Stage III melanoma: the decisions you may face

Cancer page →Second-opinion finder →

5 treatment settings, 4 with more than one named option. Each section lays out the options the standard of care names, what each is for, the trials behind them with their recorded results, the side effects and cautions on record, and questions to ask. Built from the cancer page's standard-of-care rows; nothing here is advice for your case.

Other settings

Positive sentinel node, no palpable disease

One path named

Wide local excision, no completion lymph node dissection (MSLT-II), nodal ultrasound surveillance, then adjuvant systemic therapy.

Guideline

NCCN Guidelines: Melanoma: Cutaneous

The path, in plain words

Sentinel lymph node biopsyStandard of care

Removing just the first lymph node a tumour drains to, instead of all of them, to check for spread.

Avoids lymphoedema from full dissection

Also referenced:Wide local excision

The evidence behind it

MSLT-II Phase 3 NCT00297895 20171,939 peopleevidence 79
Tests Sentinel lymph node biopsy
Sentinel-node-positive melanoma: immediate completion lymph node dissection vs ultrasound surveillance
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
No melanoma-specific survival benefit; lymphoedema 24% vs 6%.
Melanoma-specific survival at 3 years (%): Completion dissection 86 vs Observation 86 · source

The main trade-offs on record

Sentinel lymph node biopsy

False negatives in ~5-10%

Questions to ask about this decision

Is Sentinel lymph node biopsy the only reasonable path for me, or is there a trial, a different sequence or a wait-and-see option?
Why: A single standard does not mean a single choice; timing and trials are decisions too.
What is each option trying to achieve: cure, long control, or relief of symptoms, and over what time?
Why: The aim shapes how much side effect and disruption is worth accepting.
How closely do I match the people in MSLT-II, and does that change what the results mean for me?
Why: Trial populations are selected; age, fitness, prior treatment and biomarkers all affect how far results carry.
What happens if I delay, or decline this step for now? Is the decision reversible?
Why: Some decisions can wait for a second opinion or a trial slot; others cannot. Knowing which is part of the choice.
Does your recommendation follow the current guideline (NCCN Guidelines: Melanoma: Cutaneous), and if it departs from it, why?
Why: Departures from guidelines are sometimes right for an individual; they should be explained.
For my situation (positive sentinel node, no palpable disease), which of the standard options do you recommend and why?
Why: Guideline options include: Wide local excision, no completion lymph node dissection (MSLT-II), nodal ultrasound surveillance, then adjuvant systemic therapy.
How do the results of MSLT-II apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Add these to your appointment list, or take the full question set for this cancer.

Early / localised

Resectable macroscopic nodal disease

3 optionsCompare side by side →

Neoadjuvant ipilimumab plus nivolumab for two cycles then surgery, with adjuvant therapy only if the pathological response is poor (NADINA); or neoadjuvant then adjuvant pembrolizumab (SWOG S1801).

Guideline

NCCN Guidelines: Melanoma: Cutaneous

The options, in plain words

NivolumabApprovedMonoclonal antibody (anti-PD-1)

Nivolumab was the second PD-1 blocker and is often combined with ipilimumab. Long-term data show about half of advanced melanoma patients alive at 10 years on the combination.

IpilimumabApprovedMonoclonal antibody (anti-CTLA-4)

Ipilimumab was the first checkpoint inhibitor (2011), and proved the immune system could be unleashed against cancer.

PembrolizumabApprovedMonoclonal antibody (anti-PD-1)

Pembrolizumab is a PD-1 blocking antibody approved in more than 40 settings, from melanoma and lung cancer to the first tumour-agnostic approval for mismatch-repair-deficient tumours in 2017, and before and after surgery in triple-negative breast cancer. A subcutaneous form arrived in 2025, and it is the backbone partner for ADCs and personalised neoantigen vaccines.

Also referenced:Major pathological response (MPR)

The evidence behind it

NADINA Phase 3 NCT04949113 2024423 peopleevidence 87
Tests Nivolumab, Ipilimumab
Resectable macroscopic stage III melanoma: two cycles neoadjuvant ipilimumab + nivolumab then surgery (adjuvant only if incomplete response) vs surgery then 12 cycles adjuvant nivolumab
12-month EFS 83.7% vs 57.2%; HR 0.32.
Event-free survival at 12 months (%): Neoadjuvant ipilimumab + nivolumab 83.7 vs Adjuvant nivolumab 57.2 · HR 0.32 · source
SWOG S1801 Phase 2 NCT03698019 2022313 peopleevidence 71
Tests Pembrolizumab
Resectable stage IIIB-IV melanoma: three doses of pembrolizumab before surgery then 15 after, vs 18 doses after surgery
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
2-year EFS 72% vs 49%; HR 0.58.
Event-free survival at 2 years (%): Neoadjuvant + adjuvant pembrolizumab 72 vs Adjuvant pembrolizumab 49 · HR 0.58 · source

The main trade-offs on record

Nivolumab all recorded rates →

Side effect	Any grade	Grade 3+
Colitis with ipilimumab (1+3 mg/kg) · Monotherapy pooled unless stated	25%	14.4%
Hepatitis with ipilimumab · Monotherapy pooled unless stated	15%	13.4%
Colitis · Monotherapy pooled unless stated	2.9%	1.7%
Hepatitis · Monotherapy pooled unless stated	1.8%	1.5%

Rates from the label or pivotal trial as recorded on the product page; each grade 3+ figure links to its source.

Ipilimumab all recorded rates →

Side effect	Any grade	Grade 3+
Colitis (with nivolumab 1+3) · Nivolumab 1 mg/kg + ipilimumab 3 mg/kg, melanoma	25%	14.4%
Hepatitis (with nivolumab) · Nivolumab 1 mg/kg + ipilimumab 3 mg/kg, melanoma	15%	13.4%
Rash (with nivolumab) · Nivolumab 1 mg/kg + ipilimumab 3 mg/kg, melanoma	28%	4.8%
Adrenal insufficiency (with nivolumab) · Nivolumab 1 mg/kg + ipilimumab 3 mg/kg, melanoma	8%	2.6%

Rates from the label or pivotal trial as recorded on the product page; each grade 3+ figure links to its source.

Pembrolizumab all recorded rates →

Side effect	Any grade	Grade 3+
Hypothyroidism (immune-mediated) · Pooled monotherapy data, >2,800 patients	8%	-
Pneumonitis (immune-mediated) · Pooled monotherapy data, >2,800 patients	3.4%	-
Colitis (immune-mediated) · Pooled monotherapy data, >2,800 patients	1.7%	-
Hepatitis (immune-mediated) · Pooled monotherapy data, >2,800 patients	0.7%	-

No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.

Rates from the label or pivotal trial as recorded on the product page; each grade 3+ figure links to its source.

Questions to ask about this decision

Between Nivolumab, Ipilimumab and Pembrolizumab, which do you recommend for me, and what about my case would make you choose differently?
Why: Guidelines list several reasonable options; the choice turns on details of your tumour, your health and your priorities.
What is each option trying to achieve: cure, long control, or relief of symptoms, and over what time?
Why: The aim shapes how much side effect and disruption is worth accepting.
How closely do I match the people in NADINA and SWOG S1801, and does that change what the results mean for me?
Why: Trial populations are selected; age, fitness, prior treatment and biomarkers all affect how far results carry.
Which side effects of Nivolumab or Ipilimumab are most likely for me, which are reversible, and which would make us stop?
Why: The recorded rates below come from labels and trials; your own risk depends on dose, other medicines and your health.
What happens if I delay, or decline this step for now? Is the decision reversible?
Why: Some decisions can wait for a second opinion or a trial slot; others cannot. Knowing which is part of the choice.
Does your recommendation follow the current guideline (NCCN Guidelines: Melanoma: Cutaneous), and if it departs from it, why?
Why: Departures from guidelines are sometimes right for an individual; they should be explained.
For my situation (resectable macroscopic nodal disease), which of the standard options do you recommend and why?
Why: Guideline options include: Neoadjuvant ipilimumab plus nivolumab for two cycles then surgery, with adjuvant therapy only if the pathological response is poor (NADINA); or neoadjuvant then adjuvant pembrolizumab (SWOG S1801).
Am I a candidate for Nivolumab, Ipilimumab, Pembrolizumab, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of NADINA and SWOG S1801 apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Add these to your appointment list, or take the full question set for this cancer.

Early / localised

Adjuvant, after upfront surgery

3 optionsCompare side by side →

One year of nivolumab (CheckMate 238) or pembrolizumab (KEYNOTE-054); dabrafenib-trametinib for one year is the alternative in BRAF V600-mutant disease (COMBI-AD).

Guideline

NCCN Guidelines: Melanoma: Cutaneous

The options, in plain words

NivolumabApprovedMonoclonal antibody (anti-PD-1)

Nivolumab was the second PD-1 blocker and is often combined with ipilimumab. Long-term data show about half of advanced melanoma patients alive at 10 years on the combination.

PembrolizumabApprovedMonoclonal antibody (anti-PD-1)

Dabrafenib + trametinibApprovedSmall-molecule kinase inhibitors (BRAF + MEK)

Dabrafenib plus trametinib is the BRAF-plus-MEK pill combination, approved for BRAF V600E lung cancer and, since 2022, for any solid tumour with that mutation.

The evidence behind it

CheckMate 238 Phase 3 NCT02388906 2017906 peopleevidence 89
Tests Nivolumab
Resected stage IIIB, IIIC or IV melanoma: one year of adjuvant nivolumab versus ipilimumab 10 mg/kg
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
12-month recurrence-free survival 70.5% vs 60.8% (HR 0.65); 4-year recurrence-free survival 51.7% vs 41.2%; no overall survival difference.
Recurrence-free survival at 12 months (%): Nivolumab 70.5 (n=453) vs Ipilimumab 10 mg/kg 60.8 (n=453) · HR 0.65 · source
Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054)Phase 3 NCT023625941,019 peopleevidence 50
Tests Pembrolizumab
Adjuvant Immunotherapy With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-risk Stage III Melanoma: A Randomized, Double- Blind Phase 3 Trial of the EORTC Melanoma Group
No headline result recorded yet.
COMBI-AD Phase 3 NCT01682083 2017870 peopleevidence 73
Tests Dabrafenib + trametinib
Resected stage III BRAF V600-mutant melanoma: adjuvant dabrafenib + trametinib 1 year vs placebo
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
10-year RFS 48% vs 32%; DMFS 63% vs 48%.
Relapse-free survival at 10 years (%): Dabrafenib + trametinib 48 vs Placebo 32 · source

The main trade-offs on record

Nivolumab all recorded rates →

Side effect	Any grade	Grade 3+
Colitis with ipilimumab (1+3 mg/kg) · Monotherapy pooled unless stated	25%	14.4%
Hepatitis with ipilimumab · Monotherapy pooled unless stated	15%	13.4%
Colitis · Monotherapy pooled unless stated	2.9%	1.7%
Hepatitis · Monotherapy pooled unless stated	1.8%	1.5%

Rates from the label or pivotal trial as recorded on the product page; each grade 3+ figure links to its source.

Pembrolizumab all recorded rates →

Side effect	Any grade	Grade 3+
Hypothyroidism (immune-mediated) · Pooled monotherapy data, >2,800 patients	8%	-
Pneumonitis (immune-mediated) · Pooled monotherapy data, >2,800 patients	3.4%	-
Colitis (immune-mediated) · Pooled monotherapy data, >2,800 patients	1.7%	-
Hepatitis (immune-mediated) · Pooled monotherapy data, >2,800 patients	0.7%	-

No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.

Rates from the label or pivotal trial as recorded on the product page; each grade 3+ figure links to its source.

Dabrafenib + trametinib all recorded rates →

Dabrafenib: take on an empty stomach. Trametinib: take on an empty stomach; both cause pyrexia.

Questions to ask about this decision

Between Nivolumab, Pembrolizumab and Dabrafenib + trametinib, which do you recommend for me, and what about my case would make you choose differently?
Why: Guidelines list several reasonable options; the choice turns on details of your tumour, your health and your priorities.
What is each option trying to achieve: cure, long control, or relief of symptoms, and over what time?
Why: The aim shapes how much side effect and disruption is worth accepting.
How closely do I match the people in CheckMate 238 and Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054), and does that change what the results mean for me?
Why: Trial populations are selected; age, fitness, prior treatment and biomarkers all affect how far results carry.
Which side effects of Nivolumab or Pembrolizumab are most likely for me, which are reversible, and which would make us stop?
Why: The recorded rates below come from labels and trials; your own risk depends on dose, other medicines and your health.
What happens if I delay, or decline this step for now? Is the decision reversible?
Why: Some decisions can wait for a second opinion or a trial slot; others cannot. Knowing which is part of the choice.
Does your recommendation follow the current guideline (NCCN Guidelines: Melanoma: Cutaneous), and if it departs from it, why?
Why: Departures from guidelines are sometimes right for an individual; they should be explained.
For my situation (adjuvant, after upfront surgery), which of the standard options do you recommend and why?
Why: Guideline options include: One year of nivolumab (CheckMate 238) or pembrolizumab (KEYNOTE-054); dabrafenib-trametinib for one year is the alternative in BRAF V600-mutant disease (COMBI-AD).
Am I a candidate for Nivolumab, Pembrolizumab, Dabrafenib + trametinib, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of CheckMate 238 and Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054) apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Add these to your appointment list, or take the full question set for this cancer.

Early / localised

Adjuvant vaccine (emerging)

2 options

Intismeran autogene with pembrolizumab met its endpoints in INTerpath-001 (2026); regulatory review pending.

The options, in plain words

Intismeran autogenePhase 3Personalised mRNA neoantigen vaccine

A custom mRNA vaccine encoding up to 34 of a patient's own tumour mutations. In August 2026 it became the first personalised cancer vaccine to win a phase 3 trial.

Personalised neoantigen (mRNA) vaccinesPhase 3

A vaccine made for one patient, encoding the unique mutations in their own tumour, to train the immune system to hunt it.

Fully personalised, low toxicity
Adjuvant setting where tumour burden is low

The evidence behind it

INTerpath-001 (V940-001)Phase 3 NCT05933577 20261,137 peopleevidence 89
Tests Intismeran autogene, Personalised neoantigen (mRNA) vaccines
Adjuvant resected stage IIB-IV melanoma: intismeran autogene + pembrolizumab vs pembrolizumab
RFS and DMFS significantly improved (HRs pending presentation).

The main trade-offs on record

Personalised neoantigen (mRNA) vaccines

6-8 week manufacturing
Cost
Neoantigen prediction is imperfect; low-TMB tumours have few targets

Questions to ask about this decision

Between Intismeran autogene and Personalised neoantigen (mRNA) vaccines, which do you recommend for me, and what about my case would make you choose differently?
Why: Guidelines list several reasonable options; the choice turns on details of your tumour, your health and your priorities.
What is each option trying to achieve: cure, long control, or relief of symptoms, and over what time?
Why: The aim shapes how much side effect and disruption is worth accepting.
How closely do I match the people in INTerpath-001 (V940-001), and does that change what the results mean for me?
Why: Trial populations are selected; age, fitness, prior treatment and biomarkers all affect how far results carry.
What happens if I delay, or decline this step for now? Is the decision reversible?
Why: Some decisions can wait for a second opinion or a trial slot; others cannot. Knowing which is part of the choice.
For my situation (adjuvant vaccine (emerging)), which of the standard options do you recommend and why?
Why: Guideline options include: Intismeran autogene with pembrolizumab met its endpoints in INTerpath-001 (2026); regulatory review pending.
Am I a candidate for Intismeran autogene, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of INTerpath-001 (V940-001) apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Add these to your appointment list, or take the full question set for this cancer.

Other settings

In-transit disease

3 options

Excision where feasible; intralesional talimogene laherparepvec or the immunocytokine daromun before surgery; isolated limb perfusion for extensive limb disease.

Guideline

NCCN Guidelines: Melanoma: Cutaneous

The options, in plain words

Talimogene laherparepvecApprovedOncolytic virus (HSV-1)

Talimogene laherparepvec (T-VEC, Imlygic) was the first approved oncolytic virus (2015), injected into melanoma skin lesions.

Isolated limb perfusion and infusionEstablished

Isolating the blood supply of an arm or leg so that chemotherapy doses 15-20 times higher than the body could tolerate can be circulated through it, to save limbs with melanoma or sarcoma that would otherwise be amputated.

Limb salvage in otherwise unresectable sarcoma
High complete response in melanoma in-transit disease
Minimal systemic toxicity when leak is controlled

ElectrochemotherapyEstablished

Brief electric pulses applied to a tumour open pores in cell membranes so that a tiny dose of bleomycin or cisplatin floods in; used for skin metastases and, increasingly, for deep tumours.

High local response with minimal systemic toxicity
Single or few sessions; day case under local/general anaesthesia
Works regardless of tumour histology

The evidence behind it

Neoadjuvant L19IL2/L19TNF- Pivotal Study Phase 3 NCT02938299214 peopleevidence 42
A Pivotal Phase III, Open-label, Randomized, Controlled Multi-center Study of the Efficacy of L19IL2/L19TNF Neoadjuvant Intratumoral Treatment Followed by Surgery Versus Surgery Alone in Clinical Stage III B/C Melanoma Patients
No headline result recorded yet.
Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C/D Melanoma Patients Phase 3 NCT03567889186 peopleevidence 41
An Open-Label, Randomized, Controlled Multi-Center Study of The Efficacy of Daromun (L19IL2 + L19TNF) Neoadjuvant Intratumoral Treatment Followed by Surgery and Adjuvant Therapy Versus Surgery and Adjuvant Therapy in Clinical Stage IIIB/C/D Melanoma Patients
No headline result recorded yet.

The main trade-offs on record

Isolated limb perfusion and infusion

Major operation; regional toxicity (Wieberdink grade)
TNF-α not approved in the US
Displaced in melanoma by systemic immunotherapy

Electrochemotherapy

Local treatment only
Requires electrodes to reach tumour (depth limits)
No US device approval; limited randomised evidence

Questions to ask about this decision

Between Talimogene laherparepvec, Isolated limb perfusion and infusion and Electrochemotherapy, which do you recommend for me, and what about my case would make you choose differently?
Why: Guidelines list several reasonable options; the choice turns on details of your tumour, your health and your priorities.
What is each option trying to achieve: cure, long control, or relief of symptoms, and over what time?
Why: The aim shapes how much side effect and disruption is worth accepting.
How closely do I match the people in Neoadjuvant L19IL2/L19TNF- Pivotal Study and Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C/D Melanoma Patients, and does that change what the results mean for me?
Why: Trial populations are selected; age, fitness, prior treatment and biomarkers all affect how far results carry.
What happens if I delay, or decline this step for now? Is the decision reversible?
Why: Some decisions can wait for a second opinion or a trial slot; others cannot. Knowing which is part of the choice.
Does your recommendation follow the current guideline (NCCN Guidelines: Melanoma: Cutaneous), and if it departs from it, why?
Why: Departures from guidelines are sometimes right for an individual; they should be explained.
For my situation (in-transit disease), which of the standard options do you recommend and why?
Why: Guideline options include: Excision where feasible; intralesional talimogene laherparepvec or the immunocytokine daromun before surgery; isolated limb perfusion for extensive limb disease.
Am I a candidate for Talimogene laherparepvec, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of Neoadjuvant L19IL2/L19TNF- Pivotal Study and Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C/D Melanoma Patients apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Add these to your appointment list, or take the full question set for this cancer.

How to read this page. Options and results come from OnCo records with their sources; the settings are the standard-of-care rows on the cancer page, and the lines of therapy are on the sequencing grid. Where a setting names one path, the choice is usually about timing, trials and where to be treated: see expert centres. OnCo is orientation, not medical advice.