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What is present now?
Only a pathology diagnosis, completely resected disease, macroscopic nodal disease or distant metastases?
Melanoma · decisions after diagnosis
Systemic melanoma treatment: how decisions are made
Do not start with the drug name. First define the clinical situation: what has been removed, the stage, whether measurable disease remains, the BRAF status and where surgery belongs in the treatment sequence.
Key idea for patients: the same diagnosis - melanoma - can lead to very different decisions. Systemic therapy may not be needed, may reduce recurrence risk after complete surgery, may be used before surgery, or may be the main treatment for active unresectable or metastatic disease.
Four questions before the drug name
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What is the stage?
AJCC 8 staging uses the primary tumour, regional nodes and distant disease - not one isolated feature.
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Is BRAF needed?
When a molecular result can change systemic treatment options, BRAF V600 becomes a clinically relevant biomarker.
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What is the treatment goal?
Reduce recurrence risk, treat before surgery, control active disease, or choose the right sequence of several treatment modalities.
Multidisciplinary review before the first treatment step when sequencing may change
This is especially important in clinically detectable, resectable stage III disease, where “surgery first” is no longer the only automatically considered pathway.
A biomarker, not a stage
BRAF V600: what the result actually means
BRAF is part of the MAPK signalling pathway. A V600 mutation can create a specific treatment opportunity - combined BRAF/MEK inhibition in appropriate clinical settings. A positive BRAF result does not define the whole treatment plan by itself.
Molecular decision pointBRAF V600
The result is interpreted together with stage, resectability, disease tempo, previous therapy and the purpose of treatment.
V600+Mutation detected →
BRAF/MEK targeted therapy may become one of the options. Immunotherapy does not disappear from the pathway - the strategy and sequence still matter.
V600 not detectedA different pathway →
V600-directed BRAF/MEK therapy does not apply, so systemic treatment decisions rely on other available approaches and the clinical context.
What happens in the BRAF → MEK → ERK pathway?
This signalling cascade carries growth and division signals inside the cell. An activating BRAF V600 mutation can keep that signal switched on. Modern targeted therapy blocks different levels of the pathway - BRAF and MEK - which is why treatment is based on combined pathway inhibition rather than the simplified idea of “one tablet for one mutation”.
After complete resection: when adjuvant treatment is discussed
In high-risk resected melanoma, the goal of adjuvant therapy is not to treat a visible tumour but to reduce the probability of recurrence. Current European guidance includes anti-PD-1 therapy for resected stage IIB-IIC melanoma and many stage III situations; BRAF/MEK targeted therapy may be relevant for selected patients with resected BRAF V600-positive stage III disease.
KEYNOTE-716 · 36 months
76.2% vs 63.4%
RFS: pembrolizumab vs placebo
In the stage IIB-IIC trial population, recurrence-free survival was higher with adjuvant pembrolizumab.
KEYNOTE-716 · 36 months
84.4% vs 74.7%
DMFS: pembrolizumab vs placebo
Distant metastasis-free survival was also higher at the trial-population level.
Important limitation
≠ your prognosis
group data are not a personal probability
Decisions depend on absolute recurrence risk, toxicity, comorbidities and individual priorities.
RFS - recurrence-free survival; DMFS - distant metastasis-free survival.
Before surgery: why the stage III paradigm changed
For resectable melanoma with macroscopic regional disease, current evidence shows that the timing of systemic therapy matters. This is why “operate now or treat first?” has become a real multidisciplinary decision rather than an automatic surgery-first rule.
SWOG S1801
72% vs 49%
2-year EFS
Neoadjuvant-adjuvant pembrolizumab was compared with adjuvant-only pembrolizumab in resectable stage III-IV melanoma.
NADINA
83.7% vs 57.2%
12-month EFS
In macroscopic, resectable stage III disease, neoadjuvant nivolumab + ipilimumab with response-driven treatment outperformed surgery-first + adjuvant nivolumab.
NADINA
59%
major pathological response
Pathological response after neoadjuvant treatment became clinically informative for subsequent decisions.
This does not mean every patient with stage III melanoma should receive treatment before surgery. These data apply to defined trial populations. Technical resectability, disease volume, toxicity risk, regimen availability and the team’s ability to deliver the sequence safely remain critical.
Immunotherapy or BRAF/MEK: this is not a simple “which is better?” table
Immunotherapy
Immune checkpoint inhibitors remove part of the braking system that limits anti-tumour immune responses.
- anti-PD-1 therapy is used in adjuvant and advanced settings;
- combination immunotherapy is used in selected advanced and neoadjuvant scenarios;
- benefit must always be weighed against immune-related toxicity.
BRAF/MEK targeted therapy
This approach requires an appropriate BRAF V600 mutation.
- it can be an adjuvant option in selected resected BRAF V600-positive situations;
- it is an important systemic option in BRAF V600-positive advanced melanoma;
- the treatment sequence is not determined by the BRAF result alone.
Safety: what should be clear before the first dose
Immune-related adverse events can affect the skin, bowel, liver, lungs, thyroid, pituitary and other organs. They can occur during treatment or after treatment has finished. Before starting therapy, patients should receive a clear plan covering symptoms to watch for, whom to contact and when not to wait for the next routine appointment.
What should I ask before immunotherapy?
What is the goal of treatment? What is the expected absolute benefit for my clinical group? Which baseline tests are needed? Which symptoms could represent immune-related toxicity? Who should I contact urgently between treatment cycles?
Why does “more intensive” not always mean “better for me”?
Combination regimens may have greater activity in the settings where they are indicated, but they can also cause more serious toxicity. The clinical choice balances evidence, disease tempo, comorbidity, toxicity risk and treatment goals.
Ukrainian care context
Ukraine’s current national regulatory reference remains the Unified Clinical Protocol for primary and specialised care “Malignant melanoma of the skin”, approved by Ministry of Health Order No. 1064 of 9 June 2023.
This page marks it as the current Ukrainian standard while also separating it from newer international evidence published in 2024-2026, including neoadjuvant strategies. A guideline recommendation, a registered indication, actual drug access and reimbursement are not the same thing.
View the current Ukrainian protocol and evidence-based guideline →
Five questions to bring to the MDT
- What is the exact AJCC 8 stage, and which findings establish it?
- Has all known disease been removed, or is macroscopic regional or distant disease still present?
- Is BRAF V600 or other molecular testing needed now?
- What is the purpose of systemic therapy - reducing recurrence risk, treating before surgery or controlling active disease?
- What are the expected benefits, risks, alternatives and real-world availability of each strategy?
Reviewed sources
ESMO Clinical Practice Guideline - Cutaneous melanoma, 2025
EADO/EDF/EORTC consensus guideline - Treatment update 2024/2025
SWOG S1801 - neoadjuvant/adjuvant pembrolizumab
NADINA - neoadjuvant nivolumab + ipilimumab
KEYNOTE-716 - final DMFS analysis
Ukraine - current protocol and evidence-based guideline
This page explains treatment-decision principles and is not an individual treatment plan. Strategy for a specific patient should follow complete staging and multidisciplinary review.