 or 4 were reported in 54 % of the patients who received the combination therapy as compared with 24 % of the patients who received ipilimumab monotherapy . Select adverse events with potential immunologic causes were consistent with those in a phase 1 study , and most of these events resolved with immune-modulating medication . CONCLUSIONS The objective -response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy . Combination therapy had an acceptable safety profile . ( Funded by Bristol-Myers Squibb ; Clinical Trials.gov number , NCT01927419 . ) BACKGROUND Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation ( HSCT ) permits relapse of hematologic cancers . We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte-associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect . METHODS We conducted a phase 1/1b multicenter , investigator-initiated study to determine the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer after allogeneic HSCT . Patients received induction therapy with ipilimumab at a dose of 3 or 10 mg per kilogram of body weight every 3 weeks for a total of 4 doses , with additional doses every 12 weeks for up to 60 weeks in patients who had a clinical benefit . RESULTS A total of 28 patients were enrolled .  Immune-related adverse events , including one death , were observed in 6 patients ( 21 % ) , and graft-versus-host disease ( GVHD ) that precluded further administration of ipilimumab was observed in 4 patients ( 14 % ) . No responses that met formal response criteria occurred in patients who received a dose of 3 mg per kilogram . Among 22 patients who received a dose of 10 mg per kilogram , 5 ( 23 % ) had a complete response , 2 ( 9 % ) had a partial response , and 6 ( 27 % ) had decreased tumor burden . Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia . Four patients had a durable response for more than 1 year . Responses were associated with in situ infiltration of cytotoxic CD8 + T cells , decreased activation of regulatory T cells , and expansion of sub population s of effector T cells in the blood . CONCLUSIONS Our early-phase data showed that administration of ipilimumab was feasible in patients with recurrent hematologic cancers after allogeneic HSCT , although immune-mediated toxic effects and GVHD occurred . Durable responses were observed in association with several histologic subtypes of these cancers , including extramedullary acute myeloid leukemia . ( Funded by the National Institutes of Health and others ; Clinical Trials.gov number , NCT01822509 . ) PURPOSE To compare survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck ( SCCHN ) treated with gefitinib 250 or 500 mg/day or st and ard methotrexate . PATIENTS AND METHODS Four hundred eighty-six patients with recurrent SCCHN were r and omly assigned to oral gefitinib 250 mg/day , gefitinib 500 mg/day , or methotrexate 40 mg/m(2 ) intravenously weekly . Primary end point was overall survival , secondary end points were objective response rate ( ORR ) , safety , symptom improvement , and quality of life ( QOL ) . Exploratory end points included association of efficacy with epidermal growth factor receptor gene copy number and other biomarkers . RESULTS Neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate ( hazard ratio [ HR ] , 1.22 ; 95 % CI , 0.95 to 1.57 ; P = .12 ; and HR , 1.12 ; 95 % CI , 0.87 to 1.43 ; P = .39 , respectively ) . In the gefitinib 250 mg/day , 500 mg/day , and methotrexate groups , respectively , median overall survival was 5.6 , 6.0 , and 6.7 months ; ORRs ( Response Evaluation Criteria in Solid Tumors ) were 2.7 % , 7.6 % and 3.9 % , with no statistically significant difference between either gefitinib arm and methotrexate . No unexpected adverse events were observed , except for tumor hemorrhage-type events with gefitinib ( 8.9 % , gefitinib 250 mg/day ; 11.4 % , gefitinib 500 mg/day ; 1.9 % , methotrexate ) . QOL improvement rates ( Functional Assessment of Cancer Therapy-Head & Neck total score ) were 13.4 % , 18.0 % , and 6.0 % for gefitinib 250 mg/day , 500 mg/day , and methotrexate , respectively . CONCLUSION In patients with recurrent or metastatic SCCHN , while responses with gefitinib were seen , neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate . With the exception of tumor hemorrhage-type events with gefitinib , the adverse event profiles were generally consistent with those previously observed
Head and neck cancer ( HNC ) is a fatal malignancy with an overall long-term survival of about 50 % for all stages .
The diagnosis is not rarely delayed , and the majority of patients present with loco-regionally advanced disease .
The rate of second primary tumors after a diagnosis of HNC is about 3–7 % per year , the highest rate among solid tumors .
Currently , a single-modality or a combination of surgery , radiotherapy and chemotherapy ( CHT ) , is the st and ard treatment for stage III – IV HNC .
For the recurrent/metastatic setting , in the last 40 years great efforts have been made in order to develop a more effective CHT regimen , from the use of methotrexate alone , to the combination of cisplatin ( CDDP ) and 5-fluorouracile ( 5FU ) or paclitaxel .
Recently , the introduction of cetuximab , an anti-EGFR monoclonal antibody , to the CDDP–5FU doublet ( EXTREME regimen ) has improved the overall response rate , the progression-free survival and the overall survival ( OS ) compared to CHT alone .
Nowadays , the EXTREME regimen is the st and ard of care for the first-line treatment of recurrent/metastatic head and neck carcinoma ( RMHNC ) .
In the last years , new promising therapies for RMHNC such as immune checkpoint inhibitors ( ICIs ) , which have demonstrated favorable results in second-line clinical trials , gained special interest .