Metastatic Melanoma: Managing Benefit and Risk with the New Systemic Therapies



Provided by the Johns Hopkins University School of Medicine and 
the Institute for Johns Hopkins Nursing.

Supported by an educational grant from Merck & Co, Inc.


OVERVIEW
Recent advances in the understanding of the immunology and molecular biology of melanoma have changed the therapeutic landscape of patients with metastatic melanoma. Research has led to the introduction of breakthrough drugs that work by targeting the mitogen-activated protein kinase (MAPK) pathway in melanoma cells, which harbors BRAF mutations (targeted therapy) or turning off normal brakes (CTLA-4, PD-1) in the immune system (checkpoint inhibitors). This new generation of therapies, which has demonstrated improved objective response rates and overall survival in large randomized clinical trials, is the focus of this learning initiative. It will help guide healthcare professionals who treat patients with metastatic melanoma, including oncologists, oncology nurses, and oncology physician assistants. This interactive case activity will provide a thorough a review of the emerging knowledge about the molecular biology and immunology of metastatic melanoma and the new systemic therapies that have been built on that knowledge. It also will discuss the latest clinical evidence supporting the place of these drugs in the melanoma treatment paradigm. In addition we will discuss the unique side effects of these new treatments. Finally, the activity will assist practitioners in developing individualized treatment plans for patients with this often lethal, but now more treatable, cancer.
GOAL
The goal of this activity is to provide oncology healthcare providers with the most up-to-date information on the issues of treating and managing patients with metastatic melanoma.
TARGET AUDIENCE
This activity is designed for oncology healthcare providers (oncologists, oncology nurses, and oncology physician assistants) who care for patients with metastatic melanoma. No prerequisites required.
LEARNING OBJECTIVES
After participating in this activity, the participant will demonstrate the ability to:
  • EVALUATE the evidence-based findings regarding the new and emergent systemic therapies for patients with metastatic melanoma.
  • ASSESS the role of immuno- and targeted therapy in the treatment paradigm for patients with metastatic melanoma.
  • IDENTIFY the criteria for recommending specific immunotherapeutic and targeted therapies for patients with metastatic melanoma based on their presentation, laboratory, radiological, and histological findings.
The Johns Hopkins University School of Medicine and the Institute for Johns Hopkins Nursing take responsibility for the content, quality, and scientific integrity of this CME/CNE activity.
CE INFORMATION
Accreditation Statements — This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Johns Hopkins University School of Medicine and the Institute for Johns Hopkins Nursing. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.
The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.
Credit Designation Statements — The Johns Hopkins University School of Medicine designates this enduring material for a maximum of .5 AMA PRA Category I CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
This .5 contact hours of educational activity is provided by the Institute for Johns Hopkins Nursing. Nurses should claim only those contact hours actually spent in the activity. Statements will be awarded for this educational activity until May 11, 2018.
The estimated time to complete this activity: 30 minutes.
Release date: May 20, 2016    Expiration date: May 20, 2018


Introduction
Melanoma is one of the most lethal human cancers and has historically been among the most resistant to contemporary chemotherapeutic approaches. It is the most serious form of skin cancer and has the highest mortality rate of all skin cancer types, leading to a rapid decline in the health in people who often are in the prime of life.1 The worldwide incidence of melanoma is about 132 000 cases per year. The number of new cases has been increasing in recent decades in Western nations, thought largely to be a result of increased recreational exposure to ultraviolet radiation and improved early detection.2 Risk factors for melanoma include skin and hair color and the pre-existence of more than 20 benign nevi: white patients are 5 and 10 times more likely than Asian and black patients, respectively, to develop melanoma.3
About 20% of older melanoma patients present with distant metastases; until recently, these patients would be considered incurable at diagnosis, having less than a 10% chance of 5-year survival.4 Patients who present with a thin (<1 mm) primary melanoma will have a cure rate of more than 95%. Each year, about 10 000 Americans die from melanoma.5 In the metastatic setting, the best prognosis is for metastases in the skin, subcutaneous tissue, or lymph nodes. Patients with lung metastases or with a combination of lung and skin or subcutaneous metastases, have an intermediate prognosis. The poorest prognosis is for metastases to other visceral sites (the liver, bone, and brain) or any site combined with an elevated lactate dehydrogenase. The American Joint Committee on Cancer Melanoma Staging Database estimates the 1-year survival rates for these 3 prognostic groups to be 62%, 53%, and 33%, respectively.6
Standard treatment for patients with melanoma involves surgical removal of the primary tumor and surrounding normal tissue (wide excision). A sentinel lymph node biopsy is also performed if the primary melanoma is 1 mm or smaller in Breslow depth (≥.75 mm in melanoma with high risk features). If the regional lymph nodes are involved, then a completion lymph node dissection is still considered the standard of care. Patients with melanomas that have metastasized to distant lymph nodes and/or other organs are treated with systemic therapy, which, until recently, was ineffective for most patients. The most frequently used cytotoxic drug for treating patients with metastatic melanoma has been dacarbazine, which offers an objective response rate of about 10%, a figure comparable to supportive care with no documented improvement in survival.7 Other drug regimens, such as a combination of carboplatin and paclitaxel or biochemotherapy show higher response rates, but again, does not demonstrate improvement in survival. Immunotherapy with high-dose interleukin-2 (IL-2) also has a low overall response rate, but this therapy was approved for the treatment of patients with metastatic melanoma because it induces a durable complete remission in about 7% of patients. However, IL-2 is a potentially toxic treatment that must be given in the hospital and is not a good option for many patients. Thus, until recently, no cancer therapy had been shown to improve survival in patients with metastatic melanoma; as a result, patients’ average survival was only 6 to 8 months.1
Fortunately, recent advances in the understanding of the molecular biology and immunology of melanoma have changed the therapeutic landscape. Research has led to the introduction of breakthrough drugs that work by targeting the mitogen-activated protein kinase (MAPK) pathway in melanoma cells that harbor BRAF mutations (targeted therapy) or by turning off normal brakes (CTLA-4, PD-1) in the immune system (checkpoint inhibitors). This new generation of therapies, which has demonstrated improvement in response and overall survival rates, is the focus of this educational activity.

Decision Point 1
SL is a 57-year-old white female who presents to her physician with a suspicious pigmented lesion on her shoulder that has changed shape and size in recent months. Biopsy of the lesions shows a melanoma with a Breslow depth of 3.00 mm, ulceration present, and a mitotic rate of 5/mm2. A chest X-ray shows 3 nodules in the lungs. A computed tomography scan of chest, abdomen, and pelvis confirm the presence of 3 lung nodules and no other evidence of metastasis. A fine-needle aspiration of 1 lung nodule confirms the diagnosis of metastatic melanoma. 

Which of the following would NOT be part of the current workup for SL’s disease? 
Genetic mutation analysis of biopsied tissue 
Measurement of lactate dehydrogenase 
Review of chemotherapeutic options 
A brain magnetic resonance imaging (MRI) study to complete the staging work-up 


Therapies Targeted to Genetic Aberrations

The discovery of the missense mutation at codon 600 in the BRAF gene, which produces a constitutively active abnormal BRAF kinase, up-regulates the MAPK pathway even in the absence of extracellular growth signaling (Figure 1).9-10







This discovery led to the development of the first selective BRAF V600 inhibitors, vemurafenib and dabrafenib. About 80% to 90% of BRAF mutations are V600E missense mutations; the remainder have V600K, V600D,V600R, and less common mutations.11Both agents have been shown to improve overall survival in large randomized clinical trials of patients with metastatic melanoma. Compared with dacarbazine subjects, treatment-naïve vemurafenib patients carrying the BRAFV600 mutation experienced significantly longer overall survival (OS) and progression-free survival (PFS) (13.6 months vs 9.7 months, p = .0008; and 5.3 months versus 1.6 months, p<.001, respectively).12 Dabrafenib also produced striking clinical results.13-14 In the same patient cohort and using the same comparator, dabrafenib patients showed a significant improvement in PFS (6.9 months versus 2.7 months, p<.001) and a preliminary advantage in OS (18.2 months versus 15.6 months). The toxicity profiles of the BRAF inhibitors in both studies were favorable, with common adverse events including fatigue, arthralgia, rash, and photosensitivity, hyperkeratosis, and fever. The most clinically relevant side-effect particular to BRAF inhibitors is cutaneous squamous cell carcinomas (SCC) and keratoacanthomas, which are manageable via surgical resection without further risk of recurrence.12
Although BRAF inhibitors are effective in treating patients with advanced melanoma in the with the V600 mutation, for most patients, the benefits are of short duration. The median PFS is only 6 months, and the rate of complete responses is less than 5%.10 Several mechanisms of resistance to BRAF inhibition have been reported, but unfortunately, there does not appear to be one that’s common and easy to target. One approach to overcome resistance to BRAF inhibitors is to simultaneously target mutant BRAF and the next downstream kinase, MEK. Trametinib is an MEK1/MEK2 inhibitor that has been shown to be effective in patients with BRAF V600E/V600K mutant metastatic melanoma.15 When given to patients with metastatic melanoma as a single agent, trametinib showed a median PFS of 4.8 months versus 1.5 months (p <.0001) for those receiving dacarbazine or paclitaxel. Follow-up data showed a median OS of 15.6 versus 11.5 months (p = NS), even though 65% of chemotherapy patients crossed over to the trametinib arm.16 The drug was well tolerated; the most common side effects were rash, diarrhea, fatigue, dermatitis, and edema.
Despite experiencing improvement in survival, nearly all patients receiving MEK inhibition therapy, as with those given anti-BRAF drugs, soon develop resistance to treatment; however, there are some long-term responders (>3 years). Two landmark studies, the Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects with BRAF-mutant Melanoma (COMBI-D) and the Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma (COMBI-V) study, demonstrated the merits of combining BRAF and MEK inhibition. The COMBI-d trial compared the combination of dabrafenib and trametinib with dabrafenib plus placebo as first-line treatment of 423 patients with unresectable or metastatic BRAFV600E/K mutant melanoma.17 Combination BRAF/MEK inhibition therapy produced a 25% improvement in PFS, relative to BRAF inhibition alone. The interim analysis of OS showed that combined dabrafenib and trametinib reduced the risk of mortality by 37% (p = .023).18 In the COMBI-V study, 704 patients with treatment-naïve metastatic BRAF mutant melanoma were randomized to dabrafenib and trametinib or vemurafenib alone.19 Again, the efficacy results favored combination therapy: the overall response rate (ORR) was 64% with combination therapy versus 51% for vemurafenib alone (p <.001); median PFS was 11.4 versus 7.3 months (risk reduction [RR] = 44%, p<.001), and median duration of response was 13.8 months versus 7.5 months. The 12-month analysis of OS also showed a 31% RR for those receiving dabrafenib and trametinib (p <.005). Perhaps one of the most noteworthy findings of the COMBI-d and COMBI-v trails related to safety: BRAF/MEK combination therapy markedly reduced the incidence of skin toxicities (as expected, other adverse events such as hypertension and diarrhea were higher in the combination-therapy cohort). In the COMBI-D trial, rates of SCC were 2% and 9% for dabrafenib and trametinib versus dabrafenib and placebo, respectively; percentages of hyperkeratosis (3% vs 32%), alopecia (7% vs 26%), and hand-foot syndrome (5% vs 27%) also favored combination therapy. In the COMBI-V trial, the rates of cutaneous SCC and keratoacanthomas were 1% and 18% for combination therapy versus vemurafenib alone.19 Comparable results were reported for the other adverse events noted above. The reduction in SCC with combined BRAK/MEK inhibition therapy may be a consequence of the action of single-agent BRAF-inhibition, which paradoxically activates the MAPK pathway in SCC lesions.20 Complementary use of an MEK inhibitor shuts down this activated pathway, thereby reducing the incidence of SCC. In this context, it is important to recognize that the BRAF inhibitor itself does not cause SCC; instead, the drug accelerates the growth of pre-existing tumors.8
Additional trials using new BRAF/MEK inhibitors and other mechanisms to overcome BRAF resistance are now underway or are being planned for the future. Other genetic anomalies, such as mutated NRAS, (found in about 15% to 25% of melanoma patients) are now being assessed in clinical trials.21 Mutated GNAQ and GNA11, which are seen in the majority of patients with ocular melanomas are also the subject of clinical investigation.22 A large randomized trial of a MEK inhibitor in ocular melanoma was recently presented and showed disappointing results after promising results in a phase II trial. Mutations in C-KIT have been identified in up to 20% of patients with melanomas in chronically sun-damaged areas, acral lentiginous melanomas, and mucosal melanomas23; it also the subject of targeted therapy research. Results from these studies are eagerly anticipated. The wide range of strategies to identify potential targets of genetic mutation implicated in the etiology of metastatic melanoma demonstrate the importance of understanding tumor biology prior to implementing drug-development projects.8
Decision Point 2

The genetic analysis of SL’s biopsied metastasis confirms they are negative for the BRAF mutation. 




Which treatment approach would be MOST APPROPRIATE for SL? 

IL-2 

Nivolumab or pembrolizumab 
Dabrafenib and trametinib 
Ipilimumab 


Nivolumab and Ipilimumab 


Immunotherapies for Treating Metastatic Melanoma
The first immunotherapy approved by the Food and Drug Administration for use in treating patients with surgically unresectable or metastatic melanoma was high-dose IL-2 in 1998. The overall objective response rate is only 15%, and the complete response rate is 7%. Many of the responses are durable, with some of the initial IL-2 patients having been followed for more than 30 years. However, high dose IL-2 is associated with serious side-effects and must be administered in the hospital. Patients must have an excellent performance status and no coronary artery disease to be candidates for IL-2 therapy. Currently, the NCCN guidelines suggest that high-dose IL-2 be given after the newer drugs have failed.

More recent research on the immune response to melanoma has focused on the brakes, or checkpoints, that inhibit the cytotoxic T–cell, which has long been known as the key component in eradicating melanoma. One of the key inhibitory checkpoints that protects the healthy human host from autoimmune disease is the CTLA-4 antigen on T-cells.1 At the same time as the T-cell is activated through the dual signaling of the T-cell receptor and the CD28 molecule, CTLA-4 is also activated and dampens the immune response (Figure 2).25


Ipilimumab is a monoclonal antibody that targets the CTLA-4 molecule on T-cells. In so doing, the drug turns off the brake, or inhibits the CTLA-4 checkpoint, allowing the T-cell response to melanoma to proceed. Two important phase III studies demonstrated the clinical relevance of the mechanism and the benefits of the drug. In the first study, ipilimumab plus a melanoma peptide vaccine were compared with ipilimumab alone or the vaccine alone in patients with unresectable or metastatic melanoma who had progressed after one line of therapy. In the patients who received ipilimumab, the median overall survival was 10 months versus 6.4 months for the patients who received vaccine only.25 The large randomized study was the first to show a survival benefit in patients with metastatic melanoma. A second study, which used a higher dose of ipilimumab, compared dacarbazine alone with the combination of ipilimumab/dacarbazine in treatment-naïve metastatic melanoma patients.7 It found the co-therapy offered a significantly better median survival of 11.2 months compared with 9.2 months for dacarbazine alone (p <.001). More importantly, both studies showed a doubling in the probability of survival at 1, 2, and 3 years for patients who received ipilimumab. Both studies also were noteworthy in showing that ipilimumab was associated with distinctive grade 3/4 immune-related adverse events, including colitis, dermatitis, hepatitis, thyroiditis, and hypophysitis. These serious adverse events, which are related to the drug’s mechanism of action and were not unexpected, were reported in 15% of patients. These toxicities can be life-threatening and require prompt recognition and treatment. In most cases, the toxicities will respond to high dose-steroid treatment. A second-line of immunosuppressive therapy, such as infliximab, may occasionally be required.
Another immunotherapeutic approach for patients with melanoma focuses on another checkpoint molecule on the T-cell, programmed cell death-1 (PD-1). PD-1 interacts with the PD-1 ligand (PD-L1), which is expressed on the surface of many tumor cells and by tumor-infiltrating lymphocytes; the resulting interaction of PD-1 and PDL1 suppresses the functioning of T-lymphocytes and helps tumors evade immune regulation (Figure 2).1,25 Indeed, increased expression of PD-L1 is correlated with a poor prognosis in patients with multiple tumor types.26
Targeting the negative interaction between PD-1 and PD-L1 with monoclonal antibodies such as pembrolizumab and nivolumab has yielded the best single-agent immunotherapeutic findings to date. Pembrolizumab and nivolumab are approved for patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab or a BRAF inhibitor. A phase III study of nivolumab in 418 treatment-naïve patients with unresectable or metastatic melanoma and no BRAF mutation compared the drug with dacarbazine and found a significant difference in the median PFS (5.1 months vs 2.2 months, p <.001) and 12-month landmark survival rate (72.9% vs 42.1%, p <.001).27-28 Two large phase III trials of patients being treated with pembrolizumab have been reported; in the larger study, 834 patients with unresectable or metastatic melanoma who had received no more than one prior therapy and were PD-1-inhibitor naïve were given either of 2 doses of pembrolizumab or ipilimumab.29 The median PFS for pembrolizumab was 5.5 months compared with 2.8 months for ipilimumab (p <.001). The overall response rate for pembrolizumab was 37%, significantly higher than ipilimumab. The safety profile was good for both drugs: the grade III to IV adverse-event rate was about 10%. Autoimmune pneumonitis was a rare but potentially fatal complication of the anti-PD1 drugs.
Perhaps the most promising immunotherapeutic approach is a combination of CTLA-4 and PD-1 blockade. Striking results were reported in early studies, and phase III findings comparing front-line nivolumab plus ipilimumab with either drug on its own showed the combination yielded significantly better median PFS relative to ipilimumab alone (11.5 vs 2.9 months, p <.001).30-31Results for OS remain to be reported. As expected, treatment related grade 3/4 toxicities occurred more frequently in the combination arm (55%) vs either ipilimumab (27.3%) or nivolumab (16.3%). Most of the immune adverse events resolved. There was 1 treatment-related death in the nivolumab-alone arm.
Conclusions
The current moment is an auspicious one for clinicians who treat patients with advanced melanoma. Eight new drugs have been approved since 2011, including talimogene laherparepvec (T-VEC), the first oncolytic viral therapy, which was designed to be injected into surface tumors. In a pivotal study, T-VEC demonstrated a sustained response rate of 6 months or more, although no survival benefit was reported. These drugs have revised the therapeutic paradigm for patients with advanced and metastatic disease.
Today, the BRAF/MEK-inhibitor combination has become the standard treatment option in patients with BRAF-mutant melanomas. Because the vast majority of patients will develop resistance to the BRAF/MEK combination other targeted agents are now under investigation, including P13K, AKT, and ERK inhibitors; it is hoped that these may overcome or delay resistance to anti-BRAK/MEK therapy. The 3 immune-checkpoint inhibitors already approved in the United States have proven to be invaluable as single agents and in combination with treating melanoma. Future studies will help establish the optimum sequence and combination of targeted and immunotherapies in patients with stage III and IV melanoma. Despite the clinical value of these novel treatments, their high price tag is a concern, especially for patients who must take them for many months.1 Conversely, when survival is greatly extended, the benefit becomes more visible and direct. One way to improve the cost-benefit profile would be to develop new biomarkers to improve patient selection, so that those who are unlikely to benefit from a particular regimen will be spared the cost and risk of serious adverse events. Unfortunately, at this time, there are no reliable biomarkers that predict response to the new immunotherapies. Still, the new targeted and immune therapies, which have increased response rates from about 10% to more than 50% in a very brief time, provide much hope for patients with metastatic melanoma. We already know that ipilimumab as a single agent leads to a 22% chance of 10-year survival. Further follow-up with the anti- PD-1 drugs is predicted to show a high chance of long-term survival.
REFERENCES

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