Cutaneous Melanoma Medication

Updated: Mar 22, 2022
  • Author: Susan M Swetter, MD; Chief Editor: Dirk M Elston, MD  more...
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Medication

Medication Summary

Ipilimumab, a CTLA-4 blocker, was FDA approved in 2015 for resected stage III melanoma, although the risk of immune-related adverse events tempered enthusiasm for the high-dose regimen in the adjuvant setting. [152, 113]  The high-dose regimen is not recommended in current NCCN melanoma clinical practice guidelines.

Talimogene laherparepvec (Imlygic) was approved in 2015. It is a genetically modified, live-attenuated herpes simplex virus programmed to replicate within tumors and produce the immune-stimulatory protein granulocyte macrophage colony-stimulating factor (GM-CSF). It is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery.

Considering new developments in adjuvant immunotherapy (checkpoint inhibitors) and and targeted agents (BRAF/MEK inhibitors), adjuvant IFNα is no longer used in the adjuvant setting. Immune checkpoint inhibition with the PD-1 inhibitor pembrolizumab was FDA approved in December 2021 for adjuvant therapy in resected stage IIB and IIC patients, following pathologic staging with SLNB (as in the KEYNOTE-716 trial).

Checkpoint inhibitors such as nivolumab and pembrolizumab are PD-1 inhibitors and are often used a monotherapy for patients with metastatic/unresectable stage III/IV disease and for those who lack the BRAF V600 mutation and are not eligible for targeted therapy with BRAF/MEK inhibitors. Ipilimumab is a different checkpoint inhibitor, a CTLA-4 blocker, and was approved by the FDA in 2015 for resected stage III melanoma, although the risk of immune-related adverse events have tempered enthusiasm for the high-dose regimen in the adjuvant setting. [152, 114] . Ipilimumab may be used as a second line agent for individuals who have progression on PD-1 inhibition, but is more commonly used with the PD-1 inhibitor nivolumab for dual checkpoint blockade in patients with unresectable stage III/IV melanoma.

Talimogene laherparepvec (Imlygic) was approved in 2015. It is a genetically modified, live-attenuated herpes simplexvirus programmed to replicate within tumors and produce the immune-stimulatory protein granulocyte macrophage colony-stimulating factor (GM-CSF). It is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery.

Targeted therapy with BRAF/MEK inhibitors is used in patients with advanced melanoma and have a BRAF V600 mutation; however, immunotherapy with immune checkpoint blockade is the preferred initial option in terms of efficacy and durable responses. Dabrafenib/trametinib is an adjuvant treatment option for patients with resected stage III or recurrent disease and who have a BRAF V600-activating mutation.

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Immunomodulatory Agents

Class Summary

Immunomodulatory agents enhance host immunity for cancer surveillance and eradication.

Interferon alfa-2b (Intron A)

Interferon alfa-2b is a protein product manufactured by recombinant DNA technology. It is produced naturally by cells in the body to combat infections and tumors. Its 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.

Interferon alfa-2b is generally initiated within 56 days of surgery and typically administered by medical oncologists. However, its use has been supplanted by superior adjuvant therapy options (immune checkpoint inhibitors and BRAF/MEK inhibitors).

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Antineoplastics, Monoclonal Antibodies

Class Summary

Monoclonal antibodies may be considered for unresectable or metastatic melanoma. Examples include inhibitors of programmed death-1 (PD1) protein, a T-cell co-inhibitory receptor, and a lymphocyte activation gene-3 (LAG-3) blocking antibody. 

Ipilimumab (Yervoy)

Ipilimumab is a targeted T-cell antibody. It is a recombinant, human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody indicated for unresectable or metastatic melanoma. CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The proposed mechanism of action is indirect, possibly through T-cell–mediated antitumor immune responses. Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kd. It is produced in mammalian (Chinese hamster ovary) cell culture.

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.

Pembrolizumab (Keytruda)

Pembrolizumab binds PD-1 ligands to PD-1 receptor found on T-cells, which inhibits T-cell proliferation and cytokine production. It is indicated as monotherapy in the adjuvant setting for unresectable or metastatic melanoma. It is also indicated for adjuvant treatment of Stage IIB, IIC, or III melanoma following complete resection in adult and pediatric patients aged 12 years and older.

Nivolumab (Opdivo)

Nivolumab is indicated for as monotherapy in the adjuvant setting for resected stage III and stage IV melanoma or for treatment of unresectable or metastatic melanoma. Dual checkpoint blockade is FDA-approved for the combination of ipilimumab and nivolumab.

Nivolumab/relatlimab (Opdualag)

Fixed dose combination indicated for treatment of adults and pediatric patients aged 12 years and older with unresectable or metastatic melanoma. Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody and relatlimab is a lymphocyte activation gene-3 (LAG-3) blocking antibody. The combination results in increased T-cell activation compared to activity of either antibody alone. 

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Antineoplastics, Other

Class Summary

Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Mitogen-activated extracellular signal regulated kinase (MEK) inhibitors are used in combination with BRAF inhibitors or in single-agent therapy.

Vemurafenib (Zelboraf)

Vemurafenib is a BRAF inhibitor indicated for unresectable or metastatic melanoma with BRAF-V600 mutation as detected by an FDA-approved test. It is not recommended for use with wild-type BRAF melanoma. BRAF inhibitors are not generally used as monotherapy, but rather in combination with MEK inhibitors. The approved regimens are vemurafenib/cobimetinib, dabrafenib/trametinib, and encorafenib/cobemetinib.

Trametinib (Mekinist)

Trametinib is a MEK inhibitor used in combination with dabrafenib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations.

Dabrafenib (Taflinar)

Dabrafenib is a BRAF protein kinase inhibitor used in combination with trametinib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations. The combination of dabrafenib/trametinib is FDA approved in the adjuvant setting for resected stage III melanoma.

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Oncolytic Immunotherapy

Class Summary

These agents are used adjunctively following the resection of lesions.

Talimogene laherparepvec (Imlygic)

Talimogene laherparepvec is an oncolytic herpes simplex virus. It  is a genetically modified, live-attenuated herpes simplex virus programmed to replicate within tumors and to produce the immune stimulatory protein GM-CSF. It causes lysis of tumors, followed by the 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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