# Stage III melanoma (after surgery)

Source: https://onco.cc/cancers/stage-iii-melanoma/  
OnCo record `stage-iii-melanoma` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Stage III melanoma has spread to nearby lymph nodes but not further, and after surgery a year of immunotherapy, or of targeted pills if the cancer has a BRAF mutation, roughly halves the chance of it coming back. The newest trials show that giving immunotherapy before the operation instead of after works even better and lets most people stop treatment early.

## Summary

Stage III melanoma is defined by regional nodal, satellite or in-transit disease and is staged by primary thickness and ulceration together with the number and size of nodal deposits. MSLT-II (2017) showed that removing the whole nodal basin after a positive sentinel node does not improve melanoma-specific survival, so most patients now keep their nodes and are watched with ultrasound. For decades the only adjuvant drug was high-dose interferon alfa, with a small relapse-free benefit and heavy toxicity; adjuvant ipilimumab (EORTC 18071, 2015) improved survival but at the cost of frequent severe immune toxicity.

CheckMate 238 (2017) showed nivolumab beat ipilimumab for recurrence-free survival (70.5 against 60.8 percent at one year) with a third of the serious toxicity, and KEYNOTE-054 (2018) showed pembrolizumab beat placebo (75.4 against 61.0 percent at one year, 55.4 against 38.3 percent at five years). COMBI-AD (2017) showed a year of dabrafenib-trametinib halved relapse risk in BRAF-mutant disease (ten-year relapse-free survival 48 against 32 percent). Adding ipilimumab to nivolumab (CheckMate 915) or relatlimab to nivolumab (RELATIVITY-098) after surgery added nothing, so a year of single-agent anti-PD-1 antibody, or the BRAF-MEK doublet, became the adjuvant standard.

The neoadjuvant trials then changed the timing. SWOG S1801 (2022) moved three of eighteen pembrolizumab doses to before surgery and improved two-year event-free survival from 49 to 72 percent with the same total drug. NADINA (2024) gave two cycles of ipilimumab plus nivolumab before surgery and adjuvant therapy only to poor responders, and cut events by two thirds against adjuvant nivolumab (twelve-month event-free survival 83.7 against 57.2 percent); about six in ten patients had a major pathological response and needed no further treatment. Neoadjuvant immunotherapy is now the preferred approach for macroscopic nodal disease. INTerpath-001 (2026) added the personalised mRNA vaccine intismeran autogene to adjuvant pembrolizumab and met its recurrence-free survival endpoint in resected stage IIB to IV disease, confirming the phase 2b KEYNOTE-942 signal (eighteen-month recurrence-free survival 78.6 against 62.2 percent).

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Resected stage III melanoma; Node-positive melanoma; Regional melanoma; Adjuvant melanoma setting
- Tags: subtype-page
- Group: skin
- Burden: Stage III means the melanoma has reached the regional lymph nodes or produced satellite or in-transit deposits in the skin; in the eighth edition of the staging system five-year melanoma-specific survival ranges from 93 percent for stage IIIA to 32 percent for stage IIID, so it is the stage where preventing relapse matters most.
- Subtypes: Stage IIIA (microscopic nodal disease, thin primary); Stage IIIB and IIIC (clinically detected nodes, satellites or in-transit metastases); Stage IIID (thick ulcerated primary with matted or numerous nodes); Resectable macroscopic stage III (neoadjuvant immunotherapy candidates, NADINA); BRAF V600-mutant stage III (adjuvant dabrafenib-trametinib option); Sentinel node-positive with no palpable disease (observation of the basin after MSLT-II)
- Biomarkers: Sentinel node status and nodal tumour burden; Breslow thickness and ulceration of the primary; BRAF V600 mutation (adjuvant targeted therapy option); Pathological response after neoadjuvant immunotherapy (major pathological response guides omission of adjuvant therapy); Circulating tumour DNA after surgery (trials of adjuvant selection); Interferon-gamma gene signature (exploratory predictor in NADINA)

## Standard of care

- Positive sentinel node, no palpable disease: Wide local excision, no completion lymph node dissection (MSLT-II), nodal ultrasound surveillance, then adjuvant systemic therapy. ([MSLT-II](https://onco.cc/trials/mslt-ii/), [Sentinel lymph node biopsy](https://onco.cc/technologies/sentinel-node/), [Wide local excision](https://onco.cc/terms/wide-local-excision/))
- Resectable macroscopic nodal disease: 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). ([NADINA](https://onco.cc/trials/nadina/), [SWOG S1801](https://onco.cc/trials/swog-s1801/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Major pathological response (MPR)](https://onco.cc/terms/major-pathological-response/))
- Adjuvant, after upfront surgery: 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). ([CheckMate 238](https://onco.cc/trials/checkmate-238/), [Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054)](https://onco.cc/trials/nct02362594/), [COMBI-AD](https://onco.cc/trials/combi-ad/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/))
- Adjuvant vaccine (emerging): Intismeran autogene with pembrolizumab met its endpoints in INTerpath-001 (2026); regulatory review pending. ([INTerpath-001 (V940-001)](https://onco.cc/trials/interpath-001/), [Intismeran autogene](https://onco.cc/drugs/intismeran-autogene/), [Personalised neoantigen (mRNA) vaccines](https://onco.cc/technologies/neoantigen-mrna-vaccine/))
- In-transit disease: Excision where feasible; intralesional talimogene laherparepvec or the immunocytokine daromun before surgery; isolated limb perfusion for extensive limb disease. ([Talimogene laherparepvec](https://onco.cc/drugs/talimogene-laherparepvec/), [Neoadjuvant L19IL2/L19TNF- Pivotal Study](https://onco.cc/trials/nct02938299/), [Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C/D Melanoma Patients](https://onco.cc/trials/nct03567889/), [Isolated limb perfusion and infusion](https://onco.cc/technologies/isolated-limb-perfusion/), [Electrochemotherapy](https://onco.cc/technologies/electrochemotherapy/))

## State of the art

- A year of anti-PD-1 antibody or of dabrafenib-trametinib after surgery roughly halves the risk of relapse.
- Neoadjuvant immunotherapy (SWOG S1801, NADINA) beats the same drugs given only after surgery and lets most responders stop treatment early.
- The first positive phase 3 personalised cancer vaccine trial (INTerpath-001) was in this setting.

## Open problems

- Most stage IIIA patients would never have relapsed, so a year of immunotherapy with lifelong endocrine side effects in some is given to many who do not need it.
- No biomarker yet tells who can safely skip adjuvant therapy; circulating tumour DNA trials are testing this.
- Overall survival gains from adjuvant PD-1 blockade are small because relapsing patients receive the same drugs later.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Melanoma
- CheckMate 238 (NEJM 2017): https://www.nejm.org/doi/full/10.1056/NEJMoa1709030
- KEYNOTE-054 (NEJM 2018): https://www.nejm.org/doi/full/10.1056/NEJMoa1802357
- NADINA (NEJM 2024): https://www.nejm.org/doi/full/10.1056/NEJMoa2402604
- Wikipedia: https://en.wikipedia.org/wiki/Melanoma

## Connected records

- technologies: [Electrochemotherapy](https://onco.cc/technologies/electrochemotherapy/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Isolated limb perfusion and infusion](https://onco.cc/technologies/isolated-limb-perfusion/), [Personalised neoantigen (mRNA) vaccines](https://onco.cc/technologies/neoantigen-mrna-vaccine/), [Sentinel lymph node biopsy](https://onco.cc/technologies/sentinel-node/)
- targets: [BRAF](https://onco.cc/targets/braf/), [CTLA-4](https://onco.cc/targets/ctla4/), [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Dabrafenib](https://onco.cc/drugs/dabrafenib/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Interferon alfa-2a/2b](https://onco.cc/drugs/interferon-alfa/), [Intismeran autogene](https://onco.cc/drugs/intismeran-autogene/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Talimogene laherparepvec](https://onco.cc/drugs/talimogene-laherparepvec/), [Trametinib](https://onco.cc/drugs/trametinib/)
- terms: [Breslow thickness](https://onco.cc/terms/breslow-thickness/), [Event-free / disease-free survival (EFS, DFS, iDFS, RFS)](https://onco.cc/terms/efs/), [Major pathological response (MPR)](https://onco.cc/terms/major-pathological-response/), [Neoadjuvant / adjuvant / perioperative](https://onco.cc/terms/neoadjuvant-adjuvant/), [Ulceration (melanoma)](https://onco.cc/terms/ulceration-melanoma/), [Wide local excision](https://onco.cc/terms/wide-local-excision/)
- trials: [A Study of Neoadjuvant Therapy With BCD-217 (Nurulimab + Prolgolimab) in Patients With Resectable Stage III Skin Melanoma](https://onco.cc/trials/nct05751928/), [CheckMate 238](https://onco.cc/trials/checkmate-238/), [COMBI-AD](https://onco.cc/trials/combi-ad/), [Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C/D Melanoma Patients](https://onco.cc/trials/nct03567889/), [INTerpath-001 (V940-001)](https://onco.cc/trials/interpath-001/), [MSLT-II](https://onco.cc/trials/mslt-ii/), [NADINA](https://onco.cc/trials/nadina/), [Neoadjuvant L19IL2/L19TNF- Pivotal Study](https://onco.cc/trials/nct02938299/), [Phase II Trial of Neoadjuvant and Adjuvant IO102-IO103 and Pembrolizumab KEYTRUDA® in Patients With Resectable Tumors](https://onco.cc/trials/nct05280314/), [RELATIVITY-098](https://onco.cc/trials/relativity-098/), [SCIB1 and iSCIB1+ in Melanoma Patients Receiving Nivolumab With Ipilimumab or SCIB1 With Pembrolizumab (The SCOPE Study)](https://onco.cc/trials/nct04079166/), [Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054)](https://onco.cc/trials/nct02362594/), [SWOG S1801](https://onco.cc/trials/swog-s1801/), [The Efficacy and Safety of PRTX007-003 Combined With Pembrolizumab in Resectable Stage III Melanoma](https://onco.cc/trials/nct07565285/)
- people: [Alexander Eggermont](https://onco.cc/people/alexander-eggermont/), [Christian Blank](https://onco.cc/people/christian-blank/), [Georgina V. Long](https://onco.cc/people/georgina-long/), [Jeffrey S. Weber](https://onco.cc/people/jeffrey-weber/), [Sapna P. Patel](https://onco.cc/people/sapna-patel/)
- ideas: [ctDNA-guided adjuvant therapy in stage II-III melanoma](https://onco.cc/ideas/idea-ctdna-guided-adjuvant-melanoma/)
- cancers: [Acral melanoma](https://onco.cc/cancers/acral-melanoma/), [Melanoma](https://onco.cc/cancers/melanoma/)

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