Overview

Recurrent melanoma was historically treated with chemotherapy or biologic therapy.  Since 2011 several new, targeted therapies have completed evaluation in clinical trials and demonstrated improved outcomes for individuals with advanced melanoma leading to their approval by the FDA.  Individuals with advanced melanoma now have numerous treatment options and additional clinical studies are ongoing in order to determine the best way to use these new drugs in sequence or combination therapy.

Patients with recurrent or refractory metastatic melanoma may be divided into 2 groups: patients who have failed initial systemic therapy and experience progression or recurrence after an initial response to treatment or patients who have local recurrences (skin and/or regional lymph nodes) after initial surgery or surgery and adjuvant therapy.

Individuals with metastatic melanoma who have failed initial systemic therapy are infrequently cured with additional therapy. There are many choices of therapy and access to newer treatment strategies in clinical trials. These therapeutic choices may prolong survival, reduce symptoms of progressive cancer and/or offer the chance of cure. Patients need to assess their treatment options and consider their individual goals for receiving additional treatment.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19

Targeted Therapy

Unlike conventional chemotherapy drugs that attack both normal and cancerous cells, targeted therapies are designed to block specific substances or pathways in cancer cells that enable cancer to grow.  A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Cancer treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes. Think of a light switch that’s stuck in the on position, as long as the switch is on, the cancer keeps growing. What these new drugs do is cut the wire or turn the switch off.  Several targeted therapies are now available for the management of malignant melanoma.

Zelboraf® (vemurafenib) was the first to be approved in a new class of drugs known as BRAF inhibitors. It turns off a genetic mutation called BRAF V600, found in about half of patients with advanced melanoma, which allows melanoma cells to grow uncontrollably. The results of a recent clinical trial demonstrated that patients taking Zelboraf® lived for nearly 16 months on average, compared with about six months for patients who took the chemotherapy drug dacarbazine. Nearly one in four patients treated with Zelboraf® developed squamous cell cancer, a type of non-melanoma skin cancer. Other common side effects included joint pain, skin rash, hair loss, and sun sensitivity.2

Tafinlar® (dabrafenib) also targets the BRAF V600 mutation. Tumor growth was delayed by about five months in patients taking Tafinlar®, compared with two to three months for patients taking dacarbazine.8Serious side effects included new skin cancers (both squamous cell and melanoma), high fever, high blood glucose, and eye inflammation. Other, more common side effects included headache, joint pain, hair loss, and redness, swelling, and pain in the hands and the feet.3

Mekinist® (trametinib) is a BRAF inhibitor that targets the BRAF mutation in a different way than Zelboraf or Tafinlar® does. Tumor growth was delayed for about five months in patients taking Mekinist, compared with about six weeks for patients taking either dacarbazine or another chemotherapy drug, Taxol® (paclitaxel). Serious side effects included heart disease, lung diseases, and skin and eye complications. Other, more common side effects included rash, diarrhea, and swelling in the arms or legs.4

Tafinlar® plus Mekinist® The COMBI-v clinical trial compared the combination of the BRAF inhibitor Tafinlar® plus the MEK inhibitor Mekinist® with Zelboraf® alone in 704 patients with the BRAF V600mutation.  Overall response rates, duration of response and overall survival were improved with combination therapy. The median overall survival was 17.2 months with Zelboraf alone and had not been reached in the Tafinlar®/ Mekinist® treated patients.5

Treatment With Immunotherapy

Biological agents, also called immunotherapy, are treatments that stimulate or restore the ability of the immune system to fight the cancer. There are several substances that boost, direct or restore normal immune defenses and include interferons, interleukins, vaccines and newer monoclonal antibodies, which are in essence a targeted immunotherapy.

Keytruda® (pembrolizumab) is a targeted immunotherapy and the first anti-PD-1 drug, aimed at re-energizing a patient’s protective immune response to cancer to have received FDA approval in the U.S for the treatment of cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1, such as Keytruda®, may enhance the ability of the immune system to fight cancer. Data from an ongoing trial evaluating Keytruda® has demonstrated promising survival rates among patients with advanced melanoma. Among 365 patients with measureable disease 28% of those who had previously received Yervoy® and 40% of those who had not received Yervoy® had a promising response to treatment.6

Yervoy® (ipilimumab) is a targeted immunotherapy directed at a protein that prevents the body’s immune system from recognizing and killing melanoma cells. It is the first drug shown to extend the lives of patients with advanced melanoma. In the trial that led to the approval of Yervoy® in 2011, the drug added about four months to life on average. When researchers combined data from multiple studies of Yervoy®, average survival was about 11 months, and some patients were still alive after seven years. The most common side effects included diarrhea, itching, skin rash, and colitis (inflammation of the lining of the colon).7, 8

Proleukin®: Proleukin® is a biologic agent that has been approved for the treatment of metastatic melanoma. Proleukin® has traditionally been given in high doses to patients with malignant melanoma, administered either intravenously by rapid infusion or by continuous infusion. Although high doses of Proleukin® historically have been associated with severe side effects management of these has significantly improved over the past decade making this treatment more tolerable.

Long-term results from a clinical trial evaluating high-dose Proleukin® in 270 patients with metastatic melanoma have been reported; 16% of patients achieved a partial or complete disappearance of their cancer and the average duration of all responses was approximately 9 months. Approximately seven years following therapy, the overall survival rate is approximately 11%. These long-term anti-cancer responses and survival indicate that high-dose Proleukin® remains an extremely effective treatment option for a subset of patients with metastatic melanoma.9

Alpha Interferon: Alpha interferon has shown anti-cancer activity in metastatic melanoma as a single agent and in combination with chemotherapy agents and Proleukin®. As a single agent, alpha interferon is associated with a response rate of 15%, which is comparable to Proleukin® or single agent chemotherapy with DTIC. For the treatment of metastatic melanoma, alpha interferon is most often combined with chemotherapy and/or Proleukin® and is rarely used as a single agent.9, 10

Combination Therapy

As promising as all of the new, targeted therapies are they typically stop working at some point because melanoma cells find another pathway that lets them start growing again. In many cancers, combination therapy improves survival and leads to cures when compared to single agent treatment. Researchers are now testing combinations of two or more targeted therapies.

Tafinlar® plus Mekinist® The COMBI-v clinical trial compared the combination of the BRAF inhibitor Tafinlar® plus the MEK inhibitor Mekinist® with Zelboraf® alone in 704 patients with the BRAF V600mutation.  Overall response rates, duration of response and overall survival were improved with combination therapy. The median overall survival was 17.2 months with Zelboraf alone and had not been reached in the Tafinlar®/ Mekinist® treated patients.5

Chemotherapy

Although once the standard of care, chemotherapy is being replaced by newer targeted and immunotherapies in the management of advanced melanoma. Chemotherapy is till being used however in many situations and may represent an appropriate treatment option for selected patients alone or in combination with newer targeted immunotherapies. DTIC (dacarbazine) has been the standard chemotherapy agent for the treatment of metastatic melanoma, with an overall response rate of approximately 15-20% and no clinical trials directly comparing DTIC to different chemotherapy combinations have demonstrated clear superiority of drug combinations over DTIC alone. Nevertheless, several mulit-drug regimens (DTIC, platinum, Temadol®, carmustine, Avastin®) have demonstrated response rates between 30% and 50%. The duration of response to these regimens averages 6-9 months, with average survivals of 6 to 11 months. The fraction of patients surviving one and two years following treatment may be a better measure of effectiveness than average duration of survival. Using this measurement, combination chemotherapy may be superior to any single agent.1, 11, 12

Role of Surgery

The available data suggests that surgery plays a role in the management of some patients with metastatic melanoma. Patients who have a limited number of lung metastases may benefit from surgical removal if they have favorable other prognostic features, such as a long period of time between diagnosis and recurrence. Surgery in some patients can eradicate disease that has incompletely responded to chemotherapy and/or biological therapy and some of these patients will survive cancer-free for over 5 years. Surgery can also relieve symptoms of obstruction and bleeding. Selected patients with metastatic melanoma to the gastrointestinal tract can experience prolonged survival following surgical removal of the melanoma.

A frequently asked question is whether a second surgery can also provide benefit to patients who have a recurrence, or return of the cancer, after already having one surgery for metastatic melanoma. Researchers reviewed the treatment outcomes for 211 patients with stage IV metastatic melanoma who were deemed clinically free of cancer after surgery. The melanoma recurred in 131 of these patients after an average of 8 months, but ranging up to 7.5 years following initial treatment. After a second surgical removal of cancer from 1 to 3 sites to which the cancer had spread in the body, the average survival time after surgery was 18 months. At 5 years after surgery, 20% of patients in whom removal of all detectable cancer was complete were alive. The longer the interval between the initial treatment and the recurrence, the longer the survival time was after the repeat surgery. These findings show that a second surgery may benefit patients who have a recurrence of metastatic melanoma, provided that the surgical removal of all detectable cancer was complete. This is an important treatment option for patients with metastatic melanoma for whom other treatments are ineffective or for those who have a partial response to biologic therapies (or immunotherapies) or chemotherapy.1,13

Role of Radiation Therapy

Radiation therapy can relieve symptoms, especially pain from cancer that has spread to the bone. Radiation therapy should be considered in patients who have had surgical removal of a single brain melanoma.1,14, 15

Treatment Of Brain Metastasis

Melanoma that has spread to the brain accounts for 10-50% of reported deaths from melanoma. A single brain metastasis can be removed surgically and radiation therapy should be considered in patients who have had surgical removal of a single brain metastasis. There is the suggestion that radiation therapy in this situation improves survival and reduces recurrences. The decision to recommend surgery should be based primarily on whether the entire melanoma can be removed and the status and number of other organs involved with metastatic lesions.

Locally Recurrent Melanoma

Following initial treatment with surgery with or without adjuvant therapy, patients are said to have locally recurrent melanoma if the cancer returns in or near its original location and cannot be found elsewhere in the body. A physical exam, CT scan, MRI, bone and PET scan should be used to rule out distant metastasis. The major determinant of therapy and treatment outcome is whether the recurrent melanoma involves the local/regional lymph nodes.

Local Recurrence without Nodal Involvement

Following initial surgical removal of melanoma, approximately 12% of patients will experience cancer recurrence in the skin or skin graft without evidence of more widespread disease. The treatment of locally recurrent melanoma without lymph node involvement consists mainly of additional surgical removal of the cancer. To establish that the lymph nodes are not involved, patients may request a sentinel node biopsy before wide local excision. The American Joint Committee on Cancer and World Health Organization recommend sentinel node biopsy for melanoma tumors greater than 1mm.1,14

Local Recurrence with Nodal Involvement

Surgery: If recurrence involves a cutaneous melanoma tumor and nodal involvement is expected but not established a sentinel node biopsy at the time of wide local excision may be required. A regional lymph node dissection may be performed on the neck, armpit or groin depending on the site of cutaneous recurrence or presence of palpable nodes. Associated lymph node dissection side effects may include sensory numbness, diminished mobility and intermittent swelling called lymphedema. Prognosis depends on extent of nodal involvement. In one series of 26 patients who had recurrent cutaneous melanoma of the head and neck, 38% were alive and free of disease following complete dissection of neck lymph nodes. Researchers at MD Anderson report that the 5 year cancer free survival for patients with one positive node, 2 to 4 positive nodes and more than 4 positive nodes is 48%, 36% and 21%, respectively.1, 15

Isolated Limb Perfusion: For the past 40 years, patients have been treated with isolated limb perfusion in attempts to prevent amputation or mutilating surgery in patients with recurrences localized to a single arm or leg. This localized treatment strategy is believed to augment anti-cancer effects of chemotherapy compared with systemic (full body) delivery through the following mechanisms: 1) the chemotherapy agent does not become diluted prior to reaching the cancer by mixing with the rest of the blood from the body, 2) the chemotherapy agent is not broken down in the body through biochemical processes prior to reaching the cancer, 3) larger amounts of the chemotherapy agent can reach the cancer with fewer associated systemic side effects.1

Strategies to Improve Treatment

The progress that has been made in the treatment of melanoma has resulted from improved development of treatments in patients with more advanced stages of cancer and participation in clinical trials. Future progress in the treatment of melanoma will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of melanoma.

PD-1 Inhibitors Investigational immunotherapy drugs known as anti-PD-1 drugs have produced very promising response rates in early-phase clinical trials. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 may enhance the ability of the immune system to fight cancer. These drugs include Keytruda® (pembrolizumab) and nivolumab.6,16

Keytruda® is a targeted immunotherapy and the first anti-PD-1 drug, aimed at re-energizing a patient’s protective immune response to cancer to have received FDA approval in the U.S for the treatment of cancer. Data from an ongoing trial evaluating Keytruda® has demonstrated promising survival rates among patients with advanced melanoma and additional clinical trials are ongoing to determine the optimal way to use Keytruda® in the management of melanoma.6

Nivolumab like other PD-1 drugs enhances the ability of the immune system to fight cancer. A randomized Phase III clinical trial called CheckMate -066 evaluated nivolumab as initial, or first line, therapy for patients with advanced melanoma without a mutation in the BRAF gene.   Analyses revealed evidence of superior overall survival in patients receiving nivolumab compared with those who received the chemotherapy dacarbazine and the study was halted early to allow the dacarbazine patients to switch nivolumab.16

At one year, almost 73% of patients in the nivolumab group were alive, compared with 42% in the dacarbazine group, and Median progression-free survival more than doubled among patients receiving nivolumab: just over five months compared with just over two months for dacarbazine.

New Treatment Regimens: Development of new multi-drug treatment regimens that incorporate new or additional anti-cancer therapies is an active area of clinical research carried out in phase II clinical trials. Combining newer targeted and immunotherapy with chemotherapy and existing biologic agents is the focus of intensive investigation, with many clinical trials ongoing.

Yervoy + GM-CSF Patients with metastatic melanoma treated with the combination of Yervoy® (ipilimumab) and GM-CSF (granulocyte-macrophage colony-stimulating factor), had a one-year survival rate of 69% and an average survival of 17.5 months compared to 54% and 12.7 months if treated with Yervoy alone.

Yervoy®, an immune checkpoint blocker is a monoclonal antibody that targets a protein receptor, CTLA-4 that prevents the body’s defenses from attacking cancer cells. By blocking CTLA-4 Yervoy® releases the brake, allowing cell-killing T cells to assault the cancer cells.  GM-CSF is a protein that spurs the growth of white blood cells in the immune system.  Larger trials and longer follow-up are necessary to confirm these results.17

New Targeted Therapy Drugs:  Unlike conventional chemotherapy drugs that attack both normal and cancerous cells, targeted therapies are designed to block specific substances or pathways in cancer cells that enable cancer to grow.  A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Several targeted therapies have been approved for the management of malignant melanoma and doctors are working to determine the best way to use them.

Zelboraf® (vemurafenib) and Tafinlar® (dabrafenib) belong to a new class of drugs known as BRAF inhibitors. They turns off a genetic mutation called BRAF V600, found in about half of patients with advanced melanoma

Mekinist® (trametinib) is a BRAF inhibitor that targets the BRAF mutation in a different way than Zelboraf or Tafinlar®.3

As promising as all of the new, targeted therapies are they typically stop working at some point because melanoma cells find another pathway that lets them start growing again. In many cancers, combination therapy improves survival and leads to cures when compared to single agent treatment. Researchers are now testing combinations of two or more targeted therapies.

Tafinlar® plus Mekinist® The COMBI-v clinical trial compared the combination of the BRAF inhibitor Tafinlar® plus the MEK inhibitor Mekinist® with Zelboraf® alone in 704 patients with the BRAF V600mutation.  Overall response rates, duration of response and overall survival were improved with combination therapy. The median overall survival was 17.2 months with Zelboraf alone and had not been reached in the Tafinlar®/ Mekinist® treated patients.3, 4, 5

Vaccines:  Currently, no vaccine has been approved for the treatment melanoma.  Melanoma vaccines produce responses, often dramatic, in some patients, but effects are far from consistent.

The experimental cancer vaccine talimogene laherparepvec (T-VEC) has been demonstrated to promote tumor shrinkage, trigger a systemic immune response and prolong survival in some patients with advanced melanoma.  T-VEC is a type of immunotherapy that uses a specially designed virus to destroy cancer cells. It is injected directly into the tumor. After acting locally within the tumor, it is intended to prompt an immune response against cancer cells elsewhere in the body.

Preliminary results showed that 64 percent of injected tumors shrank by half.  The vaccine shrank tumors that were directly injected as well as those that were not injected—indicating that the vaccine was triggering the immune system to fight the distant tumors.18

PV-10 is a 10% solution of Rose Bengal, which was originally used as an agent to stain necrotic tissue in the cornea. Its potential use in melanoma was discovered while exploring different formulations for use in photodynamic cancer therapy.  PV-10 was developed to be administered directly into solid tumors was discovered to destroy tumors without the need for light activation.  Initial trials report an overall response rate of 51%, and a complete response rate of 26% in individuals with refractory melanoma.19

Phase I Trials: New anti-cancer drugs continue to be developed and evaluated in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and whether the drug has any anti-cancer activity in patients with advanced melanoma.

References

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3 Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X.
4 Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. New England Journal of Medicine. 2012;367(2):107-14. doi: 10.1056/NEJMoa1203421.
5 Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. New England Journal of Medicine.2012;367(18):1694-703. doi: 10.1056/NEJMoa1210093.
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7 Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. New England Journal of Medicine. 2011;364(26):2517-26. doi: 10.1056/NEJMoa1104621.
8 Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. Paper presented at: 38th Congress of the European Society for Medical Oncology; September 27–October 1, 2013; Amsterdam, Netherlands. Abstract LBA24.
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10 Bottomley A, Coens C, Suciu S et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected Stage III melanoma: A Phase II randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group. Journal of Clinical Oncology. 2009;27:2916-2923.
11 Rao RD, Holtan SG, Ingle JN et al. Combination of Paclitaxel and Carboplatin as Second-Line Therapy for Patients with Metastatic Melanoma. Cancer. 2006;106:375-82.
12 Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma. Cancer. 2009; 115: 119-127.
13 Journal of Surgical Oncology, Vol 71, No 4, pp 209-213, 1999
14 Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: Results of the EORTC 22952-26001 Study. Journal of Clinical Oncology [early online publication]. November 1, 2010.
15 Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. The Lancet Oncology. 2012; 13(6): 589-597.
16 Robert C, Long GV, Brady B, et al. Nivolumab in Previously Untreated Melanoma without BRAF Mutation. New England Journal of Medicine [early online publication]. November 16, 2014.
17 Hodi, F. Stephen, MD, et al. “Ipilimumab Plus Sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma: A Randomized Clinical Trial.” The Journal of the American Medical Association. doi:10.1001/jama.2014.13943. November 5, 2014.
18 Andtbacka RH, Ross MI, Delman K, et al: Responses of injected and uninjected lesions to intralesional tal-imogene laherparepvec (T-VEC) in the OPTiM Study and the Contribution of Surgery to Response. Presented at the Society of Surgical Oncology Cancer Symposium in Phoenix, Arizona March 12-15, 2014. Abstract 52.
19 Thompson JF, Agarwala S, Smithers M, et al. Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma. Annals of Surgical Oncology, October 2014.

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