recently it has been evaluated in metastatic melanoma patients with braf v600e mutation after progression of earlier systemic treatment ( phase 2 trial brim2 ) .
vemurafenib was also tested in a phase 3 trial ( brim3 ) in previously untreated patients .
food and drug administration ( fda ) in august 2011 and the european medicines agency ( ema ) in february 2012 for the treatment of metastatic melanoma with braf mutation .
updated overall survival ( os ) results of the brim3 study have been presented at the asco meeting this year .
the overall response rate in patients treated with vemurafenib was 57% [ 5.6%  complete response ( cr ) , 51.3  partial response ( pr ) ] compared with 8.6% ( 1.2%  cr , 7.4%  pr ) observed in patients receiving dacarbazine ( dtic ) .
median progression - free survival ( pfs ) was also longer in patients treated with the study drug ( 6.9 vs. 1.6 months ; hr 0.38 ; 95% ci : 0.320.46 ; p <
0.001 ) as well as median os ( 13.6 vs. 9.7 months ; hr 0.70 ; 95% ci : 0.570.87 ; p < 0.001 ) . in patients treated with vemurafenib , adverse cutaneous skin carcinoma , keratoacanthoma and skin papilloma
james larkin presented results of an open - label , multicenter safety study of vemurafenib in patients with metastatic melanoma .
of 1964 screened patients , 914 were enrolled in the study and 834 evaluable for toxicity analysis .
70% of patients received prior systemic treatment due to metastatic melanoma ( 14%  ipilimumab , 2%  mek and braf inhibitors ) .
adverse events ( aes ) were observed in 66% of patients ( 88% were related to vemurafenib ) .
the most frequently observed any grade aes were arthralgia ( 31% ) , rash ( 29% ) , fatigue ( 22% ) , photosensitivity ( 21% ) and nausea ( 15% ) .
the most common were rash ( 3.6% ) , arthralgia ( 3.1% ) and cutaneous cell carcinoma / keratoacanthoma ( 4.3% ) . in 6% of patients
treatment was discontinued due to aes ( mainly arthritis and abdominal pain ) . at the time of study analysis 302
patients were evaluable for tumor assessment at week 8 of treatment ; 61% developed objective responses , and 29% stable disease ( sd ) .
another active braf kinase inhibitor in the treatment of metastatic melanoma patients is dabrafenib ( gsk2118436 ) .
results of a randomized , open - label , multicenter phase 3 study ( break-3 ) comparing the efficacy of dabrafenib and dtic in patients with braf v600e mutated metastatic melanoma were presented at the meeting .
the study enrolled 250 previously untreated patients . in one study arm patients received oral dabrafenib at a dose of 150 mg twice a day . in the second arm dtic at a dose of 1000 mg / m was administered in three - week intervals .
31% of patients presented greater than 1 ecog performance status and 66% of enrolled patients had stage m1c melanoma .
patients treated with the study drug also demonstrated longer median pfs  5.1 vs. 2.7 months ( hr 0.30 ; 95% ci : 0.180.53 ; p < 0.0001 ) .
the most frequent adverse events observed in patients treated with dabrafenib were hyperkeratosis ( 37% ) , headache ( 32% ) , pyrexia ( 28% ) , arthralgia ( 27% ) and skin papillomas ( 24% ) .
serious adverse events ( saes ) included pyrexia ( 6% ) , squamous cell carcinoma ( 6% ) and new primary melanoma ( 2% ) .
a number of clinical trials showed low efficacy of anti - cancer agents in melanoma patients with brain metastases .
however , small molecules have demonstrated some efficacy in patients with solid tumors with concomitant brain metastases .
dabrafenib in a phase 2 study ( break - mb ) in patients with braf v600e / k mutation with intracranial lesions demonstrated high clinical efficacy .
127 patients were recruited to one of the two study arms , but only 41 patients reached 8-week disease assessment at the time of interim analysis .
patients in cohort a did not receive any prior brain metastasis treatment before entering the trial .
patients in group b before enrolment developed intracranial progression following prior brain therapy . unconfirmed overall intracranial response rate ( oirr ) was 53% in patients with braf v600e mutant in both study cohorts .
the unconfirmed oirr in patients with braf v600k mutation was 20% and 50% , respectively , in arms a and b. these preliminary results confirm efficacy of dabrafenib in melanoma patients with intra- and extracranial metastases with acceptable toxicity .
trametinib is a reversible , highly selective allosteric inhibitor of mek 1/2 activation and kinase activity .
results of a phase 3 ( metric ) study comparing trametinib with chemotherapy in patients with braf v600/k mutant advanced or metastatic melanoma were presented at the asco conference .
273 patients were randomized in a 2 : 1 ratio to receive trametinib or paclitaxel / dtic .
patients with disease progression after chemotherapy were allowed to cross over to the trametinib arm .
the overall response rate observed in the study drug arm was 24% compared with 7% in patients treated with chemotherapy . in the group receiving trametinib the median pfs was greater than in the control arm  4.8 vs. 1.4 months ( hr 0.44 ; 95% ci : 0.310.64 ; p < 0.0001 ) .
analysis of os demonstrated that 81% of patients in the trametinib group were alive after 6 months of follow - up , compared with 67% in the chemotherapy group ( hr 0.53 ; 95% ci : 0.300.94 , p < 0.01 ) .
the most common adverse events observed in patients treated with trametinib were skin rash , diarrhea , edema , hypertension and fatigue .
typical adverse events connected with mek inhibitor treatment included chorioretinopathy ( < 1% ) and decreased ejection fraction ( 7% ) .
jeffrey weber has presented encouraging results of a phase i / ii study presenting safety and efficacy of dabrafenib combined with trametinib in braf v600 mutant metastatic melanoma patients .
the overall response rate observed in the study was 56% with 4 cr , 39 pr , 29 sd and 3 pd .
overall pfs was 7.4 months . the most frequently noted saes were pyrexia ( 6.5% ) , fatigue ( 6.5% ) and dehydration ( 6.5% ) .
the combination of dabrafenib and trametinib was associated with a lower incidence of mek inhibitor related rash and braf inhibitor induced hyperproliferative skin lesions when compared to the single agents .
encouraging results of a chinese phase ii trial comparing first line treatment of rh - endostatin ( angiogenesis inhibitor ) plus dtic with dtic alone in patients with advanced melanoma have been presented .
patients treated with rh - endostatin plus dtic showed longer pfs  5.0 vs. 1.5 months ( 95% ci : 2.457.55 ; p = 0.004 ) and longer os 
treatment with rh - endostatin combined with dtic was well tolerated , with grade 34 toxicity ( mainly elevated transaminase and thrombocytopenia ) observed only in 1.7% of patients .
a new agent , cabozantinib , has been tested in a randomized phase ii trial in patients with metastatic cutaneous / mucosal ( 70% ) and ocular ( 30% ) melanoma .
toxicity of the study drug was comparable to that of other vegfr ( vascular endothelial growth factor receptor ) tkis ( tyrosine kinase inhibitors ) .
interim analysis of a single arm phase ii trial assessing another vegfr tki , pazopanib , and paclitaxel in first - line treatment for unresectable stage iii and iv melanoma demonstrated a 48% overall response rate .
grade 3 and 4 hypertension was observed in 28% , transaminitis in 21% , neutropenia in 14% of patients .
studies of mtor ( mammalian target of rapamycin kinase ) inhibitors in two small phase ii studies demonstrated efficacy . in one trial in advanced melanoma patients temsirolimus was combined with bevacizumab and showed pr in 19% and sd in 56% of patients ; the most notable responses were seen in patients with braf wild type tumors .
another trial enrolled metastatic melanoma patients to evaluate the combination of everolimus with paclitaxel and carboplatin .
ipilimumab is a fully human monoclonal antibody ( mab ) targeting cytotoxic t - lymphocyte antigen-4 ( ctla-4 ) .
currently ipilimumab and vemurafenib are the only two new drugs approved for the treatment of metastatic melanoma .
( 2010 ) and subsequently in europe ( 2011 ) in the second line treatment after failure of chemotherapy ( mdx010 - 20 study ) .
( 2010 ) in previously untreated patients with metastatic melanoma . during the asco meeting omid hamid presented the results of the ipilimumab u.s . expanded access program ( eap ) in patients with unresectable stage iii or iv melanoma .
the study also enrolled patients with brain metastases ( 27% ) , ocular melanoma ( 5% ) and mucosal melanoma ( 4% ) .
906 patients were treated with ipilimumab in a dose of 10 mg / kg every 3 weeks ( 4 doses  induction phase ) followed by 10 mg/ kg every 12 weeks ( maintenance phase ) until progression or unacceptable / unmanageable toxicity of the treatment
the most common were diarrhea ( 10% ) , colitis ( 8% ) , endocrinopathies ( 4% ) , and dermatitis ( 0.8% ) .
incidence of saes such as hepatitis ( 0.24% ) , intestinal perforations ( 0.36% ) and drug - related death ( 0.24% ) was consistent with that seen in other trials evaluating 10 mg / kg ipilimumab monotherapy .
currently a phase i / ii trial evaluating ipilimumab in combination with vemurafenib is ongoing with the first enrolled metastatic melanoma ( braf v600 mutant ) patient in november 2011 .
paul chapman s group demonstrated interesting results of hypersensitivity skin reactions in melanoma patients treated with vemurafenib after previous ipilimumab therapy .
the investigators observed drug - related rash associated with vemurafenib in 13 out of 16 treated patients ( 81% ) .
four patients developed grade 3 maculopapular rash which occurred within 8 days of starting the vemurafenib treatment .
they did not progress to life - threatening reactions such as anaphylaxis or stevens - johnson syndrome and did not necessitate discontinuation of vemurafenib treatment .
the incidence of grade 3 rash was higher than that observed in patients treated with vemurafenib in the phase iii brim3 trial ( 25% vs. 8% ; p = 0.02 ) .
ipilimumab has also shown some activity in patients with metastatic melanoma and brain metastases , particularly when metastases were small and asymptomatic .
results of a phase 2 study of these patients were published recently in lancet oncology .
the intracranial response rate was 24% ( patients neurologically asymptomatic without corticosteroid treatment ) and 10% ( patients with neurological symptoms on a stable dose of corticosteroids ) .
activity of ipilimumab and fotemustine in metastatic melanoma patients has been tested in the nibit - m1 trial .
86 patients with asymptomatic brain metastases were enrolled in the study ( 7 patients had prior whole brain radiotherapy or radiosurgery ) .
patients received 4 doses of ipilimumab 10 mg / kg every 3 weeks plus fotemustine 100 mg / m weekly for 3 weeks , followed by ipilimumab every 12 weeks ( from week 24 ) combined with fotemustine every 3 weeks ( from week 9 ) .
the immune related ( ir ) disease control rate ( irdcr = cr + pr + + sd using the ir response criteria ) was 50% and immune related overall response rate ( irorr = cr + pr ) was 40% .
another trial evaluated the development of brain metastases in metastatic melanoma patients treated with ipilimumab and temozolomide .
of 64 enrolled patients ( 2 with a history of prior brain metastases ) , 11 ( 17% ) developed brain metastases at a median follow - up of 41 weeks .
a new interesting anti - cancer agent is anti - pd-1 ( bms-936558 , mdx-1106 ) , a fully human mab that blocks the programmed death-1 ( pd-1 ) co - inhibitory receptor expressed by activated t - cells .
the study drug was administered intravenously every 2 weeks until pd or cr , for a maximum of 12 cycles .
the most common included gastrointestinal ( 4% ) , endocrine ( 2% ) and hepatobiliary disorders ( 1% ) .
of the 20 patients that responded to the treatment , 12 developed a response lasting over 1 year .
bms-936558 was also evaluated in combination with a multipeptide vaccine in a phase i study in 30 previously treated patients with metastatic melanoma .
patients were vaccinated with mart-1/gp100/ny - eso-1 peptides with adjuvant montanide isa 51 together with bms-936558 ( 1 , 3 or 10 mg / kg ) every 2 weeks for 24 weeks , followed by bms-936558 alone every 3 months .
responses to the treatment were observed in all study cohorts ( 1/3/10 mg / kg  2 pr/5 pr/2 pr and 1 sd ) .
immunological tests demonstrated decreased pd-1 receptor on cd4 + and cd8 + lymphocytes and increased ctla4 receptors , and a dose - related decrease in cd8 t - cells while cd4 t - cells increased .
investigators from russia presented results of a trial evaluating efficacy of a dendritic cell ( dc)-based vaccine in patients with high risk resected melanoma ( stage iii and iv ) .
patients ( stage iii  46 , iv  10 ) were treated with autologous monocyte - derived dc vaccine primed with autologous tumor lysate , administered intradermally every 26 weeks until disease progression . in the control group 53 patients ( stage iii  47 , iv 
at a median follow - up of 22 months disease - free survival ( dfs ) was significantly longer in patients treated with the vaccine ( hr 0.45 ; 95% ci : 0.290.69 ; p < 0.05 ) although there was no difference in os between the study arms ( hr 0.71 ; 95% ci : 0.401.25 ; p = 0.23 ) .
the investigators observed a significant correlation between reduction of risk and vaccine - induced strong delayed type hypersensitivity reaction .
at the asco meeting investigators reported on a phase 3 trial ( optim ) evaluating effectiveness of intratumoral injections of talimogene laherparepvec ( t - vec ) compared with subcutaneous administration of gm - csf ( granulocyte - macrophage colony - stimulating factor ) in patients with advanced and metastatic melanoma .
t - vec ( formally oncovex ) is an oncolytic hsv1 that selectively replicates in tumors inducing a systemic anti - tumor immune response enhanced by local gm - scf expression .
an interesting strategy consisting of cd40 ligand / interferon- matured autologous dc immunized with gp100 antigen hla ( human leukocyte antigen ) i restricted peptides in patients with metastatic melanoma has been shown . out of 7 treated patients 2 pr were noted and 1 cr with a duration of over 3 years .
the investigators demonstrated a significant correlation of il-12 production by dcs with ttp ( time to progression ) .
other early phase immunotherapy trials included : intra - lesional administration of tg1042 ( adenovirus expressing interferon - gamma ) combined with adoptive til ( tumor infiltrating lymphocytes ) transfer ; tcr - il-2 ( t - cell receptor - interleukin-2 ) fusion protein in combination with cisplatin ; hyperacute - melanoma vaccine combined with pegylated interferon ; and autologous til infusion combined with lymphodepleting chemotherapy and low - dose il-2 .
 the 2012 asco ( american society of clinical oncology ) annual meeting has been held once again at the mccormick conference center in chicago , illinois , where asco has booked a 10-year run for the meeting . 
 the meeting was attended by more than 30,000 oncology professionals from around the world . of more than 4500 abstracts published at the meeting , 
 310 were related to melanoma . here 
 we report the results of the most interesting clinical trials presented at the meeting . apart from updated overall survival ( os ) 
 results of a phase 3 study evaluating the efficacy of vemurafenib and some new data on ipilimumab ( expanded access program [ eap ] and treatment of patients with brain metastases ) we report on practice changing trials : a phase 3 ( break ) trial evaluating efficacy of dabrafenib and a phase 3 study ( metric ) assessing trametinib in the treatment of metastatic melanoma patients . 
 another encouraging treatment strategy is combination of dabrafenib and trametinib evaluated in a phase i / ii study . 
 results of new immune checkpoint targeting by monoclonal antibody anti - pd1 ( bms-936558 ) in an early phase trial in monotherapy or in combination with a multipeptide vaccine in metastatic melanoma patients are presented . 
 also , results of dendritic cell - based vaccine ( randomized phase ii trial ) immunization in patients with high risk resected melanoma are shown . 
 furthermore , results of other melanoma immunotherapy strategies evaluated in early phase studies are reported . 
Kinase inhibitors
Immunotherapy