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Immunotherapy of advanced melanoma with immune checkpoint inhibition
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Immunotherapy of advanced melanoma with immune checkpoint inhibition

Disclosures: Jeffrey A Sosman, MD Grant/Research/Clinical Trial Support: BMS; GSK [oncology (Nivolumab, trametinib and palbociclib)]. Consultant/Advisory Boards: Amgen [oncology (T-VEC)]. Michael B Atkins, MD Consultant/Advisory Boards: Novartis (everoliumus); Pfizer (axitinib); Genentech (vemurafenib, MPDL); BMS (ipilimumab/nivolumab); Merck (pembrolizumab), GlaxoSmithKline (pazopanib, dabrafenib/trametinib). Michael E Ross, MD Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2015. | This topic last updated: Mar 18, 2015.

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 efficacy of immune checkpoint inhibitors in the treatment of advanced melanoma. The toxicity associated with these agents is discussed separately, as is an overview of the management of advanced melanoma is presented separately. (See "Toxicities associated with checkpoint inhibitor immunotherapy" and "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.

Tissue studies have demonstrated that individual melanomas are frequently associated with a large number of somatic mutations, and these collections of somatic mutations appear to be unique in each melanoma [3]. These mutations may result in the presentation of cancer specific antigens that serve as the targets for checkpoint inhibitor immunotherapy. Ultimately, the number and specific sites of such somatic mutations may be able to predict which patients will have a response to immunotherapy.

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, pembrolizumab) 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 [4]:

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) [4].

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 Response Evaluation Criteria In Solid Tumors (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 (IL-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 overall survival in patients with advanced melanoma and is associated with a plateau in the survival curve beyond three years.

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 [5]. 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, hazard ratio [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 IL-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 [6].

The phase III trial limited enrollment to patients who were HLA-A*0201 positive because of the use of the gp100 vaccine [5]. 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 [7]. 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 [8]. 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 [9,10]. 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 12 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, three, and five years consistently favored treatment with ipilimumab (47 versus 36 percent, 29 versus 18 percent, 21 versus 12 percent, and 18 versus 9 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 survival — Although only a minority of patients achieves a complete response, such responses appear to be of prolonged duration in most cases.

This is illustrated by a combined analysis of 1861 patients from two randomized trials, eight other prospective trials, and two retrospective studies of ipilimumab [11]. For the entire series, the median overall survival was 11.4 months. The three-year survival for the 254 patients with at least three-year follow-up was 22 percent (26 and 20 percent for previously untreated and previously treated patients, respectively). With maximum follow-up of 10 years, there was a plateau in the survival curve with 21 percent survival beyond three years, which was independent of prior therapy or ipilimumab dose.

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 [5]. 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 [12]. 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 [5], 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 [5]. 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".)

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-related adverse events (irAEs) have been observed. The most common serious manifestations include enterocolitis, hepatitis, dermatitis, and endocrinopathies, but other organ systems can also be involved. These are generally different from the toxicities associated with other classes of antineoplastic agents and require specialized management. The toxicity of associated with ipilimumab and with other checkpoint inhibitors is discussed separately. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

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 [13,14]. Based upon this, a phase III trial was conducted in which previously untreated patients were randomly assigned to either tremelimumab or chemotherapy [15]. 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 [16,17]. 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. Both pembrolizumab and nivolumab have received regulatory approval in the United States for patients with disease progression following ipilimumab treatment, and, if a BRAF V600 mutation is present, with a BRAF inhibitor.

Pembrolizumab — Pembrolizumab is an anti-PD1 monoclonal antibody that has been extensively evaluated in both ipilimumab naïve and previously treated patients [18-20].

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 [21]. Results from this study were updated at the 2014 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 [19]. 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 [21].

Preliminary analyses studied PD-L1 expression in the tumor as a predictive marker for responsiveness to pembrolizumab [22]. 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. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

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) [20]. There was also no significant difference in the safety profile.

Based upon these results, two phase III trials are being conducted, one in patients whose disease was refractory to ipilimumab, and the other in patients who were treatment naïve.

In the KEYNOTE-002 trial, 540 patients with ipilimumab-refractory advanced melanoma were randomly assigned to pembrolizumab (2 mg/kg every three weeks), pembrolizumab (10 mg/kg every three weeks) or chemotherapy (carboplatin plus paclitaxel, paclitaxel alone, dacarbazine, or temozolomide per institutional standard) [23]. Treatment continued on this schedule until progressive disease.

Preliminary results were presented at the 2014 Society of Melanoma Research Congress.

Progression-free survival assessed by central review, the primary endpoint of the trial, was significantly improved with both pembrolizumab treatment regimens compared with chemotherapy. The six-month progression-free rates were 34, 38, and 16 percent for pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, and chemotherapy, respectively (pembrolizumab 2 mg/kg versus chemotherapy hazard ratio 0.57, 95% CI 0.45-0.73, and pembrolizumab 10 mg/kg versus chemotherapy hazard ratio 0.50, 95% CI 0.39-0.64).

The objective response rates (complete plus partial) were 21, 26, and 4 percent, respectively, for pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, and chemotherapy, respectively.

Treatment was relatively well tolerated, with grade 3-5 adverse events reported in 11 and 14 percent of the pembrolizumab treatment arms, and 26 percent of those managed with chemotherapy. The most common pembrolizumab-related adverse events were fatigue, pruritus, and rash. Grade 3 immune related toxicity was reported in two patients treated with pembrolizumab 2 mg/kg (hepatitis, hypophysitis), and in eight patients given pembrolizumab 10 mg/kg (hepatitis, colitis, pneumonitis, and iritis or uveitis.

A second phase III trial is comparing pembrolizumab with ipilimumab (NCT01866319) in treatment naïve patients; results are pending

Pembrolizumab (at a dose of 2 mg/kg every three weeks) was approved by the US Food and Drug Administration in September 2014 for patients who have progressed on treatment with ipilimumab [24]. For melanoma patients whose tumors express a BRAF V600 mutation, pembrolizumab is intended for use after treatment with ipilimumab and a BRAF inhibitor.

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.

In a phase I/II dose escalation cohort expansion study, 107 patients were treated at doses from 0.1 to 10 mg/kg every two weeks for up to 96 weeks [16,25-27]. Results from this study were updated at the 2014 Society of Melanoma Research Congress and provide data on the longest duration of treatment with nivolumab [25-27]:

Median overall survival was 17 months, and the one, two, three, and four-year overall survival rates were 63, 48, 42, and 32 percent, respectively.

Objective complete or partial responses were observed in 34 of 107 patients (32 percent). In 21 cases, treatment was discontinued for reasons other than progressive disease: 14 of these 21 continue progression free.

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.

These results have led to the conduct of three phase III trials:

Previously untreated patients – In the Checkmate 066 trial (NCT01721772), 418 previously untreated patients with wild type BRAF melanomas were randomly assigned to nivolumab (3 mg/kg every two weeks) or dacarbazine (1000 mg/m2 every three weeks) [28].

Overall survival was significantly increased in those treated with nivolumab (one year survival rate 73 versus 42 percent; hazard ratio [HR] for death 0.42, 99.8% CI 0.25-0.73). Progression free survival was also increased with nivolumab (median 5.1 versus 2.2 months), as was the objective response rate (40 versus 14 percent).

Previously treated patients – In the Checkpoint 037 phase III trial (NCT01721746), patients were randomly assigned in a 2:1 ratio to either nivolumab or chemotherapy (either dacarbazine or carboplatin plus paclitaxel) [29]. All patients had received prior anti-CTLA4 therapy and a BRAF inhibitor if a V600 mutation was present in their tumor. The trial accrued 405 patients; published results of a planned interim analysis are based upon 167 patients (120 treated with nivolumab and 47 treated with chemotherapy) with a minimum follow-up of ≥6 months.

Objective responses by independent review were significantly more common in patients treated with nivolumab compared with chemotherapy (38 of 120 [32 percent, 95% CI 23.5-40.8] versus 5 of 47 [10 percent, 95% CI 3.5-23.1]). Median duration of response was longer with nivolumab (median not reached, 36 of 38 still in remission, versus 3.5 months for chemotherapy treated patients). Tumor responses were seen with nivolumab in patients with BRAF mutations who had progressed on a prior BRAF inhibitor (6/26 = 23 percent) and appeared to be independent of benefit from prior ipilimumab treatment.

In a third phase III trial (NCT01844505) that is ongoing, patients are being randomized to receive either ipilimumab, nivolumab, or the combination of the two agents.

Nivolumab (at a dose of 3 mg/kg every three weeks) was approved by the US Food and Drug Administration in December 2014 for patients who have progressed on treatment with ipilimumab [24]. For melanoma patients whose tumors express a BRAF V600 mutation, pembrolizumab is intended for use after treatment with ipilimumab and a BRAF inhibitor.

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 [30]. 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 dose levels studied, or between those who were ipilimumab naïve versus ipilimumab treated.

Toxicity — A wide range of adverse events (irAEs) has been reported with anti-PD1 monoclonal antibody therapy. Although less frequent than with ipilimumab, the most serious of these include pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, and thyroid dysfunction. The toxicity associated with these agents is discussed separately. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

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

BMS-936559 — BMS-936559 binds to PD-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 [17]. The trial includes 207 patients, including 55 with melanoma. Overall, potentially immune-related adverse events were seen in 39 percent of patients.

There were nine 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 PD-L1. Initial results of a phase I dose escalation study were presented at the 2013 ASCO meeting [31]. 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 [32]. The data from this study were updated at the 2014 American Society of Clinical Oncology (ASCO) meeting [33].

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 [33].

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 [33].

Overall survival in the original cohort of 53 patients at one and two years was 94 and 88 percent, respectively [33].

Treatment-related adverse events were observed in 93 percent of cases. Severe treatment related adverse events were reported in 49 percent of cases [32]. Treatment was discontinued because of adverse events in 11 cases (21 percent). (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Combined immune checkpoint blocking antibodies plus targeted therapy'.)

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 two armed phase II trial comparing the combination of nivolumab plus ipilimumab with ipilimumab alone and a three armed phase III trial comparing the combination of nivolumab plus ipilimumab compared with each of these checkpoint inhibitors as a single agent are each underway; enrollment is complete to both trials and results are pending (NCT01844505).

Ipilimumab plus GM-CSF — In a randomized phase II trial, the addition of granulocyte-macrophage (GM) colony-stimulating factor (CSF) to ipilimumab may increase overall survival and decrease serious toxicity compared with ipilimumab alone. However, the evidence supporting this is derived from a trial that used a higher dose of ipilimumab than is currently approved and in which maintenance therapy was included as a component of the protocol. The clinical implications of these results require further study and confirmation.

In the phase II trial conducted by Eastern Cooperative Oncology Group (ECOG), 245 patients with advanced melanoma were randomly assigned to ipilimumab plus GM-CSF or ipilimumab alone [34]. 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.

At a median follow-up of 13 months, overall survival was significantly improved by the addition of GM-CSF to ipilimumab (median 17.5 versus 12.7 months, one-year survival rates 69 versus 53 percent, hazard ratio [HR] 0.64, p = 0.01). However, there was no difference in the objective response rate with or without GM-CSF (15 percent on each treatment arm) and no significant difference in the progression-free survival (34 versus 30 percent at six months, HR 0.87).

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. (See "Toxicities associated with checkpoint inhibitor immunotherapy" and "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Ipilimumab plus GM-CSF'.)

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 [35].

OX40 — OX-40 is another TNF receptor, which also acts as a costimulatory factor for T cells. A MAb targeting this receptor has begun phase I study [36].

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.)

An analysis of pooled data from both phase III trials as well as from other phase II studies indicates that there is a plateau with 21 percent overall survival beginning at three years and extending out to at least 10 years. (See 'Long-term survival' above.)

For patients without a V600 BRAF mutation, we recommend immunotherapy (high dose interleukin-2 [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.)

For patients who have progressed on ipilimumab, we recommend treatment with an anti-PD-1 monoclonal antibody (pembrolizumab or nivolumab) (Grade 1A). Additional randomized clinical trials are currently ongoing with anti-PD-1/PD-L1 monoclonal antibodies, both as single agents and in combination with ipilimumab and other agents. Participation in clinical trials remains a priority for patients with this disease in order to continue to improve treatment outcomes. (See 'Pembrolizumab' above.)

Immunotherapy with ipilimumab, and to a lesser extent pembrolizumab, and other checkpoint inhibitors can cause a broad range of immune-related adverse events (irAEs), which can be serious or fatal. The most common of these are enterocolitis, hepatitis, dermatitis, and endocrinopathies. Regular monitoring for irAEs, prompt medical attention and early administration of corticosteroids are essential for the appropriate management these side effects and to prevent their progression to more serious toxicity. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

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