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Cutaneous Melanoma Medication

  • Author: Susan M Swetter, MD; Chief Editor: Dirk M Elston, MD  more...
 
Updated: Mar 28, 2016
 

Medication Summary

High-dose interferon (IFN) alfa-2b was the first  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,[121] although a benefit in both disease-free and OS was suggested in a study of low-dose IFN in resected stage III patients in a German Dermatologic Cooperative Oncology Group study.[122] A 2012 analysis of adjuvant therapy with low-dose pegylated IFN (PEG-IFN) administered for 36 months versus low-dose IFN for 18 months in melanoma patients with macrometastatic nodes did not reveal differences in disease-free survival, distant metastasis-free survival (DMFS), or OS, suggesting lack of superiority of adjuvant low-dose PEG-IFN.[123] 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, was FDA approved 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.[74, 95]

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.

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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.

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Antineoplastics, Monoclonal Antibodies

Class Summary

Monoclonal antibodies are considered second-line treatment for unresectable or metastatic melanoma. The agents also include inhibitors of programmed death-1 (PD1) protein, a T-cell co-inhibitory receptor, pembrolizumab and nivolumab.

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 is indicated for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor

Nivolumab (Opdivo)

 

Nivolumab is indicated for unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor.

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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.

Trametinib (Mekinist)

 

Trametinib is a MEK inhibitor indicated as a single agent or in combination with dabrafenib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations.

Dabrafenib (Taflinar)

 

Dabrafenib is a BRAF protein kinase inhibitor indicated as a single agent for unresectable or metastatic melanoma with BRAF V600E mutation, or in combination with trametinib for BRAF V600E or V600K mutations.

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Oncolytic Immunotherapy

Class Summary

These agents are used adjunctively following the resection of lesions.

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. 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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Contributor Information and Disclosures
Author

Susan M Swetter, MD Director, Pigmented Lesion and Melanoma Program, Professor, Department of Dermatology, Stanford University Medical Center and Cancer Institute, Veterans Affairs Palo Alto Health Care System

Susan M Swetter, MD is a member of the following medical societies: American Academy of Dermatology, Women's Dermatologic Society, American Society of Clinical Oncology, Society for Melanoma Research, Eastern Cooperative Oncology Group, American Medical Association, Pacific Dermatologic Association, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael J Wells, MD, FAAD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

John G Albertini, MD Private Practice, The Skin Surgery Center; Clinical Associate Professor (Volunteer), Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine; President-Elect, American College of Mohs Surgery

John G Albertini, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery

Disclosure: Received grant/research funds from Genentech for investigator.

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.

Acknowledgements

Günter Burg, MD Professor and Chairman Emeritus, Department of Dermatology, University of Zürich School of Medicine; Delegate of The Foundation for Modern Teaching and Learning in Medicine Faculty of Medicine, University of Zürich, Switzerland

Günter Burg, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, International Society for Dermatologic Surgery, North American Clinical Dermatologic Society, and Pacific Dermatologic Association

Disclosure: Nothing to disclose.

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Superficial spreading melanoma, left breast, 1.3-mm Breslow depth.
Lentigo maligna melanoma, right lower cheek. Centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ).
Acral lentiginous melanoma (1-mm Breslow depth), left sole. Diagnostic punch biopsy site is located superiorly.
Malignant melanoma. Courtesy of Hon Pak, MD.
Cutaneous melanoma with characteristic asymmetry, irregular borders, and color variation. Courtesy of Wendy Brick, MD.
Table. AJCC 2002 Revised Melanoma Staging
Stage TNM Classification Histologic/Clinical Features 5-Year Survival Rate, %
0 Tis N0 M0 Intraepithelial/in situ melanoma 100
IA T1a N0 M0 ≤1 mm without ulceration and mitotic rate < 1/mm2 97
IB T1b N0 M0



T2a N0 M0



≤1 mm with ulceration or mitotic rate ≥1/mm2



1.01-2 mm without ulceration



91-94
IIA T2b N0 M0



T3a N0 M0



1.01-2 mm with ulceration



2.01-4 mm without ulceration



79-82
IIB T3b N0 M0



T4a N0 M0



2.01-4 mm with ulceration



4 mm without ulceration



68-71
IIC T4b N0 M0 >4 mm with ulceration 53
IIIA T1-4a N1a M0



T1-4a N2a M0



Single regional nodal micrometastasis, nonulcerated primary



2-3 microscopic positive regional nodes, nonulcerated primary



78
IIIB T1-4b N1a M0



T1-4b N2a M0



T1-4a N1b M0



T1-4a N2b M0



T1-4a/b N2c M0



Single regional nodal micrometastasis, ulcerated primary



2-3 microscopic regional nodes, nonulcerated primary



Single regional nodal macrometastasis, nonulcerated primary



2-3 macroscopic regional nodes, no ulceration of primary



In-transit met(s)* and/or satellite lesion(s) without metastatic lymph nodes



54-59
IIIC T1-4b N2a M0



T1-4b N2b M0



Any T N3 M0



Single macroscopic regional node, ulcerated primary



2-3 macroscopic metastatic regional nodes, ulcerated primary



4 or more metastatic nodes, matted nodes/gross extracapsular extension, or in-transit met(s)/satellite lesion(s) and metastatic nodes



40
IV Any T any N M1a



Any T any N M1b



Any T any N M1c



Distant skin, subcutaneous, or nodal mets with normal LDH levels



Lung mets with normal LDH



All other visceral mets with normal LDH or any distant mets with elevated LDH



< 20
*Met is metastasis.
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