Key points
- Melanoma that has spread is no longer the disease with little hope it once was: immunotherapy and targeted tablets have greatly lengthened patients' lives since 2011 [2]; in a large study, about a third of patients were alive ten years later [5].
- The backbone of treatment is anti-PD-1 immunotherapy (pembrolizumab or nivolumab); adding a second drug, ipilimumab, increases the effect and also the side effects [1, 6, 7].
- A BRAF test is needed for all patients with stage 3 and 4 disease; if a mutation is found, BRAF and MEK targeted tablets are also an option [1, 10].
- In stage 3 melanoma that can be operated on, starting immunotherapy before surgery gave better results than immunotherapy only after surgery [15, 16, 1].
- After surgery for high-risk melanoma, a year of immunotherapy lowers the risk of it coming back [12, 13].
The story of melanoma treatment: from dacarbazine to immunotherapy
Melanoma is a cancer of the pigment-making cells of the skin and is mostly linked to sunlight and tanning devices [2]. Early melanoma is usually cured with surgery [2]; see the warning signs in What are the symptoms of skin cancer?. The big problem was melanoma that spread to other parts of the body.
For years the main treatment for melanoma that had spread was chemotherapy with dacarbazine [3]. In a large study, this drug shrank the tumour in only about 1 in every 20 patients [3]. Researchers tried again and again to lengthen these patients' lives and did not succeed [4].
The turning point came in 2010: ipilimumab, a drug that takes the brakes off the immune system, lengthened patients' lives in a large study; a goal that until then had been out of reach [4]. A year later, the targeted tablet vemurafenib, in patients whose tumour had a BRAF mutation, shrank the tumour in almost half of patients and lowered the risk of death [3].
Then the anti-PD-1 drugs arrived: pembrolizumab and nivolumab. Both worked better than ipilimumab [5, 6]. At ten-year follow-up of a large study, about 1 in every 3 patients who had received pembrolizumab were still alive [5]. In another study, with the combination of nivolumab and ipilimumab, patients typically lived for nearly 6 years; and almost all those whose disease was under control 3 years after starting treatment had not died of melanoma ten years later [6].
These drugs then moved to earlier stages: a year of immunotherapy after surgery [12], and today immunotherapy before surgery, which improved results in two studies [15, 16].
Treatment today by stage
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High-risk stage 2: after surgery
In thicker stage 2 melanomas, a year of pembrolizumab after surgery lowered the risk of the disease coming back [13]. Make this decision with your specialist.
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Stage 3 that can be operated on: immunotherapy before surgery
Pembrolizumab: 3 doses before surgery and 15 doses after it; in a study, this sequence controlled the disease better than pembrolizumab only after surgery [15]. Nivolumab with ipilimumab: 2 doses before surgery; after surgery, only those whose tumour had not responded well received further treatment. In a large study, it controlled the disease much better than surgery followed by nivolumab, but severe side effects were more common [16]. The European guideline recommends both approaches [1].
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If you have already had surgery
A year of immunotherapy (pembrolizumab or nivolumab) after surgery lowers the risk of the cancer coming back [12, 1]. If you have a BRAF mutation of the V600E type, a year of dabrafenib with trametinib tablets is also an option [14, 1]. Treatment should start within 12 weeks of surgery [1]. Doses: Adjuvant pembrolizumab
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Stage 4 or melanoma that cannot be operated on
Pembrolizumab or nivolumab on its own is a standard first treatment [1, 5]. The combination of nivolumab and ipilimumab is stronger, but caused severe side effects in more than half of patients [7, 6]; the European guideline prefers it when it can be given safely, especially when melanoma has reached the brain without causing symptoms [1]. Nivolumab combined with the newer drug relatlimab is another option; in a large study it controlled the disease better than nivolumab alone, and its severe side effects occurred in fewer than 1 in every 5 patients [8, 9, 1]. See: Nivolumab with ipilimumab
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If you have a BRAF mutation
The two tablets dabrafenib and trametinib taken together act quickly [1], and at five years about 1 in every 3 patients on these tablets was alive [10]. But in one study, starting with combination immunotherapy and keeping the tablets for later gave longer survival [11]. This is why the tablets are mostly chosen first when a quick response is needed or immunotherapy is not suitable [1].
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If the disease progresses
BRAF tablets if they have not been used before, other immunotherapy combinations, or in selected patients TIL cell therapy [1]. In TIL therapy, immune cells are taken from a piece of the patient's own tumour, multiplied in large numbers in a laboratory and given back to the patient; in patients most of whom had not responded to immunotherapy, it controlled the disease better than ipilimumab [17]. This treatment is demanding and is given in specialist centres [17, 1]; in the United States a TIL product called lifileucel has been approved [20].
When should I call my doctor?
With immunotherapy (pembrolizumab, nivolumab, ipilimumab): report a new cough, chest pain or breathlessness, diarrhoea or severe stomach pain, yellowing of the skin or eyes, severe nausea or vomiting, easy bruising or bleeding, a severe skin rash, and signs of thyroid, adrenal gland or blood sugar problems (extreme tiredness, headache, thirst and passing a lot of urine) straight away; these side effects can appear even after treatment has ended [18]. With dabrafenib and trametinib: tell your doctor about any fever; fever is more common and more severe with these two tablets. Also report changes in your vision, unusual bleeding, signs of heart failure, and any new skin lesion or change in your moles [19]. If you have severe breathlessness or confusion, call your local emergency number. See: Side effects of immunotherapy
Frequently asked questions
Can melanoma that has spread be treated successfully?
Today many patients live for years with their disease under control: about 1 in every 3 patients in a large study was alive ten years later [5], and almost all those whose disease was under control 3 years after starting nivolumab (alone or with ipilimumab) had not died of melanoma ten years later [6]. See: What is metastasis, and can it be treated?
How long does immunotherapy continue?
In advanced disease, pembrolizumab was given for up to about 2 years in the main study, and most of those who completed these 2 years were alive 8 years later [5]. After surgery, treatment lasts one year [12, 1].
Is one immunotherapy drug better, or two?
The combination of nivolumab and ipilimumab controls the disease more [6], but it caused severe side effects in more than half of patients [7]. Pembrolizumab or nivolumab on its own is also a standard first treatment [1, 5]. The choice depends on the state of the disease, whether it has reached the brain, your general health and your own wishes [1].
If I have a BRAF mutation, are tablets or immunotherapy better?
Why is immunotherapy given before surgery?
What is TIL cell therapy?
For physicians
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Background: BRIM-3 (675 patients with BRAF V600E): response 5% with dacarbazine versus 48% with vemurafenib, 6-month survival 64% versus 84% and a 63% relative reduction in the risk of death [3]. MDX010-20 (676 previously treated patients): median OS 10.1 months with ipilimumab versus 6.4 months with gp100 (HR 0.66); grade 3–4 immune-related adverse events 10 to 15% [4].
First line in advanced disease: KEYNOTE-006 (834 patients; 10-year follow-up): median OS 32.7 versus 15.9 months with ipilimumab (HR 0.71), 10-year survival 34.0% versus 23.6%, 8-year survival 80.8% in patients who completed at least 94 weeks of pembrolizumab [5]. CheckMate 067 (945 patients; minimum 10-year follow-up): median OS 71.9 months (nivolumab + ipilimumab), 36.9 months (nivolumab) and 19.9 months (ipilimumab); HR for death 0.53 and 0.63 versus ipilimumab; median melanoma-specific survival more than 120 months with the combination; in patients alive and progression-free at 3 years, 10-year melanoma-specific survival 96%, 97% and 88% [6]; grade 3–4 treatment-related adverse events 55.0% with the combination, 16.3% with nivolumab and 27.3% with ipilimumab [7]. RELATIVITY-047 (714 patients): median PFS 10.1 versus 4.6 months (HR 0.75) and grade 3–4 adverse events 18.9% versus 9.7% [8]; at the 4-year update, OS 52.0% versus 42.8% (descriptive) [9]. ESMO 2025: nivolumab + ipilimumab preferred for all patients regardless of BRAF if it can be given safely; anti-PD-1 monotherapy also recommended (I, A); nivolumab + relatlimab (I, B); asymptomatic brain metastases preferably nivolumab + ipilimumab (II, A) [1]. See Management of brain metastases. Doses: Pembrolizumab · Nivolumab + ipilimumab · Nivolumab + relatlimab.
BRAF V600: COMBI-d and COMBI-v (563 patients on dabrafenib + trametinib): 5-year PFS 19% and 5-year OS 34%; in complete responders (19%), 5-year OS 71% [10]. DREAMseq (265 patients): 2-year OS 71.8% when starting with nivolumab + ipilimumab versus 51.5% when starting with dabrafenib + trametinib (P=0.010) [11]. Dose: Dabrafenib + trametinib.
Adjuvant and neoadjuvant treatment: KEYNOTE-054 (1,019 patients with stage III disease; follow-up 6.9 years): 7-year RFS 50% versus 36% (HR 0.63) and DMFS 54% versus 42% (HR 0.64) [12]. KEYNOTE-716 (976 patients, IIB–IIC): 48-month RFS 71.3% versus 58.3% (HR 0.62) [13]. COMBI-AD (870 patients, final analysis): HR for overall survival 0.80 (P=0.06; not significant), 0.75 in V600E; HR for relapse-free survival 0.52 [14]. SWOG S1801 (313 patients, resectable IIIB–IVC): 2-year EFS 72% with neoadjuvant–adjuvant versus 49% with adjuvant only (P=0.004); grade ≥3 adverse events 12% versus 14% [15]. NADINA (423 patients with macroscopic stage III disease): 12-month EFS 83.7% versus 57.2% (HR 0.32); major pathological response 59.0%, with 12-month RFS 95.1%; grade ≥3 adverse events 29.7% versus 14.7% [16]. ESMO 2025: neoadjuvant nivolumab + ipilimumab (I, A) or neoadjuvant + adjuvant pembrolizumab (II, A); omission of adjuvant therapy after a major pathological response (I, A); adjuvant anti-PD-1 or dabrafenib + trametinib in V600E, starting within 12 weeks (I, A); adjuvant targeted therapy not recommended in V600K (II, D) [1]. Doses: S1801 · NADINA · Adjuvant pembrolizumab.
TIL: NKI phase 3 trial (168 patients; 86% refractory to anti-PD-1): median PFS 7.2 versus 3.1 months with ipilimumab (HR 0.50), objective response 49% versus 21% and median OS 25.8 versus 18.9 months; grade ≥3 adverse events in all TIL patients [17]. ESMO: an aggressive option for selected patients (II, B) [1]. Lifileucel (AMTAGVI) is approved in the United States [20]. Dose: TIL.
Scientific evidence
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Scientific evidence
12 itemsSeven-year analysis of adjuvant pembrolizumab versus placebo in stage III melanoma in the EORTC1325 / KEYNOTE-054 trial
Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma
Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Long-term follow-up, crossover, and rechallenge with pembrolizumab in the phase III KEYNOTE-716 study
Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma
Nivolumab plus relatlimab in advanced melanoma: RELATIVITY-047 4-year update
Cutaneous melanoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up
Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma
Pembrolizumab versus ipilimumab for advanced melanoma: 10-year follow-up of the phase III KEYNOTE-006 study
Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma
Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma
Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
Read more
Related cancer types
References
20 referencesShow all references, 14 with a study cardClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
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- 8Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma
- 9Nivolumab plus relatlimab in advanced melanoma: RELATIVITY-047 4-year update
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- 14Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma
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- 18KEYTRUDA (pembrolizumab) injection, for intravenous use: Prescribing Information
- 19TAFINLAR (dabrafenib) capsules / tablets for oral suspension: Prescribing Information
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This page is based on reputable scientific sources and was last updated on 28 October 2026. The content of this website is for educational and informational purposes only and does not replace consultation, diagnosis or treatment by a specialist physician. Consult your treating physician about any treatment decision.
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