Melanoma Staging and Treatment: Immunotherapy and Targeted Therapy
Sam Anderson
AJCC 8th Edition Staging and Prognostic Factors
Melanoma treatment has been transformed by immunotherapy and targeted therapy, with outcomes for advanced disease improving dramatically over the past decade. For the dermatologist, surgical oncologist, or medical oncologist managing melanoma patients, accurate staging drives every subsequent clinical decision — from the extent of surgical margins to the role of adjuvant immunotherapy and the selection of systemic therapy for metastatic disease. This review covers the current AJCC staging framework and the evidence-based treatment approach across disease stages.
The AJCC 8th edition staging system for cutaneous melanoma uses Breslow thickness, ulceration, and mitotic rate as primary tumor prognostic factors. T1a lesions (less than 0.8 mm, non-ulcerated) carry a 10-year melanoma-specific survival of 98%, while T4b lesions (greater than 4.0 mm, ulcerated) have a 10-year survival of 75%[2]. Sentinel lymph node biopsy is recommended for lesions with Breslow thickness above 0.8 mm or T1b[11] (less than 0.8 mm with ulceration), based on MSLT-I data showing a 20% positivity rate in this population.
Immune Checkpoint Inhibitors in Advanced Melanoma
The CheckMate 067 trial established nivolumab plus ipilimumab as the benchmark for first-line metastatic melanoma treatment, achieving a 6.5-year overall survival rate of 49% for the combination versus 42% for nivolumab monotherapy and 23% for ipilimumab monotherapy[1]. However, grade 3-4 adverse events occurred in 59% of combination-treated patients[2]. The RELATIVITY-047 trial demonstrated relatlimab plus nivolumab (Opdualag) as an alternative with a more favorable toxicity profile: progression-free survival of 10.1 months versus 4.6 months for nivolumab monotherapy (HR 0.75, p=0.006) with grade 3-4 events in 21%[3].
BRAF-Targeted Therapy
Approximately 40-50% of cutaneous melanomas harbor BRAF V600E/K mutations. The COLUMBUS trial demonstrated encorafenib plus binimetinib achieves a median PFS of 14.9 months and OS of 33.6 months[4]. Current NCCN guidelines recommend first-line immunotherapy over targeted therapy for most BRAF-mutant patients, reserving BRAF/MEK inhibition for patients requiring rapid tumor response (brain metastases, high tumor burden with symptomatic disease) or those who progress on immunotherapy. The DREAMseq trial confirmed this sequencing, showing 2-year OS of 72% for immunotherapy-first versus 52% for targeted therapy-first (p=0.0095)[5].
Adjuvant Therapy: Stage III and High-Risk Stage II
Pembrolizumab (KEYNOTE-054) and nivolumab (CheckMate 238) are both approved for adjuvant therapy in resected stage III melanoma. KEYNOTE-054 showed a 4-year recurrence-free survival of 54.4% versus 42.1% for placebo[6]. The KEYNOTE-716 trial extended adjuvant pembrolizumab to high-risk stage IIB/IIC disease (patients with hereditary risk factors should also be assessed), demonstrating a 35% reduction in distant metastasis-free survival events (HR 0.64, p=0.0029)[7]. Adjuvant dabrafenib plus trametinib is an alternative for BRAF-mutant stage III patients per the COMBI-AD trial (5-year RFS 52% versus 36%)[8].
Neoadjuvant Immunotherapy: The Emerging Frontier
The SWOG S1801 trial demonstrated that neoadjuvant pembrolizumab (3 cycles before surgery, 15 cycles after) improved 2-year event-free survival to 72% versus 49% for adjuvant-only pembrolizumab in resectable stage IIIB-IV melanoma (HR 0.59, p=0.004)[9]. Pathologic complete response rates of 25-30% with dual checkpoint blockade are being explored in the NADINA trial (neoadjuvant nivolumab plus ipilimumab), with early results showing pCR in 59% of patients[10]. These findings are reshaping the treatment paradigm toward a neoadjuvant-first approach for resectable high-risk disease. For a broader overview of checkpoint inhibitors, see our clinical guide for oncologists.
Surveillance After Treatment: Catching Recurrence Early
Melanoma surveillance after definitive treatment is a lifelong commitment for both the patient and the dermatologist. The highest recurrence risk is in the first three years, but late recurrences — five, ten, even fifteen years after initial treatment — are well documented and distinguish melanoma from most other solid tumors. For patients with stage IIB or higher disease, surveillance typically includes clinical skin examinations and lymph node assessment every 3-6 months for the first 3 years, then every 6-12 months through year five, and annually thereafter. Cross-sectional imaging (CT or PET-CT) is recommended for stage III-IV disease during the high-risk surveillance period, though the optimal imaging frequency and modality continue to be debated. Patient education on self-skin examination and the recognition of concerning new lesions or nodal changes is an essential complement to scheduled clinical surveillance.
Limitations and Evolving Questions
Melanoma treatment has advanced more rapidly than almost any other solid tumor, but significant challenges remain. The selection between BRAF-targeted therapy and immunotherapy for BRAF-mutant advanced melanoma is informed by DREAMseq but involves clinical judgment about tempo of disease, tumor burden, and patient tolerance for immune-related adverse events. The optimal duration of adjuvant immunotherapy is not established — whether patients can safely stop after one year or need longer treatment is an active area of investigation. And the neoadjuvant paradigm, while producing impressive pathologic response rates, is still being defined in terms of which patients can safely forgo surgery after complete pathologic response and which require completion surgery regardless. The pace of progress in melanoma is remarkable, but the clinical decisions are becoming more complex, not simpler.
References
- Six-Year Survival and Durable Responses in CheckMate 067: Nivolumab Plus Ipilimumab in Advanced Melanoma (Wolchok et al., J Clin Oncol 2022) PubMed 34818112
- Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma (CheckMate 067, Wolchok et al., NEJM 2017) PubMed 28564569
- Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma (RELATIVITY-047, Tawbi et al., NEJM 2022) PubMed 34986285
- Overall Survival with Encorafenib and Binimetinib in BRAF-Mutant Melanoma (COLUMBUS, Dummer et al., Lancet Oncol 2018) PubMed 30219628
- DREAMseq: Sequencing of BRAF Inhibitor and Anti-PD1 in Melanoma (Atkins et al., J Clin Oncol 2023) PubMed 36166727
- Pembrolizumab vs Placebo After Complete Resection of High-Risk Stage III Melanoma (KEYNOTE-054, Eggermont et al., NEJM) PubMed 38319859
- Pembrolizumab versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma (KEYNOTE-716, Luke et al., Lancet 2022) PubMed 35367007
- Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma (COMBI-AD, Long et al., NEJM 2017) PubMed 28891408
- Neoadjuvant versus Adjuvant Pembrolizumab in Resectable Stage IIIB-IV Melanoma (SWOG S1801, Patel et al., NEJM 2023) PubMed 36856617
- Neoadjuvant Nivolumab plus Ipilimumab vs Adjuvant Nivolumab in Macroscopic Stage III Melanoma (NADINA, Blank et al., NEJM 2024) PubMed 38828984
- Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in Melanoma (MSLT-I, Morton et al., NEJM 2014) PubMed 25776246
Frequently Asked Questions
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