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Medically reviewed by Dr. C.H. Weaver M.D. updated 10/2022

Stage III melanoma includes cancers of any thickness that have spread to the regional lymph nodes. Optimal treatment of stage III melanoma consists of surgical removal of the cancer and systemic treatment to reduce the risk of cancer recurrence and prolong survival. Systemic treatment may be delivered before or after surgery. In order to receive optimal treatment of stage III melanoma all patients should

  • Have NGS Biomarker testing to test for genetic mutations that can be targeted with precision cancer medicines.
  • Discuss the role of systemic treatment before surgery with their physician. 

Treatment of Stage III Melanoma

Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Many patients with stage III melanoma are at high risk for disease recurrence because undetectable cancer cells referred to as micrometastases have already broken away from the primary cancer and traveled through the lymph and blood system to other locations in the body. The delivery of systemic treatment before surgery is referred to as "neoadjuvant" and after surgery as “adjuvant” therapy.6,7,8

The combination of surgery and systemic therapy is the standard of care because the combination delay the time to cancer recurrence and prolong survival when compared to either therapy alone. 

Adjuvant vs Neoadjuvant Therapy

Treatment of stage IIIB traditionally consisted of the surgical removal of the cancer followed by systemic adjuvant treatment.  Researchers have increasingly been evaluating pre-operative treatment referred to as “neoadjuvant” therapy directed at undetectable cancer cells that may have already spread throughout the body.

Anti-PD-1 immunotherapies rely on the presence of pre-existing T cells coming in contact with cancer cells in the body to produce an immune response. Resection of the melanoma removes the majority of these anti-tumor T cells that reside in the tumor. Researchers theorized that if anti-PD-1 blockade treatment is given before surgery, the immune response could be stronger and immunologic memory would be longer given that it is taking place in the bulk of the tumor.

In a clinical trial in patients with operable stage IIIB and IV melanoma patients were randomly assigned to receive neoadjuvant treatment with three doses of Keytruda immunotherapy, followed by surgery and 15 doses of adjuvant Keytruda or upfront surgery followed by 18 doses of Keytruda.

With a median follow-up of 15 months 72% of patients treated with neoadjuvant therapy survived without melanoma recurrence compared with 49% treated with adjuvant therapy suggesting that neoadjuvant therapy may offer better outcomes. 

Surgical Treatment of Stage III Melanoma

Standard surgical treatment for patients with stage III melanoma is removal of the primary cancer with up to 2-centimeter (over an inch) margins of the adjacent skin, depending on the thickness of the primary tumor, and removal of all of the regional lymph nodes. Outcomes of patients with stage III melanoma relate primarily to the extent of lymph node metastasis.

Lymphatic mapping and sentinel lymph node biopsy (SLNB) are used to assess the presence of melanoma cells in the regional lymph nodes in order to help determine which patients may require regional lymph node dissections (LNDs) and systemic adjuvant therapy.

SLNB should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping. If metastatic melanoma is detected, a complete lymph node dissection (CLND) can be performed in a second procedure. Patients can be considered for a CLND if the sentinel node(s) is microscopically or macroscopically positive.1-5

Precision Cancer Medicines

Precision cancer medicines that target the genetic makeup of cancer and immuno-oncology (drugs that use your immune system to help fight cancer) improve the outcomes of individuals with melanoma when compared with traditional chemotherapy. These therapies are designed to target the cancer cells while minimizing damage to normal, healthy cells. Genomic (NGS) testing of a patient’s cancer for unique biomarkers can identify differences at the genetic level, and determine whether which precision medicines or immunotherapy is best for each individual. 

The current NCCN guideline state that patients with stages IIIA, IIIB, IIIC/D melanoma (sentinel node positive) should be treated with "Checkpoint Inhibitor" immunotherapy or the combination of Tafinlar/Mekinstfor patients with BRAFV600-activating mutations.

For patients who have stage III microscopic satellite or in-transit disease, systemic therapy can be considered if they have no evidence of disease after surgery or a less than complete resection. Local therapy options for less than complete excision include talimogene laherparepvec (T-VEC), Bacille Calmette-Guérin (BCG), interferon or interleukin-2, topical imiquimod for superficial dermal lesions and consideration of radiation therapy if not used previously. Regional therapy options include melphalan delivered by isolated limb perfusion or isolated limb infusion.

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.8-12

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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

Combination Therapy

Combination of a BRAF and a MEK inhibitor appears to decrease the emergence of disease resistance that occurs in patients treated with BRAF inhibition alone. The combination of Taflinar plus Mekinist significantly improves survival compared to treatment with single agent Taflinar, when compared to no adjuvant therapy. The combination reduced the risk of disease recurrence or death by 53% and the 3-year overall survival rate was 86% in the combination-therapy group compared to 77%. Overall 4-year rates of relapse-free survival are reported to be 54% compared to 38% with placebo.12


Immunotherapy treatment of melanoma 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

PD-1 “Checkpoint Inhibitors”: PD-1 is a protein that inhibits certain types of immune responses, allowing cancer cells to evade an attack by immune cells. Opdivo (nivolumab) and Keytuda (pembrolizumab) are checkpoint inhibitors that block the PD-1 pathway and can enhance the ability of the immune system to fight cancer. Both Keytruda and Opdivo are approved as adjuvant therapy for melanoma because they improve survival. Opdivo has also been shown to be superior to Yervoy for the management of stage IIIb/c melanoma following complete surgical resection.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. Yervoy has been demonstrated to improve survival in stage III melanoma patients who are at high risk of recurrence following complete surgical resection.7 Yervoy has also been demonstrated to be superior to Interferon treatment for stage III disease.17

Intralesional Therapy

Imlygic® (talimogene laherparepvec), the first ever FDA-approved oncolytic virus therapy, is approved for the treatment of melanoma sites in the skin and lymph nodes that cannot be surgically removed. Imlygic is given through a series of injections directly into the melanoma over the course of 6 months.

Imlygic is a genetically modified live oncolytic herpes virus therapy. When Imlygic is injected into the site of the cancer the modified herpes virus replicates inside cancer cells and causes the cancer cells to rupture and die. Imlygic may also promote tumor shrinkage, trigger a systemic immune response and prolong survival in some patients with advanced melanoma. After acting locally within the tumor, it is intended to prompt an immune response against cancer cells elsewhere in the body.

Preliminary results showed that 64 percent of injected tumors shrank by half. The vaccine shrank tumors that were directly injected as well as those that were not injected—indicating that the vaccine was triggering the immune system to fight the distant tumors.15

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: As promising as all of the new, 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.

BRAF & MEK: The combination of a novel BRAF inhibitor Braftovi (encorafenib) with a MEK Mektovi (binimetinib) 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.16

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.


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  8. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma
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  13. Robert C, Long GV, Brady B, et al. Nivolumab in Previously Untreated Melanoma without BRAF Mutation. New England Journal of Medicine [early online publication]. November 16, 2014.
  14. United States Food and Drug Administration. News Release. FDA approves first-of-its-kind product for the treatment of melanoma. Available here. Accessed October 27, 2015.
  16. [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.](