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Medically reviewed by Dr. C.H. Weaver M.D. 8/2020

Since 2011 several new, precision cancer medicines and immunotherapies have completed evaluation in clinical trials and demonstrated improved outcomes for individuals with advanced melanoma leading to their approval by the FDA. Individuals with advanced melanoma now have numerous treatment options and additional clinical studies are ongoing in order to determine the best way to use these new drugs in various combinations.

Patients with recurrent or refractory metastatic melanoma may be divided into 2 groups: patients who have failed initial systemic therapy and experience progression or recurrence after an initial response to treatment or patients who have local recurrences (skin and/or regional lymph nodes) after initial surgery or surgery and adjuvant therapy.

Individuals with metastatic melanoma who have failed initial systemic therapy are infrequently cured with additional therapy but can still experience prolonged survival with additional treatment. There are many choices of therapy and access to newer treatment strategies in clinical trials. These therapeutic choices may prolong survival, reduce symptoms of progressive cancer and/or offer the chance of cure. Patients need to assess the treatment options and consider their individual goals when electing to receive additional treatment.

Local Recurrence without Nodal Involvement

Following initial surgical removal of melanoma, approximately 12% of patients will experience cancer recurrence in the skin or skin graft without evidence of systemic disease. The treatment of locally recurrent melanoma without lymph node involvement consists mainly of additional surgical removal of the cancer. (1,2)

Local Recurrence with Nodal Involvement

If recurrence involves a cutaneous melanoma tumor and nodal involvement is expected but not established a sentinel node biopsy at the time of wide local excision may be required. A regional lymph node dissection may be performed on the neck, armpit or groin depending on the site of cutaneous recurrence or presence of palpable nodes. Associated lymph node dissection side effects may include sensory numbness, diminished mobility and intermittent swelling called lymphedema. Prognosis depends on extent of nodal involvement. (1,2)

Isolated Limb Perfusion: For the past 40 years, patients have been treated with isolated limb perfusion in attempts to prevent amputation or mutilating surgery in patients with recurrences localized to a single arm or leg. This localized treatment strategy is believed to augment anti-cancer effects of chemotherapy compared with systemic (full body) delivery through the following mechanisms:

  1. the chemotherapy agent does not become diluted prior to reaching the cancer by mixing with the rest of the blood from the body
  2. the chemotherapy agent is not broken down in the body through biochemical processes prior to reaching the cancer
  3. larger amounts of the chemotherapy agent can reach the cancer with fewer associated systemic side effects. (1,2)

Recurrence Following Systemic Therapy

Individuals with recurrent or progressive melanoma can be treated with additional systemic therapy, immunotherapy, or chemotherapy drugs that they have not previously been treated with. Patients should consider:

  • Genomic testing to identify whether precision cancer medicines can be used to target treatment - retesting may identify a new cancer driving mutation that can be treated
  • Participation in a clinical trial evaluating newer drugs or combinations.
  • Individuals that fail PD-1 immunotherapy treatment may respond to chemotherapy and should discuss this option with their doctor.

Role of Radiation Therapy

Radiation therapy can relieve symptoms, especially pain from cancer that has spread to the bone. Radiation therapy should be considered in patients who have had surgical removal of a single brain melanoma.

Treatment of Brain Metastasis

Melanoma that has spread to the brain accounts for 10-50% of reported deaths from melanoma. A single brain metastasis can be removed surgically, and radiation therapy should be considered in patients who have had surgical removal of a single brain metastasis. There is the suggestion that radiation therapy in this situation improves survival and reduces recurrences. (2)

Strategies to Improve Treatment

The progress that has been made in the treatment of melanoma has resulted from patient participation in clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of melanoma.

Precision Cancer Medicines & Immunotherapy

The purpose of precision cancer medicine to define the genomic alterations in the cancers DNA that are driving that specific cancer. Precision cancer medicine utilizes molecular diagnostic & genomic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.

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As promising as all of the new, precision cancer medicines are they typically stop working at some point because melanoma cells find another pathway that lets them start growing again. In many cancers, combination therapy improves survival and leads to cures when compared to single agent treatment. In addition to developing new precision cancer medicines and immunotherapies, researchers are testing various combinations of two or more drugs with encouraging results.

Yervoy + GM-CSF Yervoy® is a monoclonal antibody that targets a protein receptor, CTLA-4 that prevents the body’s defenses from attacking cancer cells. GM-CSF (granulocyte-macrophage colony-stimulating factor) is a protein that spurs the growth of white blood cells in the immune system. Patients with metastatic melanoma treated with the combination of Yervoy® and GM-CSF had a one-year survival rate of 69% and an average survival of 17.5 months compared to 54% and 12.7 months if treated with Yervoy alone. Larger trials and longer follow-up are necessary to confirm these results. (3)

BRAF & MEK: The combination of a novel BRAF inhibitor encorafenib (LGX 818) with a MEK inhibitor binimetinib (ARRY 162) significantly delayed cancer recurrence compared to treatment with Zelboraf (vemurafenib) alone. Zelboraf was the first BRAF inhibitor approved for treatment of advanced melanoma and represented a breakthrough by significantly improving survival compared with chemotherapy, replaced the latter as a treatment option. (4)

Ulixertinib is a novel ERK1/2 kinase inhibitor. A great number of cancers, including melanoma and lung cancers, have mutations in the MAPK/ERK pathway, and while current therapies target proteins in this cascade, many patients develop resistance to current drugs.

The ERK gene is the final regulator in the MAPK/ERK pathway, and when upstream inhibition of this protein cascade fails, ERK signaling is reactivated, resulting in renewed MAPK signaling. Targeting ERK for inhibition may allow the opportunity to thwart resistance from upstream mechanisms. Ulixertinib has demonstrated clinical responses in BRAF-mutant cancers resistant to BRAF and MEK inhibitors. Ulixertinib has been given fast track designation by the FDA and will undergo further evaluation in a variety of cancers. (5)

Epacadostat is an agent that blocks an enzyme called IDO1, which is implicated in the growth and spread of cancer cells. The immunosuppressive effects of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity help cancer cells evade immunosurveillance. In single-arm studies, epacadostat combined with the PD-1 inhibitors Keytruda or Opdivo (nivolumab) improved response rates compared with studies of the immune checkpoint inhibitors alone. (6)

Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein found on the cell surface of effector T cells and regulatory T cells (Tregs) and functions to control T cell response, activation and growth. Inhibiting LAG-3 allows T cells to regain their cytotoxic function and potentially affect cancer cell growth. Targeting the LAG-3 pathway in combination with other potentially complementary immune pathways may be a key strategy to more effectively activate the antitumor immune response.

Proof-of-concept data show that combining anti-LAG-3 with Opdivo in PD-1/PD-L1 refractory patients may help patients overcome resistance and restore T cell function. These results indicate that anti-LAG-3 therapy in combination with Opdivo may offer clinical benefit, particularly for patients whose cancers contain immune cells that express LAG-3. (7)

PV-10 is a 10% solution of Rose Bengal, which was originally used as an agent to stain necrotic tissue in the cornea. Its potential use in melanoma was discovered while exploring different formulations for use in photodynamic cancer therapy. PV-10 was developed to be administered directly into solid tumors was discovered to destroy tumors without the need for light activation. Initial trials report an overall response rate of 51%, and a complete response rate of 26% in individuals with refractory melanoma. (8)

Vaccines: Currently, no vaccine has been approved for the treatment melanoma. Melanoma vaccines produce responses, often dramatic, in some patients, but effects are far from consistent.

Phase I Trials: New anti-cancer drugs continue to be developed and evaluated in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and whether the drug has any anti-cancer activity in patients with advanced melanoma.


  1. Cancer Facts & Figures 2013. American Cancer Society website. Available here. Accessed January 17, 2014.
  2. Journal of Surgical Oncology, Vol 71, No 4, pp 209-213, 1999.
  3. Hodi, F. Stephen, MD, et al. “Ipilimumab Plus Sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma: A Randomized Clinical Trial.” The Journal of the American Medical Association. doi:10.1001/jama.2014.13943. November 5, 2014.
  4. [Dummer R et al “Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with]( [BRAF-mutant melanoma (COLUMBUS): A multicenter, open-label, randomized phase III trial”]( [Lancet Oncol]( [2018; DOI:10.1016/S1470-2045(18)30161-X.](
  5. Cancer Discovery ulixertinib
  6. Press Release. Updated Phase 1 Data Reinforce the Clinical Profile of Epacadostat in Combination with Keytruda® (Pembrolizumab). Available here. Accessed September 30, 2016.
  8. Thompson JF, Agarwala S, Smithers M, et al. Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma. Annals of Surgical Oncology, October 2014.
  9. Oncology. 2019 Dec 3. Epub ahead of print.