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Anti-CTLA-4 immunotherapy in advanced melanoma
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2012. | This topic last updated: Mar 28, 2012.

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 interferon alfa for intermediate- and high-risk melanoma".)

Most patients with stage IV disease (table 1A-B) require systemic treatment. Immunotherapy with ipilimumab, an anti-CTLA4 (cytotoxic T lymphocyte-associated antigen 4) antibody, significantly increases overall survival in patients with advanced melanoma who have failed on previous systemic therapy and has been approved for use in patients with metastatic or unresectable melanoma. The efficacy and toxicity profile of ipilimumab in patients with advanced melanoma will be reviewed here.

CHOICE OF THERAPY FOR DISSEMINATED DISEASE — Approaches that have been shown to provide clinically important benefit for patients with disseminated melanoma in appropriately selected patients include immunotherapy with high-dose interleukin-2 (IL-2), immunotherapy with ipilimumab, a monoclonal antibody targeting CTLA-4, and inhibition of the MAP kinase pathway with vemurafenib in patients whose tumors contain a V600 mutation in the BRAF gene.

There are no randomized trials that compare these different approaches and there are no data on the appropriate sequencing of these therapies. Until such data are available, the choice of treatment needs to be individualized. Treatment decisions depend upon multiple factors including the overall condition of the patient (eg, age and comorbidity), a molecular analysis for the presence of a V600 mutation in the BRAF gene, and the extent of metastatic disease.

  • Immunotherapy with high-dose interleukin-2 (IL-2) is associated with long-term disease-free survival in a small minority of carefully selected patients and may actually result in cure. Because of the severe multiorgan toxicity associated with this therapy, treatment with high-dose IL-2 is limited to patients with excellent organ function who are treated by experienced clinicians in specialized programs capable of providing the necessary intensive care. There currently are no data on the activity of high-dose IL-2 in patients who have previously been treated with either ipilimumab or vemurafenib. (See "Immunotherapy for advanced melanoma", section on 'Interleukin-2'.)
  • Ipilimumab is a monoclonal antibody that targets CTLA-4. Treatment with ipilimumab significantly increases median overall survival in both previously untreated and previously treated patients with metastatic or unresectable melanoma. Responses in patients treated with ipilimumab may develop slowly and patients may have a transient worsening of disease before disease stabilizes or tumor regresses.

    Similar to IL-2, a small subset of patients treated with ipilimumab experience long-term disease-free survival. However, in contrast to IL-2, ipilimumab appears to show activity in patients with central nervous system metastases and to be tolerable in older patients and those with comorbidities. Further, ipilimumab has shown activity in patients whose disease has progressed after IL-2 therapy. Due to its toxicity profile, ipilimumab is not considered safe in patients with a history of symptomatic autoimmune disease.

    Thus, patients with BRAF wild-type tumors who are not considered candidates for or do not have access to IL-2 therapy, and have no history of autoimmunity, should receive ipilimumab. For patients with BRAF V600 mutant tumors who are not candidates for, do not have access to, or have progressed after IL-2 therapy, treatment with ipilimumab rather than vemurafenib may be preferred, especially in those with a limited metastatic disease burden and/or minor disease related symptoms.
  • Vemurafenib is a specific inhibitor of activated BRAF and has been shown to significantly increase survival in patients whose tumor contains a V600 mutation in the BRAF gene. The use of vemurafenib should be limited to patients whose tumor contains this mutation. Vemurafenib produces rapid tumor regressions in the vast majority of patients with V600 mutant melanoma including those with extensive tumor burden and significant disease-related symptoms. Median progression-free survival is typically around six months; however, tumor regressions last for more than a year in many patients. Continued treatment appears necessary to maintain efficacy. Side effects are typically modest and do not generally restrict or limit treatment.

    Thus, vemurafenib may be preferred over ipilimumab or high-dose IL-2 in those patients whose tumors contain a V600 mutation where a prompt response to treatment is desirable due to symptoms or the presence of bulky disease, or when there is a contraindication to ipilimumab or IL-2 therapy. Vemurafenib has shown anti-tumor activity in patients whose disease has progressed after IL-2 or ipilimumab. (See "Molecularly targeted therapy for metastatic melanoma", section on 'BRAF inhibition'.)
  • Although cytotoxic chemotherapy has been widely used in patients with metastatic disease, neither single agent chemotherapy nor combination chemotherapy has been shown to consistently improve overall survival. Single agent chemotherapy (dacarbazine, temozolomide, fotemustine) should be reserved for patients who are not candidates for treatment with high-dose IL-2, ipilimumab, or vemurafenib. (See "Cytotoxic chemotherapy for metastatic melanoma".)
  • In carefully selected patients, excision of one or a limited number of distant metastases can delay the need for systemic treatment or occasionally produce durable benefit. (See "Surgical management of metastatic 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 bound to specific MHC molecules. This interaction requires the presence of a costimulatory molecule (B7).

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 unabated immune response against the tumor. In addition, this interaction can cause a breaking of tolerance to other host tissues that leads to potentially severe or even life threatening autoimmune adverse events.

EFFICACY OF IPILIMUMAB — Evaluation of the effectiveness of ipilimumab therapy, both in clinical trials and in individual patients, requires an understanding of the different patterns of response seen with this class of agents.

Patterns of response — The observed patterns of response to treatment with ipilimumab differ from those with cytotoxic chemotherapy or molecularly targeted agents in several important respects [2]:

  • 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 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 [2].

  • 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 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 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.

Impact on survival — Based upon results from phase I and phase II studies, two major phase III trials have been conducted.

Previously treated patients — Ipilimumab was studied in a placebo-controlled phase III trial, in which 676 patients were randomly assigned in a 3:1:1 ratio to ipilimumab plus a glycoprotein 100 (gp100) vaccine, ipilimumab alone, or gp100 alone [3]. 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 interleukin-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 the two groups that received ipilimumab (median 10.0 and 10.1 versus 6.4 months, in the ipilimumab plus gp100, ipilimumab alone, and gp100 groups, hazard ratios [HR] for death 0.68 and 0.66 versus gp100 alone, respectively). Overall survival rates for the three groups 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 1A-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.

The phase III trial limited enrollment to patients who were HLA-A*0201 positive because of the use of the gp100 vaccine [3]. 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 [4]. In this analysis, ipilimumab had similar activity regardless of HLA type.

Patients with untreated brain metastases were excluded from the phase III trial [3]. Other studies and case reports have observed antitumor activity with ipilimumab treatment in patients with brain metastases. (See "Systemic therapy for brain metastases", section on 'Melanoma'.)

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 [5]. 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, one, two, and three year survival rates 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 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 [6]. Nearly 9 percent of treated patients experienced a complete response of which all but one have lasted between 54 and 99 months. The responses could be very 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.

Brain metastases — 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'.)

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 [3]. More recent protocols 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 'Impact on survival' 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 [7]. 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, particularly for those events considered immune-related:

  • 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)

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 [3], 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.

Future directions — The EORTC melanoma group is conducting a phase III trial in patients with high-risk stage III disease (EORTC 18071, NCT00636168) [8]. In this trial, patients are being randomly assigned to ipilimumab (dose 10 mg/kg every three weeks for four cycles then every 12 weeks for a total of three years treatment) or to placebo following complete resection to determine whether such treatment can prevent disease recurrence [9].

In addition, a cooperative group trial comparing ipilimumab to interferon alpha in patients with resected stage IIIB, IIIC or IV disease is anticipated to start in the United States in mid 2011 (NCT01274338) [8].

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

TOXICITY OF IPILIMUMAB — Ipilimumab’s presumed mechanism of action is to break down tolerance to tumor-associated antigens in the melanoma. At the same time, this break down of tolerance may result in autoimmune reactions against self antigens. 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 [3]. 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 [7]. (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 [3,7,10,11]. 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 [12,13].

Treatment requires interruption of ipilimumab and the use of corticosteroids [14]. 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.

Enterocolitis — 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 [3]. 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 [15].

Symptoms of colitis can develop rapidly and become life-threatening [16-19]. Bowel perforation, sepsis, and death have been reported as complications of ipilimumab therapy [16,19,20]. In the phase III trial, the median time to development of moderate or severe enterocolitis after initiating ipilimumab therapy was six to seven weeks [14].

Meticulous attention to gastrointestinal symptoms is required to prevent progression to more serious complications [14]. 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 [11].

Upper gastrointestinal tract involvement has also been reported, including involvement of the esophagus, duodenum, and ileum [21].

Hepatitis — Immune-mediated hepatitis has been seen in 2 to 9 percent of patients treated with ipilimumab [3,7,10]. At least one death due to liver failure has been reported; this was attributed to a delay in the initiation of steroid therapy [10]. The reported incidence of hepatoxicity exceeds 30 percent when ipilimumab is combined with dacarbazine, and the combined used of these agents should be avoided [5].

Hepatic function (transaminase and bilirubin) should be monitored prior to each dose of ipilimumab [14]:

  • Grade 2 hepatic toxicity: AST or ALT >2.5 times the upper limit of normal (ULN) but ≤5 times the UNL, 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 [14]. (See 'Treatment of immune-mediated toxicity' above.)

Dermatitis — Dermatologic side effects are common with ipilimumab therapy and can be manifested by pruritus, rash, vitiligo, and alopecia [22]. 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) [3,14]. 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. 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 [23]. In the phase III trial, nine patients treated with ipilimumab (1.8 percent) had severe or life-threatening hypopituitarism [3,14]. 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 [14]. 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" and "Clinical manifestations of adrenal insufficiency in adults".)

In addition to the endocrine manifestations of hypophysitis, swelling of the pituitary can sometimes be detected on imaging studies and may result in neurologic symptoms including headache or visual abnormalities [22,24]. Swelling of the pituitary must be distinguished from brain metastasis.

Primary thyroid disease can be manifested 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" 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 [17,25,26].
  • Neurologic complications include Guillain Barre syndrome [3,27], inflammatory myopathy [28], aseptic meningitis [29], temporal arteritis [10], inflammatory enteric neuropathy causing constipation [30], and posterior reversible encephalopathy syndrome [31].
  • Autoimmune pancreatitis [32].
  • Hematologic manifestations that have been reported include red cell aplasia [33], pancytopenia [34], and autoimmune neutropenia [35].
  • Sarcoidosis [36,37].
  • Systemic vasculitis, including kidney disease [10,38].
  • Acquired hemophilia A due to the presence of a factor VIII inhibitor [39]. (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 similar activity compared with ipilimumab in phase I and II clinical studies in previously treated patients [40,41]. This activity provided the basis for a phase III clinical trial in which tremelimumab was compared to chemotherapy (either temozolomide or dacarbazine) in 655 previously untreated patients with metastatic melanoma [42].

Preliminary results of that phase III trial were presented at the American Society of Clinical Oncology (ASCO) meeting in 2008. There was no statistically significant difference in the objective response rate (9.1 versus 10.1 percent for tremelimumab and chemotherapy, respectively) or for overall survival (median 11.8 and 10.7, hazard ratio 1.04, respectively). However, longer follow-up is required to determine whether tremelimumab produces more durable responses than cytotoxic chemotherapy.

SUMMARY AND RECOMMENDATIONS

Choice of therapy — The treatment of metastatic melanoma depends upon multiple factors that include the overall condition of the patient (eg, age and comorbidity), a molecular analysis for the presence of a V600 mutation in the BRAF gene, and the extent of metastatic disease. There are no randomized trials that compare these different approaches and there are no data on the appropriate sequencing of these therapies.

  • For patients with metastatic melanoma whose tumor does not contain the V600 mutation in BRAF and who will not be treated with interleukin-2, we recommend treatment with ipilimumab rather than cytotoxic chemotherapy (Grade 1A). Patients whose tumor does not contain a V600 mutation in BRAF should not be treated with vemurafenib. (See 'Efficacy of ipilimumab' above and 'Toxicity of ipilimumab' above.)
  • For patients with metastatic melanoma that contains an activating mutation at the V600 site in BRAF:

  • For patients with metastatic melanoma who are able to tolerate the toxicity associated with intensive therapy and who have access to such treatment, regardless of the presence or absence of a V600 mutation in BRAF, we suggest high-dose IL-2 therapy rather than ipilimumab or vemurafenib (Grade 2B). High-dose IL-2 is associated with prolonged disease free survival in a minority of carefully selected patients and may actually result in cure in about 5 percent of such patients. (See "Immunotherapy for advanced melanoma", section on 'High-dose IL-2'.)

Dose and schedule of ipilimumab

  • 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 autoimmune side effects in some cases. (See 'Rationale' above.)

    Results from a phase III clinical trial in previously treated patients using ipilimumab at a dose of 3 mg/kg every three weeks demonstrated a statistically significant improvement in overall survival with ipilimumab compared with a control vaccine. A phase III trial in previously untreated patients demonstrated that ipilimumab (at a dose of 10 mg/kg every three weeks) plus dacarbazine significantly increased overall survival compared with dacarbazine alone, but was associated with significant hepatotoxicity. (See 'Impact on survival' above.)
  • The optimal dosage of ipilimumab has not been definitively determined. The phase III trial in previously treated patients demonstrated prolonged survival used 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). All subsequent and ongoing clinical trials use a dose of 10 mg/kg on the same schedule, but these different dose levels have not been compared in a phase III trial. (See 'Dose and schedule' above.)
  • 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 this is not observed in patients with rapidly progressive, symptomatic disease. Specific immune-response related criteria have been developed for assessment of patients treated with immunotherapy. (See 'Patterns of response' above.)
  • The role of maintenance therapy or retreatment with ipilimumab after the initial four cycles of therapy is uncertain. We suggest not giving maintenance therapy with ipilimumab following the initial four cycles of treatment until further data on this approach are available. Reinduction therapy with ipilimumab may be considered if patients initially respond and then progress. (See 'Impact on survival' above.)
  • The combination of ipilimumab plus dacarbazine does not appear to improve the efficacy of ipilimumab alone and is associated with a significant increase in the 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 of ipilimumab' above.) Treatment requires interruption of ipilimumab, the use of corticosteroids, and is based upon the severity of the observed toxicity [14]:

  • 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.

  • Phase III trials are currently assessing the role of adjuvant ipilimumab therapy in patients with resected high-risk stage III melanoma. Adjuvant immunotherapy with ipilimumab is not indicated outside the setting of a formal clinical trial. (See 'Future directions' above.)

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