Malignant Melanoma Medication

Updated: Jan 31, 2020
  • Author: Winston W Tan, MD, FACP; Chief Editor: Dirk M Elston, MD  more...
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Medication

Medication Summary

Chemotherapy agents used for adjuvant treatment of melanoma include dacarbazine, cisplatin, and vinblastine. Nivolumab, ipilimumab, or interferon (IFN) alfa-2b are options for 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 (American Joint Committee on Cancer [AJCC] stage IIB) and regional lymph node metastasis (stage III). IFN is given in high doses, as trials of low-dose IFN have shown no benefit in disease-free relapse or overall survival (OS) rates. [95] Nivolumab and pembrolizumab are options for adjuvant therapy of resected advanced melanoma.

Dabrafenib plus trametinib is also a useful combination for BRAF V600E or V600K mutation–positive unresectable or metastatic melanoma. Additionally, it is approved for adjuvant therapy in combination with trametinib for melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection. [32]

Intralesional injection with talimogene laherparepvec is approved for skin metastasis.

For metastatic melanoma, the first approach would be to determine the BRAF status of the melanoma. If BRAF mutation is present, the therapy of choice would be the combination of a BRAF inhibitor and MEK inhibitor. For tumors with wild-type BRAF, the option would be combination treatment with nivolumab and ipilimumab or nivolumab or pembrolizumab. The treatment approach should be individualized depending on the patient's performance status and underlying comorbidities.

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Antineoplastic Agents

Class Summary

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

Dacarbazine

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

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

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 in adults and adolescents aged 12 y or older. Additionally, it is indicated for the adjuvant treatment of adults with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy. It is also used off-label in previously untreated patients with BRAF V600 wild-type, unresectable or metastatic melanoma in combination with nivolumab. Note, nivolumab is approved in combination with ipilimumab.

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 as a single agent for unresectable or metastatic melanoma with BRAF V600 E mutation. It is indicated in combination with trametinib for BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. Additionally, it is approved for adjuvant therapy in combination with trametinib for melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection.

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 indicated as a single agent or in combination with dabrafenib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by with the THxID BRAF mutation test. Additionally, it is approved for adjuvant therapy in combination with dabrafenib for melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection.

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. It is also indicated for adjuvant treatment of resected, high-risk stage 3 melanoma.

Tamoxifen

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.

Binimetinib (Mektovi)

Inhibits mitogen-activated extracellular signal regulated kinase (MEK) 1 and MEK 2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK)-related phosphorylation and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. It is indicated in combination with encorafenib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

Encorafenib (Braftovi)

Kinase inhibitor that targets BRAF V600E. This pathway regulates several key cellular activities, including proliferation, differentiation, survival, and angiogenesis; inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma. It is indicated in combination with binimetinib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

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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.

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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.

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