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Treatment of Stage IV – Metastatic Melanoma

Individuals with stage IV, or metastatic, melanoma have cancer that has spread from its site of origin to distant lymph nodes or other distant sites in the body, such as the liver, lungs, or brain. Significant advances in the treatment of advanced melanoma including the development of precision cancer medicines and immunotherapy have largely replaced chemotherapy and many patients are living for years as a result of these newer treatments.

Newer precision cancer medicines and immunotherapy drugs are the standard of care because they delay the time to cancer recurrence and prolong survival. Patients should discuss the role of genomic testing for determining the best therapy to be used. Systemic therapies commonly used in the treatment of Melanoma include:

BRAF & MEK Kinase Inhibitors

The BRAF and MEK genes are known to play a role in cell growth, and mutations of these genes are common in several types of cancer. Approximately half of all melanomas carry a specific BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF kinase that stimulates cancer growth. Some melanomas carry another mutation known as V600K. BRAF and MEK inhibitors block the activity of the V600E and V600K mutations respectively.1,2,3,4,5 Combinations of a BRAF and a MEK inhibitor appear to decrease the emergence of disease resistance that occurs in patients treated with BRAF inhibition alone.5

BRAF inhibitors

  • Zelboraf®(vemurafenib) BRAF V600E kinase inhibitor
  • Tafinlar®(dabrafenib) BRAF V600E kinase inhibitor
  • Braftovi® (enorafenib) BRAF inhibitor

MEK inhibitors

  • Mekinist®(trametinib) MEK V600 kinase inhibitor
  • Cotellic® (cobimetinib) MEK V600 kinase inhibitor
  • Mektovi® (binimetinib) MEK inhibitor


Immunotherapy treatment of melanoma has also progressed considerably and has also become a standard treatment. The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction, however, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the cancer.6,7

Yervoy® (ipilimumab) is a monoclonal antibody that targets CTLA4, found on the surface of T cells. CTLA4 is thought to inhibit immune responses. By targeting this molecule, Yervoy enhances the immune system’s response against tumor cells.

PD-1 “Checkpoint Inhibitors”: Drugs that block the PD-1 pathway can enhance the ability of the immune system to fight cancer and are referred to as checkpoint inhibitors for their ability to help the immune system recognize and attack cancer.  Opdivo (nivolumab) and Keytruda (pembrolizumab) is a checkpoint inhibitors that are approved for treatment of advanced melanoman and are superior to Yervoy.7,8

Proleukin® (interleukine 12) is an immunotherapy agent has traditionally been given in high doses to patients with 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.9


Although once the standard of care, chemotherapy has largely been replaced by the newer precision cancer medicines and immunotherapies in the management of advanced melanoma. Chemotherapy is still being used in some 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 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.10,11

  • DTIC (dacarbazine)
  • Platinum
  • Tamadol (temazolamide)
  • Avastin



1 Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine. 2011;364(26):2507-16. doi: 10.1056/NEJMoa1103782.

2 Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomized controlled trial. Lancet. 2012;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X.

3 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.



6 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.



9 Cancer, Vol 88, No 9, pp 2042-2046, 2003

10 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.

11 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.

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