Melanoma Treatment: Surgery, Immunotherapy, Targeted Therapy, and More
Written by North Editorial Staff | Clinically reviewed by Laura Morrissey, RN, BSN | Last reviewed: March 2026
Key Takeaways
Melanoma treatment is guided by stage, Breslow depth, BRAF mutation status, and input from a multidisciplinary team.
Surgery is the foundation of treatment for localized melanoma; for higher-stage disease, systemic therapies are central.
Immunotherapy: particularly PD-1 inhibitor drugs and CTLA-4 inhibitor drugs, has transformed outcomes for advanced melanoma, with some patients achieving long-term remission.
For the approximately 50% of melanomas with a BRAF mutation, targeted therapy with BRAF and MEK inhibitor combinations produces rapid, meaningful responses.
Tumor-infiltrating lymphocytes (TIL) therapy, lifileucel (Amtagvi), was FDA-approved in 2024 as the first TIL therapy for any cancer and offers a new option for patients who have progressed on other treatments.
Clinical trials are an important part of the treatment landscape at every stage, not a last resort.
How Is Melanoma Treatment Decided?
Treatment decisions for melanoma are guided by stage, Breslow depth, the presence of ulceration, BRAF mutation status, and overall health. A multidisciplinary team, including a surgical oncologist, medical oncologist, and often a dermatologist and radiation oncologist, evaluates the case and recommends a coordinated treatment plan. Molecular tumor testing, particularly for BRAF status, is now a standard early step.
Surgery: The Foundation of Melanoma Treatment
For the vast majority of melanomas, surgery is the first and often definitive treatment. The goal is to remove the melanoma with an adequate margin of normal tissue around it.
Wide local excision is the standard surgical approach. After biopsy confirms the diagnosis, the surgeon removes the melanoma along with a margin of normal skin. The recommended margin depends on Breslow thickness, thinner tumors require narrower margins (typically 1 cm), while thicker tumors may require margins of 1–2 cm. Wide local excision is typically performed under local anesthesia and is a routine outpatient procedure.
Sentinel lymph node biopsy is recommended for most melanomas thicker than 0.8 mm. A radioactive tracer and/or blue dye is injected near the primary tumor site; it travels through the lymphatic system to the first lymph node or nodes that drain the area, the “sentinel” nodes. The surgeon removes these nodes for pathologic examination. If cancer cells are found, the result changes the stage from II to III and informs decisions about adjuvant treatment. A sentinel node biopsy does not mean a complete node dissection, it is a staging procedure first.
Complete lymph node dissection involves removing all the lymph nodes in a regional basin (axilla, groin, or neck). With the availability of effective systemic therapies and data showing limited survival benefit from routine complete dissection in all node-positive patients, this procedure is now reserved for select situations, particularly when there is clinically detectable (palpable or imaging-visible) node involvement.
Mohs micrographic surgery is a specialized technique in which thin layers of skin are removed and examined under a microscope in real time until all tumor cells are cleared. While not the standard approach for most melanomas, Mohs is sometimes used for melanoma on the face, scalp, or other areas where tissue preservation is particularly important, and for certain subtypes like desmoplastic melanoma, where margins are harder to assess.
Immunotherapy: Harnessing the Immune System
Immunotherapy: specifically checkpoint inhibitor drugs that remove the brakes on the immune system’s natural ability to find and destroy cancer cells, has been the most transformative development in melanoma treatment in decades.
PD-1 Inhibitors
PD-1 inhibitor drugs block the PD-1 receptor on T cells, preventing cancer cells from using the PD-L1 pathway to hide from immune attack.
Pembrolizumab (Keytruda): approved for unresectable or metastatic melanoma, as adjuvant therapy after surgery in Stage IIB/IIC/III, and in neoadjuvant settings.
Nivolumab (Opdivo): approved for unresectable or metastatic melanoma and as adjuvant therapy in Stage III/IV disease.
Both have demonstrated durable responses and improved survival in advanced melanoma.
CTLA-4 Inhibitors
CTLA-4 inhibitor therapy blocks a different immune checkpoint, releasing a broader and earlier phase of immune activation.
Ipilimumab (Yervoy): the first immunotherapy approved for metastatic melanoma (2011), now most commonly used in combination with nivolumab rather than as monotherapy.
Combination Immunotherapy
The combination of nivolumab plus ipilimumab (dual checkpoint inhibitor blockade) has produced the most robust long-term survival data for Stage IV melanoma. The CheckMate 067 trial demonstrated a 5-year overall survival rate of 52% for patients receiving the combination, compared to approximately 44% for nivolumab alone and 26% for ipilimumab alone. Long-term follow-up has continued to show durable benefit for a meaningful proportion of patients. The combination is more toxic than either agent alone, however, and careful monitoring for immune-related adverse events is essential.
Relatlimab plus nivolumab (Opdualag): a newer combination targeting the LAG-3 checkpoint alongside PD-1, was FDA-approved in 2022 and represents a third combination option with a more favorable tolerability profile than nivolumab plus ipilimumab for some patients.
Immune-Related Adverse Events
Because checkpoint inhibitors broadly activate the immune system, they can cause inflammation in healthy organs. Immune-related adverse events (irAEs) can affect virtually any system, most commonly the skin, gastrointestinal tract, liver, lungs, and endocrine glands (thyroid, pituitary, adrenal). Most irAEs are manageable with corticosteroids or other immunosuppressive agents, and most resolve. However, they require active monitoring and prompt intervention. Your oncology team will educate you on symptoms to watch for and what to report.
Targeted Therapy for BRAF-Mutated Melanoma
Approximately 40–50% of cutaneous melanomas carry a BRAF mutation, most commonly the BRAF V600E variant. This mutation causes abnormal activation of a signaling pathway that drives tumor cell growth. Drugs that specifically target this pathway, BRAF inhibitors and MEK inhibitors, produce rapid, often dramatic responses in BRAF-mutated tumors.
BRAF Inhibitors
Vemurafenib (Zelboraf): the first approved BRAF inhibitor
Dabrafenib (Tafinlar): now used primarily in combination with trametinib
MEK Inhibitors
Trametinib (Mekinist): combined with dabrafenib
Cobimetinib (Cotellic): combined with vemurafenib
Why the Combination?
BRAF inhibitor monotherapy, while highly effective initially, frequently encounters resistance within months as tumors develop alternative signaling pathways. Adding a MEK inhibitor, the next step in the same pathway, delays or prevents this resistance and improves both progression-free and overall survival. The COMBI-d and COMBI-v trials established dabrafenib plus trametinib and vemurafenib plus cobimetinib, respectively, as standard of care for BRAF-mutated metastatic melanoma, with 5-year overall survival rates of approximately 34% in the COMBI-d long-term analysis.
BRAF/MEK targeted therapy is also approved for adjuvant use in resected Stage III melanoma with a BRAF V600E or V600K mutation.
Because targeted therapy only works if the tumor has a BRAF mutation, molecular testing of the tumor is essential before treatment decisions are made. Testing should be done on all patients with advanced or metastatic melanoma.
Radiation Therapy
Radiation therapy is not a primary treatment for most melanomas, as melanoma cells are relatively radiation-resistant. However, radiation plays important roles in specific situations:
Brain metastases. Stereotactic radiosurgery (such as Gamma Knife or CyberKnife) delivers precisely focused, high-dose radiation to brain metastases and is a standard approach for limited brain involvement, often used alongside systemic therapy.
Palliative radiation. When melanoma has spread to bones, the spine, or other sites causing pain or neurological symptoms, radiation can provide effective pain relief and improve quality of life.
Desmoplastic melanoma. This unusual subtype, which tends to occur on the head and neck and has a high rate of local recurrence, has a greater sensitivity to radiation than typical melanoma, and postoperative radiation to the tumor bed is often recommended after wide excision.
Lymph node basin. Radiation to a regional lymph node basin may be used in some settings to reduce regional recurrence risk, though this is not universally applied.
Treatment by Stage: A Quick Reference
Stage 0–I
Wide local excision with appropriate margins is the primary treatment. Sentinel lymph node biopsy is recommended for tumors thicker than 0.8 mm. For Stage IA, surveillance after surgery is typically sufficient. No systemic therapy is standard for Stage I unless the sentinel node is positive (which would reclassify to Stage III).
Stage II
Wide local excision plus sentinel lymph node biopsy. For Stage IIB and IIC, adjuvant pembrolizumab is FDA-approved and recommended by guidelines to reduce recurrence risk, discuss with your oncologist whether this is appropriate for your situation.
Stage III
Surgery to remove the primary tumor and involved lymph nodes, followed by adjuvant systemic therapy. The choice between PD-1 inhibitor immunotherapy and BRAF/MEK targeted therapy (for BRAF-mutated tumors) depends on mutation status, side effect profiles, and individual circumstances. Neoadjuvant (pre-surgical) immunotherapy is an increasingly studied approach.
Stage IV
Systemic treatment is the primary approach, surgery may still play a role for isolated metastases or to reduce tumor burden, but the goal shifts to systemic disease control. First-line options include:
Combination immunotherapy (nivolumab + ipilimumab, or relatlimab + nivolumab)
PD-1 inhibitor monotherapy
BRAF/MEK inhibitor combination (for BRAF-mutated tumors)
The choice depends on tumor biology, pace of disease, performance status, and patient preference. Clinical trials are an important option at this stage.
Melanoma Clinical Trials: Access to New Treatments
The treatment landscape described above was built entirely on clinical trials. Every approved immunotherapy and targeted therapy for melanoma was first studied in a trial, and the pipeline of new approaches continues to expand.
Lifileucel (Amtagvi): a tumor-infiltrating lymphocyte (TIL) therapy, was FDA-approved in February 2024 as the first TIL cell therapy approved for any cancer. It involves harvesting T cells that have already entered the tumor, expanding them in the laboratory, and reinfusing them into the patient after lymphodepletion. Lifileucel is approved for adult patients with unresectable or metastatic melanoma who have progressed on prior anti-PD-1 therapy and, if BRAF V600-mutated, a BRAF inhibitor. Next-generation TIL approaches are in active clinical trials.
Personalized cancer vaccines. mRNA-based neoantigen vaccines (such as mRNA-4157/V940, in combination with pembrolizumab) are among the most exciting emerging approaches. These vaccines are customized to each patient’s tumor mutations and are designed to train the immune system to recognize and attack cancer cells. Phase 2b data from the KEYNOTE-942 trial showed a statistically significant improvement in recurrence-free survival for patients with resected high-risk Stage III/IV melanoma receiving the vaccine plus pembrolizumab compared to pembrolizumab alone. Phase 3 trials are underway.
New combinations. Trials are studying TIL therapy earlier in treatment, novel LAG-3, TIM-3, and TIGIT checkpoint inhibitors, oncolytic viral therapies, and approaches to overcome resistance to existing treatments.
Participating in a clinical trial is not a last resort, for many patients with advanced melanoma, a trial may be the best available option and provides access to treatments that have not yet reached standard-of-care status. Ask your oncologist about available trials or search through North’s trial finder. You can also explore our full guide at melanoma clinical trials.
Questions to Ask Your Oncologist
Use this checklist when discussing treatment options with your care team:
What stage is my melanoma, and what does that mean for my treatment options?
Do I need BRAF mutation testing before we decide on treatment? Have the results come back?
What is the recommended first-line treatment for my specific situation?
Am I a candidate for adjuvant therapy? What are the benefits and risks?
Are there clinical trials I should consider?
What are the most common side effects of the recommended treatment, and how are they managed?
How will we monitor whether the treatment is working?
What happens if this treatment stops working, what are the next options?
Should I be seen at an NCI-designated cancer center or a center that specializes in melanoma?
How does my BRAF status affect my options now and in the future?
Frequently Asked Questions
What is the first-line treatment for melanoma?
For localized melanoma (Stages 0–II), the first-line treatment is surgery, wide local excision with appropriate margins. For Stage II high-risk disease, adjuvant immunotherapy may follow. For unresectable Stage III or Stage IV melanoma, the first-line treatment is systemic therapy: immunotherapy (most commonly a PD-1 inhibitor with or without ipilimumab), or BRAF/MEK targeted therapy for patients with a BRAF mutation. The choice depends on tumor biology, pace of disease, and patient factors.
What is immunotherapy for melanoma?
Immunotherapy for melanoma refers primarily to checkpoint inhibitor drugs that remove proteins that prevent the immune system from attacking cancer cells. The most commonly used agents are PD-1 inhibitors (pembrolizumab/Keytruda and nivolumab/Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy). These drugs, alone or in combination, have significantly extended survival for advanced melanoma and produce durable responses in a meaningful proportion of patients. Side effects can affect any organ and require active monitoring.
Do I need to be tested for BRAF mutation?
Yes, for any unresectable, metastatic, or Stage III melanoma. BRAF mutation testing on your tumor tissue is a standard part of workup before systemic treatment is initiated, because the results directly determine whether BRAF/MEK targeted therapy is an option. BRAF V600E and V600K are the most clinically actionable variants. This testing is typically done on the tissue from your biopsy or surgical specimen and usually comes back within 1–2 weeks.
What is TIL therapy for melanoma?
Tumor-infiltrating lymphocytes (TIL) therapy is a form of adoptive cell therapy in which immune cells (T cells) are isolated from the patient’s own tumor, grown in large numbers in the laboratory, and reinfused into the patient to attack cancer cells. Lifileucel (Amtagvi), the first FDA-approved TIL therapy for any cancer (approved February 2024), is currently approved for adults with unresectable or metastatic melanoma who have progressed on prior anti-PD-1 therapy. It is administered at specialized centers. Next-generation TIL approaches with engineered enhancements are being studied in clinical trials.
Can melanoma be cured?
Yes, early-stage melanoma is highly curable with surgery, with 5-year survival rates approaching 99% for Stage I. For Stage III melanoma treated with surgery and adjuvant immunotherapy, long-term remission is achievable for many patients. For Stage IV melanoma, “cure” in the traditional sense remains less predictable, but a meaningful proportion of patients on modern combination immunotherapy achieve durable, long-term disease control, some apparently for many years. The definition of what constitutes a cure continues to evolve as long-term trial data matures. Clinical trials remain an important pathway to better outcomes at every stage.
References
National Cancer Institute. Melanoma Treatment (PDQ), Patient Version. https://cancer.gov/types/skin/patient/melanoma-treatment-pdq
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Melanoma, Cutaneous. https://www.nccn.org/patientresources/patient-resources/guidelines-for-patients/guidelines-for-patients-details?patientGuidelineId=21
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma (CheckMate 067). N Engl J Med. 2019;381(16):1535-1546. https://pubmed.ncbi.nlm.nih.gov/31562797.
Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma (COMBI-d/COMBI-v pooled). N Engl J Med. 2019;381(7):626-636. https://pubmed.ncbi.nlm.nih.gov/31166680
Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib (COMBI-d). N Engl J Med. 2015;372(1):30-39. https://pubmed.ncbi.nlm.nih.gov/25399551.
Robert C, Ribas A, Schachter J, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results. Lancet Oncol. 2019;20(9):1239-1251. https://pubmed.ncbi.nlm.nih.gov/31345627.
Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39(24):2656-2666. https://pubmed.ncbi.nlm.nih.gov/33979178