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Malignant Melanoma Medication

  • Author: Winston W Tan, MD, FACP; Chief Editor: Dirk M Elston, MD  more...
Updated: Feb 11, 2016

Medication Summary

High-dose interferon (IFN) alfa-2b is the only adjuvant therapy approved by the US Food and Drug Administration (FDA) for high-risk resected melanoma, defined as deep primaries greater than 4 mm in Breslow depth (AJCC stage IIB) and regional lymph node metastasis (stage III). Various trials of low-dose IFN have shown no benefit in disease-free relapse or overall survival (OS) rates.[69]

Similarly, multiple melanoma vaccine trials are in progress, predominantly for stage III and IV disease, but they have not demonstrated an OS advantage to date.

Ipilimumab, a CTLA-4 blocker, enhances the T-cell response in HLA2-positive patients and demonstrates remarkable promise in patients with metastatic melanoma. It is being studied by itself and in combination with other immunotherapies and vaccines.[59]


Antineoplastic Agents

Class Summary

These agents inhibit cell growth and differentiation. Chemotherapeutic agents used to treat melanoma include dacarbazine, cisplatin, vinblastine, carmustine, and tamoxifen.



Although the mechanism of action for dacarbazine is unknown, possible actions include alkylating agent, purine metabolite, or interaction with sulfhydryl groups. The end result is inhibition of DNA, ribonucleic acid (RNA), and protein synthesis.



Cisplatin is an alkylating agent that inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of the double helix.



Vinblastine inhibits microtubule formation, which disrupts formation of the mitotic spindle, causing cell proliferation to arrest at metaphase. It is a component of the CVD regimen.

Ipilimumab (Yervoy)


Anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a humanized antibody that overcomes CTLA-4-mediated T-cell suppression to enhance the immune response against tumors. The marker CTLA-4 is associated with promoting a regulatory response by the immune system. This regulatory response has a dampening effect on the immune system. Ipilimumab is able to inhibit the effects of CTLA-4 on T cells and allows the expansion of naturally developed melanoma-specific cytotoxic T-cells. This agent is the first new agent to be approved for melanoma in over a decade.

It is indicated for the treatment of unresectable or metastatic melanoma. Additionally, it is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy. It is also indicated in previously untreated patients with BRAF V600 wild-type, unresectable or metastatic melanoma in combination with nivolumab.

Dabrafenib (Tafinlar)


Dabrafenib inhibits some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. It is indicated for unresectable or metastatic melanoma with BRAF V600 E mutation confirmed by with the THxID BRAF mutation test.

Trametinib (Mekinist)


Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation, and of MEK1 and MEK2 kinase activity. It is approved for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by with the THxID BRAF mutation test.

Pembrolizumab (Keytruda)


Pembrolizumab is a programed cell death-1 protein (PD-1) inhibitor. It is indicated as first-line treatment for unresectable or metastatic melanoma.



Tamoxifen competitively binds to the estrogen receptor, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is used in the Dartmouth regimen to possibly abrogate the multidrug resistance phenotype.

Vemurafenib (Zelboraf)


Inhibits some mutated forms of BRAF serine-threonine kinase, including BRAF-V600E. The drug is indicated for unresectable or metastatic melanoma with BRAF-V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.

Nivolumab (Opdivo)


Nivolumab is a monoclonal antibody to programmed cell death-1 protein (PD-1). It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is indicated as a single agent for unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. It is also indicated as a single agent in the first-line treatment of unresectable or metastatic BRAF V600 wild-type or mutation-positive melanoma. Combination therapy with ipilimumab for treatment of patients with BRAF V600 wild-type or mutation-positive unresectable or metastatic melanoma is superior to either drug alone.

Cobimetinib (Cotellic)


Reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.

Cobimetinib is indicated for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation in combination with vemurafenib. Cobimetinib and vemurafenib target 2 different kinases in the RAS/RAF/MEK/ERK pathway; compared with either drug alone, coadministration resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations.


Biological Response Modulators

Class Summary

Immunotherapy (biotherapy) currently used to treat patients with melanoma includes IFN and interleukin (IL)-2. An oncologist should administer these treatments.

Interferon alfa 2b (Intron A)


IFN alfa-2b is a protein product manufactured by recombinant DNA technology. The mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. It is the drug of choice for adjuvant therapy in patients with high-risk melanoma. Its immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity.

IFN alfa-2b is generally initiated within 56 days of surgery and typically administered by medical oncologists.

Peginterferon alfa 2b (Sylatron)


Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. Alfa interferons act through high-affinity cell surface receptors, which, once activated, are known to inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase the phagocytic activity of macrophages, and enhance the cytotoxicity of lymphocytes for target cells.

A covalent attachment of polyethylene glycol polymer chains to interferon molecules (known as PEGylation) can significantly increase the time the drug remains in the bloodstream, which, in turn, can reduce the frequency of dosing and potentially reduce the severity and frequency of adverse effects.

It was approved by the FDA in March 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy. It is the first therapy approved for the adjuvant treatment of melanoma in 15 years.

Interleukin 2 (Proleukin)


IL-2 is the only therapy known to cure advanced-stage melanoma. It activates T cells and amplifies their responses. It enhances natural killer cell antitumor activity.


Oncolytic Immunotherapy

Class Summary

Local treatment of lesions or nodal lesions may be needed following resection.

Talimogene laherparepvec (Imlygic)


The exact mechanism of action is unknown. Talimogene laherparepvec is a genetically modified, live, attenuated herpes simplex virus programmed to replicate within tumors and to produce the immune stimulatory protein GM-CSF. Causes lysis of tumors, followed by release of tumor-derived antigens, which together with virally derived GM-CSF may promote an antitumor immune response. It is a solution for intralesional injection that may be considered for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery.

Contributor Information and Disclosures

Winston W Tan, MD, FACP Associate Professor of Medicine, Mayo Medical School; Consultant and Person-in-Charge of Genitourinary Oncology-Medical Oncology, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Jacksonville; Vice Chairman of Education, Division of Hematology/Oncology, Mayo Clinic Florida

Winston W Tan, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Hematology, Texas Medical Association, American Society of Clinical Oncology, Philippine Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Philip Schulman, MD Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center

Philip Schulman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.

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A 1.5-cm melanoma with characteristic asymmetry, irregular borders, and color variation.
Malignant melanoma. Image courtesy of Hon Pak, MD.
Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ). Image courtesy of Susan M. Swetter, MD.
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