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Literature review current through: Jul 2014. | This topic last updated: Jul 30, 2014.

INTRODUCTION — Although the incidence of malignant melanoma is increasing, most cases are diagnosed at an early stage. In that setting, surgical excision is curative in most cases, and patients at high-risk of developing metastatic disease may benefit from adjuvant therapy with interferon alpha [1]. (See "Initial surgical management of melanoma of the skin and unusual sites" and "Adjuvant immunotherapy for melanoma".)

The management of patients with disseminated disease is a difficult problem. Approaches that have been shown to provide clinically important benefit for appropriately selected patients with disseminated melanoma include immunotherapy with high-dose interleukin-2 (IL-2), ipilimumab (a monoclonal antibody targeting CTLA-4), and monoclonal antibodies targeting the programmed death 1 protein (PD-1) or its ligand (PD-L1) [2]. Alternatively, inhibition of the MAP kinase pathway in patients whose tumors contain a V600 mutation in the BRAF gene also has an important role in appropriately selected patients. There are no randomized trials that compare the various immunotherapy approaches either to each other or to targeted therapies and there are no prospective data on the appropriate sequencing of these therapeutic approaches.

This topic reviews the role of immune checkpoint inhibitors in the treatment of advanced melanoma. An overview of the management of advanced melanoma is presented separately. (See "Overview of the management of advanced cutaneous melanoma".)

RATIONALE — Activation of cellular immunity begins when T cells recognize peptide fragments of intracellular proteins that are expressed on the surface of antigen presenting cells (APCs) bound to specific mixed histocompatibility complex (MHC) molecules. This interaction requires the presence of a costimulatory molecule (B7) and this activation results in upregulation of cytotoxic T-lymphocyte antigen 4 (CTLA-4). The CTLA-4 receptor on T lymphocytes is a negative regulator of T cell activation that outcompetes CD28 for binding to B7 on antigen presenting cells. CTLA-4 thereby serves as a physiologic “brake” on the activated immune system.

Ipilimumab is a monoclonal antibody to CTLA-4 that can prevent this feedback inhibition, resulting in an immune response against the tumor. In addition, preventing this feedback inhibition of the immune response can cause a breaking of tolerance to other host tissues that leads to potentially severe or life threatening autoimmune adverse events. (See 'Anti-CTLA-4 antibodies: Ipilimumab' below.)

A second co-inhibitory pathway uses the programmed cell death 1 receptor (PD-1), which is another inhibitory receptor present on activated T cells. When PD-1 binds to its ligand (PD-L1) (often present on tumor cells), the ability of the activated T cell to produce an effective immune response is down-modulated. Antibodies directed against PD-1 (nivolumab, MK-3475) or the PD-1 ligand thus may restore or augment an antitumor immune response and produce tumor responses in patients with advanced melanoma. (See 'Programmed death 1 protein' below.)

IMMUNE RESPONSE CRITERIA — Evaluation of the effectiveness of ipilimumab and other immune checkpoint inhibitors requires an understanding of the different patterns of response seen with this class of agents. The patterns of response to treatment with these immunotherapy agents differ from those with molecularly targeted agents or cytotoxic chemotherapy in several important respects [3]:

Patients may have a transient worsening of disease, manifested either by progression of known lesions or the appearance of new lesions, before disease stabilizes or tumor regresses. Therefore caution should be taken in abandoning therapy early. In general these delayed responses are not observed in patients with rapidly progressive, symptomatic disease.

Responses can take appreciably longer to become apparent compared with cytotoxic therapy. Continued disease regression is frequently observed well after completion of the initial induction period.

Some patients who do not meet criteria for objective response can have prolonged periods of stable disease that are clinically significant.

Immune-related response criteria have been proposed to deal with the altered patterns of response seen with ipilimumab and potentially other immunotherapies (table 1) [3].

Immune-related complete response: Complete resolution of all measureable and nonmeasurable lesions, with no new lesions. Complete response must be confirmed by a second, consecutive assessment at least four weeks later.

Immune-related partial response: A decrease in the total tumor burden of 50 percent or more compared to baseline, which must be confirmed by a second, consecutive assessment at least four weeks later. This category allows for the inclusion of progression of some lesions or the appearance of new lesions as long as the total tumor burden meets the response criterion.

Immune-related stable disease: Not meeting the criteria for either a partial or complete response or for progressive disease.

Immune-related progressive disease: An increase in tumor burden of 25 percent or more relative to the minimum recorded tumor burden. This must be confirmed by a second, consecutive assessment no less than four weeks after the initial documentation of an increase in tumor.

The use of these immune-related response criteria (table 1) are important because the application of traditional RECIST criteria (table 2) in patients treated with ipilimumab may lead to premature discontinuation of treatment in a patient who will eventually respond to treatment or have prolonged disease stabilization.

ANTI-CTLA-4 ANTIBODIES: IPILIMUMAB — Ipilimumab is a monoclonal antibody directed against CTLA-4. Its presumed mechanism of action is to break down tolerance to tumor-associated antigens in the melanoma. This mechanism of action can also result in autoimmune reactions against self antigens.

The optimal approach to integrate ipilimumab treatment with high dose interleukin-2 and with targeted therapy has not been determined in randomized clinical trials. The approach recommended here is consistent with the consensus statement of the Society for Immunotherapy of Cancer (figure 1) [2]. (See "Overview of the management of advanced cutaneous melanoma", section on 'Choice and sequence of therapy'.)

Efficacy — In two large phase III trials, ipilimumab significantly prolonged survival in patients with advanced melanoma.

Previously treated patients — In a placebo-controlled phase III trial, 676 patients were randomly assigned in a 3:1:1 ratio to ipilimumab plus a glycoprotein 100 (gp100) vaccine, ipilimumab alone, or gp100 alone [4]. All patients were HLA-A*0201 positive and had unresectable metastatic melanoma. All patients had received prior systemic treatment for advanced disease with either cytotoxic chemotherapy or IL-2.

Ipilimumab (3 mg/kg) and/or vaccine were given every three weeks for four doses. Patients with confirmed partial or complete response or stable disease for three months or more after completion of the 12 week induction period were allowed to receive reinduction with their original treatment if they subsequently had disease progression. The primary endpoint of the trial was overall survival.

Key results of this trial included the following:

Overall survival was significantly increased in patients given ipilimumab (ipilimumab plus gp100 versus gp100, median 10.0 versus 6.4 months, HR for death 0.68; ipilimumab alone versus gp100 alone 10.1 versus 6.4 months, HR 0.66). Overall survival rates for the ipilimumab plus gp100, ipilimumab alone, and gp100 alone were 44, 46, and 25 percent at 12 months and 22, 24, and 14 percent at 24 months, respectively.

Subset analyses found no evidence that the survival benefit was restricted to any particular subsets. Benefits were independent of sex, age (≤65 or >65 years), stage at presentation (M0, M1a, and M1b versus M1c), baseline LDH (normal versus elevated), or prior use of interleukin-2 (table 3A-B).

The objective response rate was significantly improved in both groups of patients treated with ipilimumab compared to gp100 alone (5.7 and 10.9 versus 1.5 percent, respectively). When objective partial or complete responses were observed, these were maintained for at least two years in 4 of 23 (17 percent) patients treated with ipilimumab plus gp100, 9 of 15 (60 percent) with ipilimumab alone and 0 of 2 with gp100 vaccine only. Responses to ipilimumab, either alone or in combination with gp100, continued to improve more than 24 weeks after initiation of therapy; five patients with stable disease eventually achieved a partial response without additional therapy, and four patients with a partial response went on to achieve a complete response.

Among 31 patients who initially received ipilimumab either alone or with gp100 and then underwent reinduction therapy with ipilimumab, six (21 percent) had an objective response to retreatment, and 15 (48 percent) had stable disease [5].

The phase III trial limited enrollment to patients who were HLA-A*0201 positive because of the use of the gp100 vaccine [4]. Retrospective analysis of 453 previously treated patients treated with ipilimumab in four phase II trials compared patients who were HLA-A*0201 positive with those who were HLA-A*0201 negative [6]. In this analysis, ipilimumab had similar activity regardless of HLA type.

Patients who were treated with high-dose IL-2 may receive substantial benefit from treatment with ipilimumab; the clinical response or duration of progression-free survival following IL-2 does not accurately predict the response to subsequent ipilimumab treatment [7]. In a retrospective analysis of 208 patients who had been treated with high-dose IL-2, there were 48 patients who subsequently were treated with single agent ipilimumab. The median overall survival was 12 months, with sustained remission beyond two years in some cases.

Previously untreated patients — In a second phase III trial, 502 patients with metastatic melanoma were randomly assigned to ipilimumab plus dacarbazine or to placebo plus dacarbazine [8]. Approximately one-fourth of patients had received prior adjuvant therapy, but those previously treated for metastatic disease were not eligible. Patients with brain metastases, ocular melanoma, mucosal melanoma, or autoimmune disease were excluded.

All patients received dacarbazine (850 mg/m2 intravenously) every three weeks for eight cycles in the absence of disease progression or significant toxicity. Patients were randomly assigned to receive either ipilimumab at a dose of 10 mg/kg or placebo on weeks 1, 4, 7, and 10. At week 24, patients with stable disease or an objective response were eligible for maintenance therapy with ipilimumab at 10 mg/kg or placebo given every twelve weeks.

Major results of this trial include the following:

Overall survival, the primary endpoint of the trial, was significantly increased in patients assigned to ipilimumab plus dacarbazine compared with placebo plus dacarbazine (median 11.2 versus 9.1 months). Survival rates at one, two, and three years consistently favored treatment with ipilimumab (47 versus 36, 29 versus 18, and 21 versus 12 percent, respectively).

The rate of disease control (objective response plus stable disease) did not differ significantly between the two groups (33 versus 30 percent), nor did the best overall response rate (15 versus 10 percent).

The overall incidence of grade 3 or 4 toxicity was significantly higher with ipilimumab plus dacarbazine compared with dacarbazine alone (56 versus 28 percent). Overall, grade 3 or 4 immune-mediated adverse reactions were significantly more common with the ipilimumab combination (38 versus 4 percent).

Hepatic toxicity was significantly more common with the combination than with dacarbazine alone (overall incidence of transaminase elevation 29 to 33 versus 6 percent). Furthermore, the incidence of hepatic toxicity was much higher compared with that observed in the phase III trial when ipilimumab was given without dacarbazine or in prior phase II trials in which ipilimumab administered at this dose and schedule. The increase in hepatic toxicity may be due to its combination with dacarbazine, which is also known to be hepatotoxic.

The incidence of other immune related toxicities (colitis, rash, hypophysitis) was less than that seen in prior studies with ipilimumab alone, perhaps suggesting that dacarbazine may have blunted these toxicities and/or the higher incidence of hepatotoxicity may have pre-empted or altered the immune toxicity profile.  

Whether this blunting of immune toxicity by dacarbazine might have also blunted the antitumor effect of ipilimumab is a matter of speculation. However, the overall pattern of toxicity and efficacy on this trial do not support the addition of dacarbazine to ipilimumab nor the use of ipilimumab at the 10 mg/kg dose compared with the approved 3 mg/kg dose.

Long-term duration of response — Although only a minority of patients achieve a complete response, such responses appear to be durable and of prolonged duration in most cases. As an example, in the composite experience from the National Institutes of Health, 177 patients were treated with ipilimumab in three studies between 2002 and 2005 [9]. Nearly 9 percent of these patients experienced a complete response, and all but one of these was ongoing at 54 to 99 months. The responses were delayed in developing, in some cases even after 30 months. The complete responses were most frequent in those who received interleukin-2 with the ipilimumab.

Dose and schedule — Ipilimumab has been studied at different doses and schedules. The approved dose of ipilimumab is 3 mg/kg by intravenous infusion given every three weeks for four doses based upon the results of the phase III trial in previously treated patients [4]. Ongoing phase III trials for which results are not yet available have used ipilimumab at a dose of 10 mg/kg by intravenous infusion given every three weeks for four doses with maintenance ipilimumab at 10 mg/kg provided every 12 weeks. (See 'Efficacy' above.)

Three dose levels of ipilimumab were compared in a double-blind phase II trial, in which 217 patients with advanced melanoma were randomly assigned to one of three dose levels: 0.3 mg/kg, 3.0 mg/kg, and 10 mg/kg [10]. Patients were treated every three weeks for four cycles, with provision for maintenance treatment every 12 weeks in patients with an objective response or stable disease.

The objective response rate (complete plus partial response) increased progressively with dose (0, 4.2, and 11.1 percent in the 0.3, 3, and 10 mg/kg groups, p = 0.002 for trend).

Overall survival improved progressively with dose (median 8.6, 8.7, and 11.4 months; one-year survival rate 39.6, 39.3, and 48.6 percent; and two-year survival rate 18.4, 24.2, and 29.8 percent, respectively), but these differences were not statistically significant.

There was an increase in the frequency of adverse events at increasing dose levels:

Serious adverse events (35, 49, and 53 percent, at 0.3, 3.0, and 10 mg/kg, respectively).

Immune-related adverse events (26, 56, and 70 percent, respectively) and serious (grade 3 to 4) immune-related adverse events (0, 7, and 25 percent, respectively).

Adverse events leading to drug discontinuation (13, 10, and 27 percent, respectively).

The 3 and 10 mg/kg doses have been compared in a phase III trial which completed accrual in 2010 (NCT01515189). The primary endpoint of the trial is overall survival; results are pending.

In some protocols, patients with an objective tumor response or stable disease after the induction period could receive an additional dose every 12 weeks as “maintenance therapy” as tolerated until disease progression. In other trials, including the initial phase III [4], patients did not receive routine maintenance therapy; however, those exhibiting disease progression after having disease response or stable disease following the induction period were allowed to undergo “reinduction” according to the same schedule if they subsequently progressed.

Brain metastases — Patients with untreated brain metastases were excluded from the initial phase III trial [4]. Preliminary results from phase II studies indicate that ipilimumab has activity in patients with brain metastases and that its safety profile in those patients is similar to that in patients without brain metastases. (See "Management of brain metastases in melanoma", section on 'Immunotherapy'.)

Adjuvant therapy — The potential role of ipilimumab as adjuvant therapy following resection of high risk melanomas is discussed separately. (See "Adjuvant immunotherapy for melanoma", section on 'Ipilimumab'.)

Ipilimumab versus targeted therapy — Clinical trials will be required to ascertain the role and optimal sequence of ipilimumab relative to molecularly targeted therapies in patients with tumors possessing characteristic mutations in BRAF. (See "Molecularly targeted therapy for metastatic melanoma".)

Toxicity — A wide range of immune-mediated adverse events have been observed. The most common serious manifestations include enterocolitis, hepatitis, dermatitis, and endocrinopathies. (See 'Rationale' above.)

In the phase III trial that demonstrated an increase in survival, immune-related adverse events occurred in approximately 60 percent of patients treated with ipilimumab; these typically did not occur until several weeks into therapy [4]. Overall, severe or life-threatening (grade 3 or 4) toxicity was seen in 10 to 15 percent of ipilimumab-treated patients, compared to 3 percent in those receiving only gp100. The phase III trial used a dose of 3 mg/kg of ipilimumab every three weeks. A somewhat higher incidence of side effects was observed with a dose of 10 mg/kg every three weeks in the randomized phase II trial that assessed the effects of dose on activity and toxicity [10]. (See 'Dose and schedule' above.)

Treatment of immune-mediated toxicity — Phase II and phase III trials have shown that prompt medical attention and early administration of corticosteroids are essential for the management of immune-related adverse events and to prevent their progression to more serious toxicity [4,10-12]. In the United States, the Food and Drug Administration (FDA) has created a Risk Elimination and Management System (REMS) to provide additional information to both healthcare providers and patients, which is available on the internet [13,14].

Treatment requires interruption of ipilimumab and the use of corticosteroids [15]. Treatment is based upon the severity of the observed toxicity:

For patients with grade 2 (moderate) immune-mediated toxicities, treatment with ipilimumab should be withheld and should not be resumed until symptoms or toxicity is grade 1 or less. Corticosteroids (prednisone 0.5 mg/kg/day or equivalent) should be started if symptoms do not resolve within a week.

For patients with grade 3 or 4 (severe or life-threatening) immune-mediated toxicities, treatment with ipilimumab should be permanently discontinued. High doses of corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) should be given. When symptoms subside to grade 1 or less, steroids can be gradually tapered over at least one month.

Gastrointestinal toxicity — Diarrhea and/or colitis are among the most common, and potentially most serious, complications of anti-CTLA4 treatment. In the phase III trial, diarrhea and/or colitis was reported in 31 percent of cases, of which 6 percent were serious or life-threatening [4]. Although the clinical presentation is similar to that with inflammatory bowel disease, the distribution of lesions and histopathology are not characteristic of Crohn’s disease or ulcerative colitis [16].

Symptoms of colitis can develop rapidly and become life-threatening [17-20]. Bowel perforation, sepsis, and death have been reported as complications of ipilimumab therapy [17,20,21]. In the phase III trial, the median time to development of moderate or severe enterocolitis after initiating ipilimumab therapy was six to seven weeks [15].

Meticulous attention to gastrointestinal symptoms is required to prevent progression to more serious complications [15]. Patients should be monitored for symptoms of enterocolitis (diarrhea, abdominal pain, mucus or blood in the stool) and appropriate treatment initiated promptly. (See 'Treatment of immune-mediated toxicity' above.)

Mild (grade 1) symptoms (less than four stools per day over baseline) can be managed symptomatically.

Colonoscopy is indicated if grade 2 symptoms (increase of four to six stools per day over baseline) or greater occur. Treatment should be initiated if colitis is observed.

For patients with severe or life-threatening enterocolitis (grade 3 or 4, increase of seven or more stools per day over baseline or other complications), treatment with ipilimumab should be permanently discontinued. High doses of corticosteroids should be given. For those who do not respond to high-dose steroid therapy within one week, treatment with infliximab should be considered. In some cases refractory to infliximab, mycophenolate may be needed.

Budesonide, an orally administered corticosteroid that is used to treat inflammatory bowel disease, was proposed as a potential way to prevent the immune-related colitis in patients treated with ipilimumab. However, this approach was not beneficial in a randomized phase II trial [12].

Upper gastrointestinal tract involvement has also been reported, including involvement of the esophagus, duodenum, and ileum [22].

Hepatitis — Immune-mediated hepatitis has been seen in 2 to 9 percent of patients treated with ipilimumab [4,10,11]. At least one death due to liver failure has been reported; this was attributed to a delay in the initiation of steroid therapy [11]. The reported incidence of hepatoxicity exceeds 30 percent when ipilimumab is combined with dacarbazine, and the combined used of these agents should be avoided [8].

Hepatic function (transaminase and bilirubin) should be monitored prior to each dose of ipilimumab [15]:

Grade 2 hepatic toxicity: AST or ALT >2.5 times the upper limit of normal (ULN) but ≤5 times the ULN, or total bilirubin >1.5 times the ULN but ≤3 times the ULN.

Grade 3 or greater hepatic toxicity: AST or ALT >5 times the ULN, or total bilirubin >3 times the ULN.

Corticosteroids are the initial treatment for grade 3 or higher hepatic toxicity. Mycophenolate may be useful in patients with persistent severe hepatic toxicity [15]. (See 'Treatment of immune-mediated toxicity' above.)

Dermatologic toxicity — Dermatologic side effects are common with ipilimumab therapy and can be manifested by pruritus, rash, vitiligo, and alopecia [23]. In the phase III trial, the incidence of dermatologic adverse events in patients treated with ipilimumab alone was 40 percent; of these, 2.5 percent were more severe (Stevens-Johnson syndrome, toxic epidermal necrolysis, full thickness dermal ulceration) [4,15]. The median time to onset of moderate or severe dermatologic toxicity was three weeks.

Mild to moderate dermatitis (rash, pruritus) can be managed symptomatically. More severe manifestations require discontinuation of ipilimumab and management with corticosteroids. (See 'Treatment of immune-mediated toxicity' above.)

Endocrinopathies — A wide range of autoimmune endocrine side effects have been reported with ipilimumab therapy [24]. Although these are less common than diarrhea and colitis, they have the potential to be serious or fatal.

Hypophysitis and hypopituitarism are uncommon side effects of anti-CTLA-4 immunotherapy [25]. In the phase III trial, nine patients treated with ipilimumab (1.8 percent) had severe or life-threatening hypopituitarism [4,15]. Several of these patients also had other endocrine side effects (hypothyroidism, adrenal insufficiency, or hypogonadism). An additional 12 patients (2.3 percent) had moderate endocrinopathies requiring hormone replacement therapy or other medical intervention. The median time to onset of endocrine symptoms was 11 weeks, but in some cases symptoms did not appear until after completion of the initial four courses of therapy.

Patients should be monitored for clinical signs or symptoms associated with pituitary, thyroid, or adrenal disease [15]. These may be nonspecific, and can include fatigue, headache, mental status changes, abdominal pain, change in bowel habits, or hypotension. Thyroid function and clinical chemistries should be monitored prior to each dose of ipilimumab and as indicated by clinical signs or symptoms. (See "Clinical manifestations of hypopituitarism" and "Diagnosis of hypopituitarism" and "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Clinical manifestations of adrenal insufficiency in adults".)

In addition to the endocrine manifestations of hypophysitis (eg, adrenal insufficiency, hypothyroidism, hypogonadism), swelling of the pituitary can sometimes be detected on imaging studies and may result in neurologic symptoms including headache or visual abnormalities [23,26]. Swelling of the pituitary must be distinguished from brain metastasis.

Primary thyroid disease can be manifested by hyperthyroidism in association with Graves disease or as hypothyroidism secondary to a destructive thyroiditis. Hypothyroidism may also be secondary to hypophysitis, panhypopituitarism, and decreased production of TSH. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Overview of the clinical manifestations of hyperthyroidism in adults".)

Treatment of endocrinopathies includes hormone replacement therapy as needed, corticosteroids, and cessation of ipilimumab based upon the severity of the complication. (See 'Treatment of immune-mediated toxicity' above and "Treatment of hypopituitarism" and "Treatment of hypothyroidism" and "Treatment of adrenal insufficiency in adults".)

Other immune-mediated adverse events — Case reports or large series have identified a number of other immune-related adverse events that affect various organ systems:

Ocular symptoms associated with ipilimumab include conjunctivitis, uveitis and scleritis, and Graves ophthalmopathy [18,27,28].

Neurologic complications include Guillain Barre syndrome [4,29], inflammatory myopathy [30], aseptic meningitis [31], temporal arteritis [11], inflammatory enteric neuropathy causing constipation [32], and posterior reversible encephalopathy syndrome [33].

Autoimmune pancreatitis [34].

Hematologic manifestations that have been reported include red cell aplasia [35], pancytopenia [36], and autoimmune neutropenia [37].

Sarcoidosis [38,39].

Systemic vasculitis, including kidney disease [11,40].

Acquired hemophilia A due to the presence of a factor VIII inhibitor [41]. (See "Acquired inhibitors of coagulation", section on 'Factor VIII inhibitors'.)

When rare immune-mediated complications are identified, management should follow the general guidelines for treatment interruption and corticosteroid. (See 'Treatment of immune-mediated toxicity' above.)

Other Anti-CTLA4 antibodies — Tremelimumab, another monoclonal antibody directed again CTLA-4, showed activity in phase I and II clinical studies in previously treated patients [42,43]. Based upon this, a phase III trial was conducted in which previously untreated patients were randomly assigned to either tremelimumab or chemotherapy [44]. Although there was a prolongation in response duration among those treated with tremelimumab, the difference in overall survival was not statistically significant.

PROGRAMMED DEATH 1 PROTEIN — The programmed death 1 protein (PD-1) is another key immune checkpoint receptor expressed by activated T cells [45,46]. PD-1 binds to its ligands PD1-L1 (B7-H1) and PD1-L2 (B7-DC), which are expressed on tumor cells, thereby causing immunosuppression and preventing the immune system from rejecting the tumor.

Monoclonal antibodies targeting both PD-1 and PD-L1 are being developed to interrupt this pathway and to augment the antitumor immune response; these have demonstrated significant clinical activity against several tumor types.

Anti-PD1 monoclonal antibodies — Three anti-PD-1 monoclonal antibodies have demonstrated activity in initial clinical trials in patients with advanced melanoma.

Nivolumab — Nivolumab is a humanized monoclonal antibody that targets the PD-1 protein. Initial studies in patients with advanced melanoma suggest that nivolumab can induce clinically meaningful tumor regression and prolong survival. Phase III trials are in progress.

A phase I/II dose escalation, cohort expansion study included 107 patients with melanoma [45,47]. Patients were treated at doses ranging from 0.1 to 10 mg/kg, given every two weeks for up to 96 weeks. Patients had advanced disease; 78 percent had visceral metastases, 36 percent had an elevated serum lactate dehydrogenase, and 62 percent had received at least two prior systemic treatments.

Results were updated 14 months after the last patients had initiated therapy at the 2014 American Society of Clinical Oncology (ASCO) meeting [47,48]:

The median overall survival was 17 months, and the one, two, and three-year survival rates were 63, 48, and 41 percent, respectively.

The objective response rate was 31 percent based upon RECIST criteria, 7 percent had stable disease persisting for at least 24 weeks, and an additional 4 percent had atypical responses based upon immune response criteria (table 1).

Remissions and disease stabilization frequently persisted after treatment discontinuation. Among patients with an objective response, 21 discontinued therapy for reasons other than disease progression. Of these, 11 continued in response for at least 24 weeks after treatment discontinuation, and 7 of the 11 were still in response after 56 weeks.

The most common adverse events were fatigue, rash, and diarrhea, which were observed in 32, 23, and 18 percent of cases, respectively. Serious (grade 3 or 4) treatment-related adverse events occurred in 24 patients (22 percent).

Expression of PD-L1 by the tumor appeared to predict for a higher response rate, longer progression-free survival, and longer overall survival compared with tumors that did not express PD-L1.

Three phase III trials using nivolumab are currently evaluating the role of nivolumab in patients with advanced melanoma.

In NCT01721746, patients who have progressed following treatment with ipilimumab were randomly assigned to nivolumab or chemotherapy with either dacarbazine or the combination of carboplatin plus paclitaxel. This trial has completed accrual and results should be forthcoming shortly.

In NCT01721772, previously untreated patients known to be BRAF wild type are being randomly assigned to nivolumab or dacarbazine.

In NCT01844505, previously untreated patients are being randomized to receive either ipilimumab, nivolumab, or the combination of the two agents. (See 'Combined anti-CTLA-4 and anti-PD-1 immunotherapy' below.)

Pembrolizumab — Pembrolizumab (MK-3475) is an anti-PD1 monoclonal antibody that has been extensively evaluated in both ipilimumab naïve and previously treated patients [49-51].

In a prospective phase I study, 411 patients with advanced melanoma were treated with pembrolizumab on one of three dose schedules (10 mg/kg every two weeks, 10 mg/kg every three weeks, or 2 mg/kg every three weeks). Seventy-seven percent of patients had received prior systemic therapies for metastatic disease. The study included 190 patients who were ipilimumab naïve (46 percent) and 221 who had been previously treated with ipilimumab (54 percent). Included in the study was a cohort of 276 patients who were randomly assigned to either 2 or 10 mg/kg given every two weeks [52]. Results from this study were updated at the 2014 American Society of Clinical Oncology (ASCO) meeting:

The overall response rate using RECIST criteria (table 2) and central review was 34 percent, including 40 percent in those who were ipilimumab naïve and 28 percent in those who had been treated with ipilimumab. Similar response rates were seen using immune-related response criteria (table 1).

Overall survival at 12 months was 69 percent and 62 percent at 18 months. The median progression-free survival was 5.5 months, and 45 percent of patients remained progression free at six months.

On multivariate analysis of the entire study population, there were no significant differences in outcomes between the three dose schedules [50]. In the randomized cohorts, there were no differences in objective response rates between those treated with either 2 mg/kg every three weeks or 10 mg/kg every three weeks [52].

Preliminary analyses studied PD-L1 expression in the tumor as a predictive marker for responsiveness to pembrolizumab [53]. Although these studies suggested that PD-L1 positivity correlated with increased responsiveness, absence of PD-L1 expression did not preclude a clinical response.

Treatment toxicity was manageable. The most common toxicities were fatigue, pruritus, rash, diarrhea, and arthralgia (36, 24, 20, 16, and 16 percent, respectively). Overall 12 percent of patients experienced grade 3 or 4 toxicity, the most common being fatigue (2 percent), and there were no treatment-related deaths. There were similar safety profiles in those previously treated with ipilimumab and in those who were ipilimumab naïve.

In a published analysis of 173 patients from this trial with ipilimumab resistant disease (≥2 cycles of ipilimumab) who were randomly assigned to either a 2 mg/kg or 10 mg/kg dose every three weeks, there was no difference in the objective response rate (26 percent for both groups using RECIST criteria) [51]. There was also no significant difference in the safety profile.

Two randomized trials are in progress or being planned, one comparing pembrolizumab with chemotherapy (NCT01704287) in patients who had previously received ipilimumab, and the other comparing pembrolizumab with ipilimumab (NCT01866319) in treatment naïve patients.

Pidilizumab — Pidilizumab (CT-011) is an anti-PD-1 monoclonal antibody that was evaluated at two dose levels in a phase II study of 103 patients with metastatic melanoma [54]. Approximately one-half of the patients had received prior treatment with ipilimumab.

Preliminary results were presented at the 2014 American Society of Clinical Oncology (ASCO) meeting. Although the objective response rate was only 6 percent, the overall survival at 12 months was 65 percent in the study population. There were no significant differences in either the objective response rate or in the 12-month survival rate between the two levels, or between those who were ipilimumab naïve versus ipilimumab treated.

Anti-PD1-L1 monoclonal antibodies — Clinical activity has been observed with two different anti-PD1-L1 monoclonal antibodies.

BMS-936559 — BMS-936559 binds to PD1-L1, thus preventing its interaction with PD-1. BMS-936559 is being tested in a dose escalation phase I/II study in pretreated patients with a variety of malignancies [46]. The trial includes 207 patients, including 55 with melanoma. Overall, potentially immune-related adverse events were seen in 39 percent of patients.

There were 9 objective responses among the 52 evaluable melanoma patients (17 percent). Five of these had an objective response lasting at least one year, and six additional cases had stable disease that was maintained for at least 24 weeks.

MPDL3280A — MPDL3280A is another monoclonal antibody that binds to PD1-L1. Initial results of a phase I dose escalation study were presented at the 2013 ASCO meeting [55]. The dose escalation component of that study included 45 patients with advanced melanoma. An overall response rate of 29 percent was reported, and 43 percent of patients were progression-free at 24 weeks. Additional clinical experience is being gained through a dose expansion cohort in patients with advanced melanoma and other malignancies.

COMBINATION REGIMENS

Combined anti-CTLA-4 and anti-PD-1 immunotherapy — The combined administration of anti-CTLA-4 immunotherapy with ipilimumab plus anti-PD-1 immunotherapy with nivolumab appears to have a higher level of anti-melanoma activity than either agent alone and has a manageable toxicity profile [56]. The data from this study were updated at the 2014 American Society of Clinical Oncology (ASCO) meeting [57].

The combination was assessed in a phase I trial in which both drugs were given in successive dose escalation cohorts. In a concurrent therapy cohort, 53 patients with advanced melanoma were treated with both drugs once every three weeks for four doses. Nivolumab was then continued every three weeks through week 24. Subsequently, therapy with both drugs was continued once every 12 weeks for a maximum of eight additional doses. In a separate sequential cohort, nivolumab was given on the same schedule to 33 patients who had received prior ipilimumab. Subsequently, another cohort of 41 patients was treated with the combination of ipilimumab plus nivolumab for four cycles, followed with nivolumab maintenance only given every two weeks for up to 84 weeks [57].

In the concurrent treatment cohort, the objective response was 42 percent (17 percent complete responses and 25 percent partial responses). Responses appeared durable, and 18 of the 22 responders continued in response at the latest follow-up [57].

Overall survival in the original cohort of 53 patients at one and two years was 94 and 88 percent, respectively [57].

Treatment-related adverse events were observed in 93 percent of cases. The most common events of any degree of severity were rash, pruritus, fatigue, and diarrhea (55, 47, 38, and 34 percent, respectively) [56]. Severe treatment related adverse events were reported in 49 percent of cases, including liver, gastrointestinal, and kidney toxicity (15, 9, and 6 percent of cases, respectively). Treatment was discontinued because of adverse events in 11 cases (21 percent).

Additional clinical experience and longer follow-up will be required to determine the optimal dose and schedule for concurrent immune checkpoint therapy as well as its role in the management of patients with advanced melanoma. A three armed phase III trial is comparing the combination of nivolumab plus ipilimumab compared with each of these other checkpoint inhibitors as a single agent; enrollment is complete and results are pending (NCT01844505).

Ipilimumab plus GM-CSF — The addition of granulocyte-macrophage (GM) colony-stimulating factor (CSF) to ipilimumab was studied in a phase II trial conducted by Eastern Cooperative Oncology Group (ECOG).

In this trial, 245 patients with advanced melanoma were randomly assigned to ipilimumab plus GM-CSF or ipilimumab alone [58]. Ipilimumab was given at a dose of 10 mg/kg every three weeks for four cycles, followed by maintenance every 12 weeks. GM-CSF (250 micrograms/day subcutaneously) was given on days 1 to 14 of each 21 day cycle.

Results of this trial were presented at the 2013 American Society of Clinical Oncology (ASCO) meeting. At a median follow-up of 13 months, there was no difference in the objective response rate with or without GM-CSF (15.5 and 14.8 percent, respectively). There also was no significant difference in the progression-free survival (34.0 versus 29.6 percent at 6 months, hazard ratio [HR] 0.92, 95% CI 0.69-1.23). However, overall survival was significantly improved by the addition of GM-CSF (median 17.5 versus 12.7 months, one-year survival rates 69 versus 53 percent, HR 0.64, p = 0.014).

The addition of GM-CSF resulted in a significant reduction in the incidence of high grade adverse events, particularly related to pulmonary and gastrointestinal toxicity. The extent to which this decrease in toxicity contributed to the improved overall survival is unclear.

It is important to note that this trial used a higher dose of ipilimumab than is currently approved and that maintenance therapy was also included as a component of the protocol. The clinical implications of these results will require further study and confirmation.

OTHER IMMUNE REGULATORY CHECKPOINTS — Monoclonal antibodies targeted against a number of other regulatory checkpoints are being evaluated in patients with advanced melanoma based upon our current understanding of the development of cellular immunity.

4-1BB — 4-1BB (CD137) is a member of the tumor necrosis factor (TNF) family and acts as a costimulatory molecule that causes T cell proliferation. A humanized MAb, BMS-663513, targeted at CD137 acts as an agonist and can cause costimulation of CD8+ and CD4+ cells.

In a preliminary report of the initial phase I study with this agent, three partial responses were observed among 54 patients with melanoma [59].

OX40 — OX-40 is another tumor necrosis factor (TNF) receptor, which also acts as a costimulatory factor for T cells. A MAb targeting this receptor has begun phase I study [60].

SUMMARY AND RECOMMENDATIONS

The CTLA-4 receptor on T lymphocytes is a negative regulator of T cell activation that blocks positive stimulatory effects to these cells mediated by other T cell receptors. The monoclonal antibody ipilimumab binds to CTLA-4 and thus prevents this feedback inhibition. This mechanism of action results in an immune response directed against melanoma, as well as a variety of autoimmune side effects. Other immune checkpoint inhibitors, particularly directed against PD-1 and the PD-1 ligand are under development, both as single agents and in combination with ipilimumab. (See 'Rationale' above.)

In a phase III clinical trial in previously treated patients, ipilimumab (3 mg/kg every three weeks for four doses) significantly improved overall survival compared with a control vaccine. In a phase III trial in previously untreated patients, ipilimumab (10 mg/kg every three weeks for four doses) plus dacarbazine significantly increased overall survival compared with dacarbazine alone, but was associated with significant hepatotoxicity. (See 'Efficacy' above.)

For patients without a V600 BRAF mutation, we recommend immunotherapy (high dose IL-2 or ipilimumab) rather than chemotherapy as the initial systemic therapy (figure 1) (Grade 1A). Targeted therapy is not indicated in patients without a characteristic V600 mutation. (See "Overview of the management of advanced cutaneous melanoma", section on 'Choice and sequence of therapy'.)

Ipilimumab represents the preferred option for many, if not the majority, of patients with stage IV melanoma considering immunotherapy. However, high-dose IL-2 represents a reasonable first line option for appropriately selected patients. (See "Overview of the management of advanced cutaneous melanoma", section on 'Immunotherapy'.)

For patients with a poor performance status or untreated brain metastases who thus are not candidates for high dose IL-2, we recommend immunotherapy with ipilimumab rather than chemotherapy (Grade 1A). (See 'Previously untreated patients' above.)

For patients with a V600 BRAF mutation and a good performance status, we suggest immunotherapy rather than targeted therapy as the initial systemic therapy (figure 1) (Grade 2C). (See "Overview of the management of advanced cutaneous melanoma", section on 'Choice and sequence of therapy'.)

Ipilimumab represents the preferred option for many, if not the majority, of patients with stage IV melanoma considering immunotherapy. However, high-dose IL-2 represents a reasonable first line option for appropriately selected patients. (See "Overview of the management of advanced cutaneous melanoma", section on 'Immunotherapy'.)

For patients with a V600 BRAF mutation who were initially treated with immunotherapy and whose disease can no longer be controlled with immunotherapy, we recommend targeted therapy with a BRAF inhibitor (vemurafenib, dabrafenib) and/or a MEK inhibitor (trametinib) rather than chemotherapy (Grade 1B). (See "Molecularly targeted therapy for metastatic melanoma".)

For patients with a V600 BRAF mutation and a poor performance status, we suggest targeted therapy rather than immunotherapy (figure 1) (Grade 2C). Immunotherapy with ipilimumab is an alternative. Immunotherapy may be considered for second-line therapy in patients who progress while on targeted therapy, although its efficacy in this setting has not been established. (See "Molecularly targeted therapy for metastatic melanoma" and "Interleukin-2 and other immunotherapies for advanced melanoma".)

The following factors should be considered when a patient is treated with ipilimumab:

The optimal dosage of ipilimumab has not been definitively determined. The phase III trial in previously treated patients demonstrated prolonged survival using a dose of 3 mg/kg repeated every three weeks for four cycles and this regimen was approved by the United States Food and Drug Administration (FDA). Many subsequent and ongoing clinical trials use a dose of 10 mg/kg on the same schedule. (See 'Dose and schedule' above.) The relative merits of 10 mg/kg versus 3 mg/kg schedule are being addressed in a randomized clinical trial.

Patients treated with ipilimumab may have a transient worsening of disease (manifested either by progression of known lesions or the appearance of new lesions) before responses develop or the disease stabilizes. Therefore caution should be taken in abandoning therapy early. In general, clinical responses are not observed in patients who have rapidly progressive, symptomatic disease after the initiation of ipilimumab therapy. Specific immune-response related criteria have been developed for assessment of patients treated with immunotherapy (table 1). (See 'Immune response criteria' above.)

The role of maintenance therapy or retreatment with ipilimumab after the initial four cycles of therapy is uncertain. Maintenance therapy with ipilimumab is not indicated following the initial four cycles of treatment until further data on this approach are available. Reinduction therapy with ipilimumab may be an option for patients who initially respond and then subsequently progress. (See 'Dose and schedule' above.)

The combination of ipilimumab plus dacarbazine did not appear to improve the efficacy of ipilimumab alone and was associated with a significant increased incidence of hepatotoxicity. Thus ipilimumab should not be given in combination with dacarbazine. (See 'Previously untreated patients' above.)

Immunotherapy with ipilimumab causes a broad range of immune-related adverse events, which can be serious or fatal. Regular monitoring for these adverse events, prompt medical attention and early administration of corticosteroids are essential for the appropriate management of immune-related adverse events and to prevent their progression to more serious toxicity. (See 'Toxicity' above.)

For grade 2 (moderate) immune-mediated toxicities, treatment with ipilimumab should be withheld and should not be resumed until symptoms or toxicity is grade 1 or less. Corticosteroids (prednisone 0.5 mg/kg/day or equivalent) should be started if symptoms do not resolve within a week.

For patients with grade 3 or 4 (severe or life-threatening) immune-mediated toxicities, treatment with ipilimumab should be permanently discontinued. High doses of corticosteroids (prednisone 1 to 2 mg/kg or equivalent) should be given. When symptoms subside to grade 1 or less, steroids can be gradually tapered over at least one month.

Anti-PD-1 monoclonal antibodies are currently being evaluated in randomized clinical trials, both as single agents and in combination with ipilimumab, for the treatment of advanced melanoma. Participation in clinical trials remains a priority for patients with this disease in order to continue to improve treatment outcomes.

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