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.
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 immunotherapy. (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, although recent advances have led to important improvements in patient outcomes. These approaches include immunotherapy (particularly with checkpoint inhibition) and targeted therapy that inhibits the MAP kinase pathway.
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.
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.)
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 . 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.
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 :
●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 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 or anti-PD-1 treatments may lead to premature discontinuation of treatment in a patient who will eventually respond to treatment or have prolonged disease stabilization.
PROGRAMMED DEATH 1 PROTEIN — The programmed death 1 protein (PD-1) is an immune checkpoint receptor expressed by activated T cells [3,4]. 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.
Nivolumab and pembrolizumab are monoclonal antibodies that target PD-1 and have established clinical activity; these agents are the preferred approach for immunotherapy in most patients with advanced melanoma. Additional antibodies targeting PD-1 and PD-L1 are being developed to interrupt this pathway.
Anti-PD-1 monoclonal antibodies
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 . 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 . 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 .
●Preliminary analyses studied PD-L1 expression in the tumor as a predictive marker for responsiveness to pembrolizumab . 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) . There was also no significant difference in the safety profile.
Based upon these results, two phase III trials were 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) . 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.
•Responses to pembrolizumab were noted in 19.2 percent (95% CI 6.6-39.4 percent) of patients who had BRAF mutant melanoma and had also received a BRAF inhibitor and 27.5 percent (95% CI 20-36 percent) of patients whose tumors were BRAF wild type.
●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.
The 2 mg/kg and 10 mg/kg doses also had similar efficacy and toxicity in the three-armed phase III trial when they were compared with ipilimumab . (See 'Anti-PD-1 versus anti-CTLA-4 antibodies' below.)
Nivolumab — Nivolumab is a monoclonal antibody that targets the PD-1 protein.
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 [3,13-15]. 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 [13-15]:
●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 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) .
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) . 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 nivolumab plus ipilimumab. Enrollment is complete and results are pending.
Adjuvant therapy — Both pembrolizumab and nivolumab are being studied in phase III trials as adjuvant therapy after complete resection of high risk melanoma. (See "Adjuvant immunotherapy for melanoma", section on 'Anti-PD1 antibodies'.)
Toxicity — A wide range of adverse events (irAEs) has been reported with anti-PD-1 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".)
Experimental agents — Additional antibodies are under development that target either PD-1 of its ligand PD-L1.
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 . 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.
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 . 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 . 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.
ANTI-PD-1 VERSUS ANTI-CTLA-4 ANTIBODIES — Pembrolizumab demonstrated significantly longer progression-free survival (PFS) and improved overall survival compared with ipilimumab as immunotherapy in patients with advanced melanoma in the phase III KEYNOTE-006 trial .
In this trial, 834 patients were randomly assigned to pembrolizumab 10 mg/kg every two weeks, pembrolizumab 10 mg/kg every three weeks, or ipilimumab 3 mg/kg every three weeks for four doses. Treatment with pembrolizumab was continued for up to two years. Approximately 35 percent of patients had a V600 BRAF mutation, and about one-half of these had received prior targeted therapy. About 3 percent of patients had received prior immunotherapy.
The co-primary endpoints of the trial were PFS and overall survival. Based upon the second planned interim analysis, the data safety monitoring committee allowed patients who had progressed on treatment with ipilimumab to be crossed over to pembrolizumab.
●PFS was significantly longer with the every two and every three week schedules of pembrolizumab (six-month PFS 47.3 versus 26.5 percent, HR 0.58, 95% CI 0.46-0.72 and six-month PFS 46.4 versus 26.5 percent, HR 0.58, 95% CI 0.57-0.72, respectively).
●With a minimum duration of follow-up of 12 months for all patients, overall survival was significantly prolonged with both pembrolizumab schedules compared with ipilimumab (one-year overall survival rate 74.1 versus 58.2 percent, HR 0.63, 95% CI 0.47-0.83, and 68.4 versus 58.2 percent, HR 0.69, 95% CI 0.52-0.90). The median survival was not reached in any of the subgroups.
●Serious (grade 3 to 5) adverse events were less frequent overall with pembrolizumab compared with ipilimumab (13 and 10 versus 20 percent, respectively). Thyroid dysfunction was more common with pembrolizumab, whereas colitis and hypophysitis were more common with ipilimumab.
There were no differences in efficacy parameters in any patient subsets, with the exception of a lack of improvement in overall survival associated with pembrolizumab in those patients whose tumors did not express PD-L1 using the Merck immunohistochemistry assay. The PFS, overall survival, response rates, and side effects profiles were fully consistent with those seen in earlier trials with both pembrolizumab and ipilimumab.
IPILIMUMAB — Ipilimumab is a monoclonal antibody directed against CTLA-4. Although ipilimumab demonstrated prolonged overall survival in randomized phase III trials, its role has decreased with the development of agents that target PD-1; anti-PD-1 antibodies (pembrolizumab, nivolumab) have become the preferred approach to immunotherapy since these agents are more active and have less toxicity.
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 to ipilimumab plus a glycoprotein 100 (gp100) vaccine, ipilimumab alone, or gp100 alone . All patients had received prior systemic treatment for advanced disease with either cytotoxic chemotherapy or IL-2.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 22, 24, and 14 percent at 24 months, respectively.
•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). 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.
●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 [21,22]. Overall survival 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 consistently favored treatment with ipilimumab (47 versus 36 percent at one year and 18 versus 9 percent at five years).
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 . 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 .
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 . 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.
Brain metastases — Patients with untreated brain metastases were excluded from the initial phase III trial . 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'.)
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".)
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.
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. The data from this study were updated at the 2014 American Society of Clinical Oncology (ASCO) meeting .
●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 .
●Overall survival in the original cohort of 53 patients at one and two years was 94 and 88 percent, respectively .
●Treatment-related adverse events were observed in 93 percent of cases. Severe treatment related adverse events were reported in 49 percent of cases . 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'.)
A similar benefit was observed in a randomized, double blind phase II trial in which 142 patients with metastatic melanoma were randomly assigned in a 2:1 ratio to ipilimumab (3 mg/kg every three weeks for four doses) plus nivolumab (1 mg/kg every three weeks) or to ipilimumab plus placebo . After discontinuation of ipilimumab, the nivolumab or placebo were continued every two weeks as maintenance.
●Among patients treated with ipilimumab plus nivolumab, there was an objective response rate of 61 percent, which included 21 complete responses (22 percent) and 35 partial responses (37 percent) combined. In contrast, there were no complete responses and 5 partial response (11 percent) in those treated with ipilimumab plus placebo. The response rates were similar in those with wild-type BRAF and those with V600 mutation positive disease. The objective response rates for the combination were 58 percent in patients whose tumors were PD-L1 positive and 55 percent in those whose tumors were PD-L1 negative.
●Serious (grade 3 or 4) adverse events were more common with the combination (54 versus 24 percent). The most common grade 3 or 4 adverse events with the combination were colitis, diarrhea, and an elevated aminotransferase level (17, 11, and 11 percent, respectively.) For those treated with ipilimumab alone, the most frequent grade 3 or 4 adverse events were diarrhea and colitis (11 and 7 percent, respectively).
●Forty-seven percent of patients on the combination of ipilimumab plus nivolumab treatment discontinued therapy during the first 15 weeks of treatment due to toxicity requiring corticosteroid immunosuppression. Such patients were not allowed to go on to maintenance nivolumab treatment. Nonetheless 36 out of 44 responses were ongoing at a minimum of nine months follow-up.
Additional information on the role of this combination regimen should come from a three armed phase III trial comparing the combination of nivolumab plus ipilimumab compared with each of these checkpoint inhibitors individually; enrollment is complete 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 . 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 .
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 .
SUMMARY AND RECOMMENDATIONS
●Checkpoint inhibitors have been shown to initiate an anti-tumor immune response directed against melanoma, although they can cause a variety of autoimmune side effects. Pembrolizumab and nivolumab, antibodies directed against the programmed death 1 (PD-1) protein, have become the preferred approach to immunotherapy in patients with advanced melanoma. Ipilimumab, an antibody directed against the CTLA-4 receptor on T lymphocytes, may retain a role in combination with anti-PD-1 antibodies. (See 'Anti-PD-1 versus anti-CTLA-4 antibodies' above.)
●Molecularly targeted therapy directed against the MAP kinase pathway is an important treatment option of patients with a characteristic BRAF V600 mutation. Targeted therapy is not indicated in patients without a characteristic V600 mutation. The optimal sequencing of targeted therapy and immunotherapy has not been definitively established. (See "Molecularly targeted therapy for metastatic melanoma" and "Overview of the management of advanced cutaneous melanoma", section on 'Choice and sequence of therapy'.)
●For good performance status patients without a V600 BRAF mutation, we recommend immunotherapy using an anti-PD-1 antibody (nivolumab, pembrolizumab) rather than the anti-CTLA-4 antibody ipilimumab, high-dose interleukin-2, or chemotherapy (Grade 1A). (See "Overview of the management of advanced cutaneous melanoma", section on 'Choice and sequence of therapy'.)
●For patients with a poor performance status without a V600 BRAF mutation, we suggest immunotherapy with ipilimumab rather than an anti-PD-1 antibody since there currently are no data on either pembrolizumab or nivolumab in this setting (Grade 2C). (See 'Efficacy' above.)
●For patients with a V600 BRAF mutation, there are only limited retrospective data on the optimal treatment sequence for using targeted therapy and immunotherapy. (See "Overview of the management of advanced cutaneous melanoma", section on 'Choice and sequence of therapy'.)
•For patients with asymptomatic metastases and a good performance status, we suggest immunotherapy with an anti-PD-1 antibody (nivolumab, pembrolizumab) rather than targeted therapy as the initial systemic therapy (Grade 2C). (See "Overview of the management of advanced cutaneous melanoma", section on 'Choice and sequence of therapy'.)
-For patients with a V600 BRAF mutation who were initially treated with an anti-PD-1 antibody and whose disease can no longer be controlled with this immunotherapy, we recommend targeted therapy using a BRAF inhibitor/MEK inhibitor combination (dabrafenib/trametinib) rather than chemotherapy (Grade 1A). (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 (Grade 2C). Immunotherapy with a checkpoint inhibitor is an alternative, and may also be useful after progression on targeted therapy. (See "Molecularly targeted therapy for metastatic melanoma" and "Interleukin-2 and experimental immunotherapy approaches for advanced melanoma".)
●Patients treated with checkpoint inhibtors 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 checkpoint inhibitor immunotherapy. Specific immune-response related criteria have been developed for assessment of patients treated with immunotherapy (table 1). (See 'Immune response criteria' above.)
●Additional randomized clinical trials are ongoing with anti-CTLA4 and anti-PD-1/PD-L1 monoclonal antibodies, both as single agents and in various combinations. Participation in clinical trials remains a priority for patients with this disease in order to define the optimal approach to treatment and to further improve outcomes.
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