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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. (See "Principles of cancer immunotherapy".)
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.
RESPONSE TO CHECKPOINT INHIBITION
Patterns of response — 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, and some partial responses may convert to complete responses with longer follow-up.
●Some patients who do not meet criteria for objective response can have prolonged periods of stable disease that are clinically significant.
Patients with RECIST-defined progressive disease (table 1) who do not have symptoms should continue on therapy and have a confirmatory scan documenting progressive disease before being switched to an alternative treatment.
Immune-related response criteria — Immune-related response criteria have been proposed to deal with the altered patterns of response seen with ipilimumab and potentially other immunotherapies (table 1) .
●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 with 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 clinical importance of immune-related response criteria was illustrated by a series of 655 patients with metastatic melanoma who were treated with pembrolizumab; these included 327 who had imaging follow-up at least 28 weeks after initiating therapy .
●Of those who survived at least 12 weeks, 84 of 592 (14 percent) had progressive disease by RECIST v1.1 but not by immune-related response criteria. Overall two-year survival for patients with progressive disease by RECIST but not immune-related response criteria was 37.5 percent, compared with 17.3 percent in those with progressive disease based upon both criteria.
●Among the 327 patients who were imaged at least 28 weeks after starting treatment, pseudoprogression (≥25 percent increase in tumor burden not confirmed at repeat imaging) was observed in 24 cases (7 percent), of which 15 occurred by 12 weeks of imaging, and nine were later.
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 [4,5]. 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 phase I study, 655 patients with advanced melanoma were treated with pembrolizumab in four treatment cohorts using one of three dose schedules (10 mg/kg every two weeks, 10 mg/kg every three weeks, or 2 mg/kg every three weeks) [10,11]. Approximately three-fourths of patients had received prior systemic therapies for metastatic disease, including 52 percent who had received prior ipilimumab. In addition to being heavily pretreated, the study population included 78 percent with M1c disease and 38 percent with a lactate dehydrogenase (LDH) greater than the upper limit of normal.
●The median overall survival was 24 months, and the 12, 24, and 36-month overall survival rates were 73, 50, and 40 percent, respectively. The 12, 24, and 36-month progression-free survival (PFS) rates were 35, 28, and 21 percent, respectively.
●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 . There were also no significant differences in outcome between those who had received prior ipilimumab and those who had not received prior immunotherapy.
●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.
●In subgroup analysis, there was no significant difference in patients whose tumors were BRAF wild type versus those with a V600 mutation.
●Treatment toxicity was manageable; 83 percent of patients experienced one or more treatment-related adverse events. The most common toxicities were fatigue, pruritus, rash, diarrhea, and arthralgia (36, 24, 20, 16, and 16 percent, respectively). Overall 14 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.
●PFS 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 [HR] 0.57, 95% CI 0.45-0.73, and pembrolizumab 10 mg/kg versus chemotherapy HR 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 [4,16-19]. Results from this study were updated at the 2016 American Association of cancer Research meeting and provide data on the longest duration of treatment with nivolumab :
●Median overall survival was 17 months, and the one-, two-, three-, four-, and five-year overall survival rates were 63, 48, 42, 35, and 34 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 PFS, 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) [20,21].Overall survival was significantly increased in those treated with nivolumab (one year survival rate 73 versus 42 percent; HR for death 0.42, 99.8% CI 0.25-0.73). PFS was also increased with nivolumab (median 5.1 versus 2.2 months), as was the objective response rate (40 versus 14 percent). Exploratory analyses found that nivolumab maintains baseline health-related quality of life levels to provide long-term benefits compared with dacarbazine .
●Previously treated patients – In the CheckMate 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-cytotoxic T-lymphocyte antigen 4 (CTLA-4) 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, patients were randomized to receive either ipilimumab, nivolumab, or nivolumab plus ipilimumab . Nivolumab was significantly improved PFS and the objective response rate compared with ipilimumab and had toxicity. The results of the nivolumab plus ipilimumab arm compared to monotherapy with either ipilimumab or nivolumab are discussed below. (See 'Combined anti-CTLA-4 and anti-PD-1 immunotherapy' below.)
An analysis of results from four non-randomized studies that included 440 patients found that patients whose tumors contained a BRAF V600 mutation had a similar response rate compared with those who had wild type BRAF (30 versus 35 percent), and that responses were of similar duration (median 11 versus 15 months). The objective response rates did not seem to be affected by prior BRAF inhibitor therapy .
Although the original approved dose of nivolumab was 3 mg/kg based upon the phase III trials, the US Food and Drug Administration (FDA) subsequently modified the approved dose regimen to 240 mg as a flat dose every two weeks, which is similar to the 3 mg/kg intravenous dose, based upon population pharmacokinetics and dose/exposure-response analyses .
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-PD-1 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. Cutaneous toxicity is also frequent. The toxicity associated with these agents is discussed separately. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)
Other antibodies — Additional antibodies are under development that target either PD-1 or its ligand PD-L1.
Atezolizumab — Atezolizumab (MPDL3280A) is an antibody that binds to PD-L1. Initial results of a phase I dose escalation study were presented at the 2013 American Society of Clinical Oncology (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.
Atezolizumab was approved in 2016 for the treatment of patients with advanced urothelial cancer. (See "Treatment of metastatic urothelial cancer of the bladder and urinary tract", section on 'Atezolizumab'.)
IPILIMUMAB — Ipilimumab is a monoclonal antibody directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Although ipilimumab demonstrated prolonged overall survival in randomized phase III trials, its role has decreased with the development of agents that target programmed death 1 protein (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 with 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 [28,29]. 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.
Adjuvant therapy — Ipilimumab is an alternative to high-dose interferon as adjuvant therapy following resection of high-risk melanomas; its role 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".)
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 [15,32].
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. Final results of the trial were presented at the 2016 American Society of Clinical Oncology annual meeting :
●PFS was significantly longer with both the two- and three-week schedules of pembrolizumab compared with ipilimumab (12-month PFS 39 and 38 versus 19 percent, and 24-month PFS 31 and 28 versus 14 percent; hazard ratio [HR] for the two-week pembrolizumab regimen versus ipilimumab 0.61, 95% CI 0.50-0.75, and HR for the three-week pembrolizumab schedule 0.61, 95% CI 0.50-0.75).
●Overall survival was significantly prolonged with both pembrolizumab schedules compared with ipilimumab (one-year overall survival rate 74 and 68 versus 59 percent, and two-year overall survival rate 55 and 55 versus 43 percent; HR for every-two-week pembrolizumab versus ipilimumab 0.68, 95% CI 0.53-0.87, and for the every-three-week pembrolizumab versus ipilimumab, HR 0.68, 95% CI 0.53-0.86).
●Serious (grade 3 to 5) adverse events were less frequent overall with pembrolizumab compared with ipilimumab (17 and 17 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.
COMBINED ANTI-CTLA-4 AND ANTI-PD-1 IMMUNOTHERAPY
Ipilimumab plus nivolumab — The combined administration of anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) immunotherapy with ipilimumab plus anti-programmed death 1 protein (PD-1) immunotherapy with nivolumab has a higher level of anti-melanoma activity than monotherapy with either nivolumab or ipilimumab, but is associated with increased toxicity. Longer follow-up and overall survival data from the phase III trial will be required to determine whether the combination should replace nivolumab monotherapy as the preferred approach for checkpoint inhibition immunotherapy.
●In the phase I study cohorts with a total of 94 patients, the updated objective response rates for the patients treated with concurrent nivolumab plus ipilimumab were 42 to 43 percent . The overall survival rate for the initial 53 patients treated with concurrent therapy was 85 percent at one year, 79 percent at two years, and 68 percent at three years. For patients with normal lactate dehydrogenase (LDH), one-year overall survival was 93 percent, and two-year overall survival was 80 percent. For patients with elevated LDH, both one-year and two-year overall survivals were 61 percent.
●In a randomized phase II trial in 142 patients, more than 75 percent with BRAF wild type tumors, the objective response rate with the combination of nivolumab plus ipilimumab was higher than with ipilimumab alone (61 percent versus 11 percent) . At a median follow-up of 24.5 months, the two-year overall survival was longer with the combination (64 versus 54 percent) . The difference in overall survival was not statistically significant. However, 62 percent of patients on ipilimumab crossed over to nivolumab therapy at time of progression, contributing to the overall survival of those initially treated with ipilimumab alone. The efficacy with the combination (objective response rates, progression-free survival [PFS], and overall survival) was similar, regardless of the PD-1 ligand (PD-L1) status.
Serious (grade 3 or 4) adverse events were more common with the combination than with ipilimumab alone (54 versus 20 percent). The most common grade 3 or 4 adverse events were gastrointestinal (20 versus 11 percent) and hepatic (13 versus 0 percent).
The most extensive results combining anti-PD-1 and anti-CTLA-4 checkpoint inhibition come from the CheckMate 067 phase III trial [23,37]. In this trial, 945 treatment-naïve patients were randomly assigned to nivolumab (1 mg/kg every three weeks) plus ipilimumab (3 mg/kg every three weeks) for four doses followed by nivolumab (3 mg/kg every two weeks), nivolumab (3 mg/kg every two weeks), or ipilimumab (3 mg/kg every three weeks for four doses). All three arms contained placebo treatments during the first 12 weeks in order to maintain the double-blind status. After the initial four cycles, either nivolumab (in the nivolumab plus ipilimumab and nivolumab alone arms) or placebo (ipilimumab arm) was continued as maintenance.
PFS and overall survival were the co-primary endpoints of the trial. Trial results were updated at the 2016 American Society of Clinical Oncology meeting (ASCO) . At a median follow-up of 21 months (minimum 18 months), results included the following:
●The median PFS for the combination regimen, nivolumab alone, and ipilimumab alone were 11.5, 6.9, and 2.9 months, respectively (hazard ratio for the combination versus ipilimumab 0.42, 95% CI 0.31-0.57, and hazard ratio for nivolumab alone versus ipilimumab 0.55, 95% CI 0.43-0.76). PFS rates at 12 months for the three regimens were 49, 42, and 18 percent, respectively, and PFS rates at 18 months for the three regimens were 46, 39, and 14 percent, respectively.
●The objective response rates for the combination, nivolumab alone, and ipilimumab alone were 58, 44, and 19 percent, respectively. The complete response rates were 12.1, 9.8, and 2.2 percent, respectively.
●Serious toxicities and the need for treatment discontinuation were more frequent with the combination than with monotherapy with either nivolumab or ipilimumab. Grade 3 and 4 adverse events for the combination, nivolumab alone, and ipilimumab alone were 55, 16, and 27 percent, respectively; treatment-related adverse events led to therapy discontinuation in 36.4, 7.7, and 14.8 percent of patients respectively. The most common adverse events of any grade with the combination were diarrhea, fatigue, and pruritus (44, 35, and 33 percent of patients, respectively).
●Patients were stratified based upon PD-L1 expression (>5 percent expression was considered positive) in an effort to identify patient subsets that might benefit from different treatment approaches. Overall 24 percent of patients had positive expression of this marker. Median PFS for patients with PD-L1 expression for the combination, nivolumab, and ipilimumab, were 14, 14, and 4 months, respectively; median PFS for those negative for PD-L1 expression were 11, 5, and 3 months, respectively. Objective response rates for those with positive PD-L1 expression were 72, 58, and 21 percent, respectively, and for those without PD-L1 expression, 55, 44, and 18 percent, respectively.
Ipilimumab plus pembrolizumab — Preliminary results from a nonrandomized expansion cohort combining pembrolizumab (2 mg/kg every three weeks) with ipilimumab (1 mg/kg for four doses) was presented at the 2016 ASCO meeting . Based upon an analysis with a median follow-up of 10 months, the objective response rate was 57 percent (including 10 percent complete responses and 47 percent partial responses). PFS was 70 percent at six months. Grade 3 or 4 toxicity was observed in 42 percent of patients; immune-related adverse events were seen in 58 percent of patients, and 25 percent experienced grade 3 or 4 immune-related toxicity. Only 25 percent of patients needed to stop therapy due to toxicity.
Sequential therapy — In a randomized phase II trial, 140 patients were randomly assigned to induction therapy with either nivolumab (3 mg/kg every two weeks for six doses) followed by ipilimumab (3 mg/kg every three weeks for four doses) or the reverse sequence . After completion of induction, both arms were maintained on nivolumab (3 mg/kg every two weeks) until progression.
The frequency of grade 3 to 5 toxicity, the primary endpoint of the trial, was higher with the nivolumab to ipilimumab induction sequence compared with ipilimumab to nivolumab (50 versus 43 percent). With a median follow-up of 18.6 months, the objective response rate was higher with the nivolumab to ipilimumab sequence (41 versus 20 percent at week 25). In an exploratory analysis, overall survival was longer with the nivolumab to ipilimumab sequence (12-month overall survival rate 76 versus 54 percent, hazard ratio 0.48, 95% CI 0.29-0.80).
The toxicity and efficacy of the nivolumab to ipilimumab sequence appeared to be similar to the combination and did not appear to offer an advantage over the combination regimen. (See 'Ipilimumab plus nivolumab' above.)
BRAIN METASTASES — Although patients with untreated brain metastases have been excluded from the initial phase III clinical trials, preliminary results from phase II studies indicate that checkpoint inhibition immunotherapy has clinical activity. (See "Management of brain metastases in melanoma", section on 'Immunotherapy'.)
NON-CUTANEOUS MELANOMA — There are only very limited data on the role of checkpoint inhibitors in the management of non-cutaneous melanomas.
●Acral melanoma – In a series of 25 patients with acral melanoma presented at the 2016 American Society of Clinical Oncology (ASCO) meeting, an objective response rate of 32 percent was reported .
●Mucosal melanoma – Both ipilimumab and anti-programmed cell death protein 1 (PD-1) antibodies (pembrolizumab, nivolumab) have demonstrated useful clinical activity in patients with mucosal melanoma, and their level of activity appears to be similar to that in patients with advanced cutaneous melanoma. (See "Mucosal melanoma", section on 'Metastatic disease'.)
●Uveal melanoma – There is only weak evidence that checkpoint inhibition immunotherapy has activity in the treatment of metastatic uveal melanoma. Retrospective series have shown a lower objective response rate and worse overall survival using either ipilimumab, or agents targeting PD-1 or its ligand (PD-L1) compared with patients with advanced cutaneous melanoma. The results from those studies are discussed separately. (See "Uveal and conjunctival melanomas", section on 'Immunotherapy'.)
Patients should be enrolled in formal clinical studies whenever possible.
OTHER IMMUNE REGULATORY CHECKPOINTS — Monoclonal antibodies targeted against a number of other regulatory checkpoints, either alone or in various combinations, are being evaluated in patients with advanced melanoma based upon our current understanding of the development of cellular immunity.
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'.)
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 cytotoxic T-lymphocyte antigen 4 (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 that includes 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'.)
•We suggest using the combination of nivolumab plus ipilimumab, if available, rather than an anti-PD-1 antibody as monotherapy (Grade 2B). In this regimen, nivolumab (1 mg/kg) is given in combination with ipilimumab (3 mg/kg) every three weeks for four doses. This is followed by maintenance nivolumab (240 mg every two weeks). (See 'Combined anti-CTLA-4 and anti-PD-1 immunotherapy' above.)
•Anti-PD-1 based immunotherapy alone (nivolumab 240 mg every two weeks or pembrolizumab 2 mg/kg every three weeks) is a suitable alternative, particularly where toxicity is a concern. (See 'Anti-PD-1 monoclonal antibodies' above.)
●For patients with a poor performance status without a V600 BRAF mutation, we suggest immunotherapy with the combination of nivolumab plus ipilimumab rather than anti-PD-1 monotherapy (Grade 2B). For patients who are not thought to be able to tolerate treatment with a combination of nivolumab plus ipilimumab, we recommend single agent anti-PD-1 rather than ipilimumab (Grade 1B). (See 'Efficacy' above and 'Dose and schedule' 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 the combination of nivolumab and ipilimumab 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 checkpoint inhibition 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".)
The optimal sequence of targeted therapy and immunotherapy in subsets of patients with BRAF mutant melanoma is currently being tested in a US Intergroup randomized phase III trial.
●Patients treated with checkpoint inhibitors 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 'Response to checkpoint inhibition' above.)
●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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