melanoma is one of the most devastating forms of cancer in terms of the number of years of life that patients lose , as it often affects younger people compared with other types of tumor . as with other cancers the shortcomings of this approach are all too clear : when treated with chemotherapy , a diagnosis of metastatic melanoma generally meant a relentless progressive disease and death in approximately 69 months . even immunotherapy , which has an accepted role in the treatment of metastatic melanoma patients , as well as those who have regional lymph node involvement that has been excised but remains at high risk of recurrence , fails to benefit more than a small minority of patients . clearly , there is a need for a more effective treatment , and recently two more targeted approaches have begun to show great promise and hopefully will change the therapeutic landscape for melanoma . the first of these is the emergence of selective inhibitors of the serine - threonine protein kinase b - raf ( braf ) for the treatment of metastatic melanoma , which have shown dramatic results in the 50% of patients whose tumors harbor an activating mutation in the oncogene encoding this kinase , braf , at least temporarily reversing the growth of the melanoma , resulting in a potential benefit in terms of life expectancy . also , recent clinical trial results with novel immunologic therapies appear to be breaking the barriers observed with the previous generation of cytokine - based immunotherapies , and have produced some dramatic results . the identification of activating mutations in braf in 5060% of melanomas in 2002 was the watershed event that opened the door for investigation of molecularly targeted therapy in melanoma . braf is a constituent of the long - studied mitogen - activated protein ( map ) kinase pathway , a well - known mediator of growth factor signals in cancer . therefore , when braf mutations were found in a large series of diverse tumor types , it was immediately apparent that these mutations might explain the involvement of this pathway in 78% of all cancers . as braf mutations are found most commonly in melanoma , laboratory investigation and clinical development of braf - targeted therapies naturally focused on this disease . the fundamental challenges that confronted the field were to understand why braf might be the tumors achilles heel rather than the other , numerous tumor - specific genetic alterations , and to develop potent and selective inhibitors . for several years following the identification of braf mutations , sorafenib was the only targeted therapy in clinical development known to have some capacity for inhibiting raf kinases . however , in phase ii trials , sorafenib demonstrated only moderate map kinase pathway inhibition and little to no clinical efficacy as a single agent . however , this moderate inhibition gave hope that more potent and selective braf inhibitors might yield better results , and consequently several braf inhibitors have entered clinical trials within the past few years . as plx4032 and gsk2118436 are the first selective braf inhibitors to show an effect in patients , i will focus mainly on them . in light of preclinical data demonstrating that plx4032 had selective antitumor effects in tumors harboring braf mutations , and because of the frequency with which braf mutations are known to occur in melanoma , 49 out of the 55 patients with various types of tumor who were enrolled during the dose escalation phase of the small preliminary phase i clinical trial of plx4032 had metastatic melanoma , and after the first evidence of measurable reductions in tumor size , the majority of patients enrolled had braf - mutant metastatic melanoma , which , rather unusually for a phase i trial , allowed not only for the characterization of safety and tolerability , but also efficacy . it was apparent that the drug only worked in the braf - mutant melanoma patients . as the dose was escalated to find the maximum tolerated dose , an increasing percentage of patients responded . by the time the highest five dose levels were evaluated , 11 of the 16 patients harboring the mutation experienced an objective response according to recist ( response evaluation criteria in solid tumors ) . dose - dependent toxicities that were commonly observed at the higher doses included rash fatigue , arthralgia , and photosensitivity . severe rash , fatigue , and arthralgia ultimately dictated the maximum tolerated dose , but could be managed by interrupting therapy , when necessary , or with dose reduction . ultimately , 32 additional patients with braf - mutant metastatic melanoma were enrolled in the extension phase of the trial and given a dose of 960 mg twice daily . a total of 81% of these patients showed measurable reduction in tumor size , two of these were tumor free , and four additional patients had minor degrees of tumor regression . progression - free survival for these patients was generally greater than 7 months but it is too early to define overall survival . as a side effect , nearly one - third of these patients developed one or more skin lesions  either well - differentiated squamous cell carcinoma or keratoacanthoma . this finding is not so surprising : it has been known for many years that a subset of squamous cell carcinomas and keratoacanthomas harbor mutations in the gene encoding hras ( a member of the ras family of small gtpases ) , and more recently it has been observed that selective braf inhibitors induce map kinase pathway signaling , particularly in the setting of ras mutations . it seems likely that these two factors interact to cause the appearance of these lesions during therapy . the clinical significance of squamous cell carcinomas and keratoacanthomas seems marginal in the setting of treatment for metastatic melanoma as they can be easily treated in most cases , but warrants more careful study . the second braf inhibitor , gsk2118436 , was evaluated in a phase i clinical trial   of similar design to the plx4032 study , and the results were even more striking . gsk2118436 is even more potent in inhibiting braf than plx4032 and is able to inhibit mutant braf kinase activity by 50% at concentrations less than 1 nm . a total of 93 patients were enrolled during the dose escalation portion of the trial , 85 of whom had metastatic melanoma , and of those , 76 had activating mutations in braf . doses ranged from 12 mg daily to 400 mg daily . at the highest dose , dose - limiting toxicities were severe pyrexia and loss of consciousness . among 35 patients treated at one of these two highest dose levels , the most common toxicities were pyrexia , fatigue , rash , the appearance of squamous cell carcinomas and keratoacanthomas , headache , nausea , and vomiting . among the 16 patients treated at the two highest dose levels , gsk2118436 only failed to halt tumor growth progression in two patients treated at the higher dose levels at or before the first restaging evaluation . of the nine patients who were enrolled with v600k mutations in braf , four had measurable responses . in addition to seeing responses in all visceral sites , treatment reduced the size of small , asymptomatic , previously untreated brain metastases in all of the subgroups of patients with this condition . taken together , the early clinical development of plx4032 and gsk2118436 clearly confirm that braf inhibitors can ( at least temporarily ) halt or reverse disease in patients with melanomas carrying this mutation , apparently improving survival times compared with historically standard treatments ( chemotherapy and interleukin-2 ) , although the follow - up times are still too short to define median overall survival times . antitumor immune therapy has also taken a leap forward recently , following a breakthrough in understanding t - cell activation and anergy . cytotoxic t - lymphocyte antigen 4 ( ctla4 ) is a t - cell surface receptor that competes with cd28 to bind with ( t - cell stimulatory ) b7 molecules on the surface of antigen presenting cells and promotes anergy . when the cd28:ctla4 ratio is high , t - cell activation ensues , whereas anergy is the result of a low ratio . thus an antibody targeting ctla4 allows the b7/cd28 interface to continue to drive t - cell activation , rather than become anergic , and this approach has been tested in the clinic in series of clinical trials spanning the past 10 years . the furthest advanced of this generation of therapies is ipilimumab , the ctla4-blocking antibody that was recently shown to increase survival in metastatic melanoma patients in a ( larger ) phase iii trial . although measurable responses were only seen in 10% of patients , or slightly less , proof - of - concept was established early on   in small trials based on the durability of these responses . some patients with advanced metastatic disease who had failed other therapies could be stabilized for months or even several years . however , a phase iii trial was clearly needed to define the true size of the subpopulation that would benefit . in the first of these trials to be analyzed , patients with metastatic melanoma who had failed standard therapy such as dacarbazine were randomly assigned to receive ipilimumab in combination with a gp-100 peptide vaccine , ipilimumab alone , or peptide vaccine alone . because the gp-100 peptide can only be recognized by the human leukocyte antigen ( hla ) marker hla - a2 , patients were randomly assigned such that 60% received ipilimumab / gp-100 , 20% received ipilimumab , and 20% received the gp-100 vaccine alone . at the time of analysis , both of the ipilimumab - treated groups had a significantly improved survival compared to the control group . this difference was best shown when looking at longer follow - up time , such as two years after initiation of study therapy ( 24% survival rate for ipilimumab alone versus 14% with vaccine alone ) . there are two features of this approach that are unique compared to other standard cancer therapies . first , some patients receiving ipilimumab have radiographic evidence of disease progression during treatment , receive no subsequent therapy , and then manifest measurable responses months later . amongst patients who demonstrate disease progression following the initial course of therapy ( typically 3 months ) , there is a small percentage who will subsequently benefit . however , it is not currently possible to prospectively distinguish between patients who will experience unchecked progression and those with a delayed response to therapy . second , ipilimumab induces activation not only of t cells that are capable of recognizing melanoma , but also of those recognizing self antigens , resulting in autoimmunity . a large percentage of patients develop some sort of mild or moderate autoimmunity in the first several months of therapy , requiring only minimal supportive care measures . the skin and gastrointestinal tract are the most common organs involved , manifesting as rash or diarrhea , but sometimes endocrine glands are involved . severe diarrhea leading to dehydration and electrolyte deficiencies is a concern , but not as much as ( rarer ) gastrointestinal perforation . amongst the endocrinopathies , the most clinically concerning is inflammation of the pituitary gland , which can lead to permanent adrenal insufficiency and hypothyroidism , and requires chronic mineral - corticoid and thyroid hormone replacement therapy . however , the life - prolonging benefit of this therapy is clear from the recently published randomized phase iii trial , and outweighs these autoimmune side effects . significant advances have been made in understanding the molecular pathophysiology , underlying genetic causes of tumors , and mediators of antitumor t - cell anergy . this has allowed the development of pharmacologic agents to specifically counter these processes . even amongst patient populations with advanced , refractory melanomas , there is clear evidence of tumor regression and improved life expectancy with oncogene - inhibitors and t - cell stimulatory therapies . braf inhibition only works in those whose tumors harbor a braf mutation ( approximately 50% of all melanomas ) , but induces responses in the vast majority of patients . ipilimumab , and other less - well - defined novel immunologic agents , are very effective in a small subgroup of patients , greatly extending life for these individuals , but as yet we do nt understand the biological basis that predicts response . with this success as a basis to build on , it can be hoped that combinations of these and other approaches will confer more than temporary respite from metastatic melanoma in the future and provide long - term benefits to a higher proportion of patients . ktf has served as a consultant for roche pharmaceuticals , glaxosmithkline , and bristol - myers squibb .
melanoma is among the leading causes of years of life lost due to cancer . 
 current chemotherapy and cytokine - based immunotherapy approaches benefit only a small percentage of patients with advanced disease . 
 however , the recent discovery of mutations in the gene encoding the serine - threonine kinase b - raf ( braf ) raises the possibility that oncogene - targeted therapy may provide a new point of vulnerability . in parallel , 
 a deeper understanding of the molecular mechanisms underlying antitumor t - cell activation and tolerance has provided a basis for developing therapies targeted against these processes . 
 results from an early phase trial with a braf inhibitor and a phase iii trial with a novel agent that activates t cells have radically altered the prospects for improving outcomes for patients with this historically treatment - refractory disease .