What is the recommended treatment course for stage 3 melanoma?

Treatment Course for Stage III Melanoma

For resectable stage III melanoma, complete surgical resection followed by adjuvant immunotherapy with nivolumab or pembrolizumab for 52 weeks is the standard of care, with neoadjuvant pembrolizumab now preferred for patients with clinically positive (bulky) lymph nodes. 1, 2

Surgical Management

• Complete lymph node dissection of the involved nodal basin is mandatory for clinically positive stage III melanoma, with wide excision of the primary site if not previously performed 2, 3
• Surgery must achieve negative margins before initiating systemic therapy 2
• For sentinel node-positive disease without clinically palpable nodes, completion lymphadenectomy remains standard, though this is evolving 1

Neoadjuvant Approach for Resectable Bulky Disease (Preferred for Clinically Positive Nodes)

Neoadjuvant pembrolizumab is now the preferred approach for resectable stage III melanoma with clinically positive lymph nodes or bulky disease, demonstrating superior outcomes compared to upfront surgery 1, 2:

• Pembrolizumab 200 mg IV every 3 weeks for 3 doses before surgery, followed by surgical resection, then 15 additional doses of pembrolizumab as adjuvant therapy 1, 2
• This approach achieves 72% event-free survival at 2 years versus 49% with adjuvant-only treatment 1, 2
• Grade ≥3 treatment-related adverse events occur in only 12% of patients 1

Alternative neoadjuvant options for specific circumstances 1:

• Nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks for 2 cycles achieves 57% pathologic response with 20% grade 3-4 immune-related adverse events (preferred combination dosing) 1
• Dabrafenib/trametinib for 4-12 weeks preoperatively for BRAF V600E/K mutant disease when immunotherapy is contraindicated (Category 2A) 1
• Talimogene laherparepvec (T-VEC) intralesional therapy for satellite/in-transit disease only, not for lymph node disease 1

Adjuvant Systemic Therapy After Upfront Surgery

For BRAF Wild-Type Disease

First-line options (choose one) 2, 3, 4:

• Nivolumab 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks for 52 weeks (12-month RFS: 70.5% vs 60.8% with ipilimumab; HR 0.65) 2, 3
• Pembrolizumab 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks for 52 weeks (12-month RFS: 75% vs 61% for placebo; HR 0.57) 2, 4

For BRAF V600E/K Mutant Disease

Equally effective options (choose based on patient factors) 2, 5:

• Anti-PD-1 therapy (nivolumab or pembrolizumab as above) - preferred by most guidelines 2
• Dabrafenib 150 mg PO twice daily + trametinib 2 mg PO once daily for 52 weeks (3-year RFS: ~60%) 1, 2, 5

Key decision point: Both immunotherapy and targeted therapy achieve similar 3-year RFS rates (~60%), but targeted therapy provides faster disease control in the first 6-12 months, while immunotherapy may offer more durable long-term responses 2. Grade 3-4 adverse events occur in 29-38% with immunotherapy versus 35-45% with targeted therapy 2.

Adjuvant Radiation Therapy

Strongly consider adjuvant radiation to the nodal basin for high-risk features 2, 3:

• Multiple positive lymph nodes (≥4 nodes)
• Large lymph nodes (>3 cm)
• Macroscopic extranodal soft tissue extension
• Head and neck location (particularly important) 3

Timing Considerations

• Initiate adjuvant therapy within 13 weeks post-surgery - this was the maximum allowed in pivotal trials 2, 4
• Do NOT delay beyond this window as efficacy data are lacking for later initiation 2

Stage-Specific Considerations

**Stage IIIA with sentinel node metastasis <1 mm**: May consider observation versus adjuvant therapy given relatively favorable prognosis (5-year survival >80%), though adjuvant therapy still improves outcomes 2

Stage IIIB-C: Adjuvant therapy strongly recommended for all patients 2, 5

Stage IIID (N3 involvement): Adjuvant therapy mandatory; strongly consider adjuvant radiation given high-risk nodal disease 5

Treatments NOT Recommended

• High-dose ipilimumab monotherapy (10 mg/kg) - inferior efficacy and excessive toxicity compared to anti-PD-1 agents 1, 2, 5
• High-dose interferon-alpha - inferior efficacy and poor tolerability 1, 2
• Biochemotherapy - no survival benefit with significant toxicity 5
• BRAF/MEK inhibitors for non-V600E/K mutations - no efficacy data 2

Monitoring During Treatment

For immunotherapy 5:

• Monitor for immune-related adverse events: colitis, hepatitis, pneumonitis, endocrinopathies (thyroid, adrenal, pituitary), dermatologic toxicities
• Check TSH, liver function tests, and comprehensive metabolic panel at each visit

For targeted therapy 5:

• Monitor for pyrexia (most common), skin rash, liver dysfunction, cardiac toxicity
• Obtain echocardiogram or MUGA scan at baseline and periodically
• Check liver function tests regularly

Management of Recurrence After Adjuvant Therapy

Oligometastatic recurrence (1-3 lesions): Consider surgical resection or stereotactic radiation combined with systemic therapy 2, 5

Systemic recurrence 2, 6:

• Patients who relapse during or after adjuvant targeted therapy respond excellently to subsequent anti-PD-1 therapy 2, 6
• Patients who relapse after adjuvant immunotherapy should receive combination immunotherapy (nivolumab + ipilimumab or nivolumab + relatlimab) or targeted therapy if BRAF-mutant 2

Timing patterns 6:

• Patients treated with immunotherapy typically recur during treatment (ON-treatment)
• Patients treated with targeted therapy typically recur after completing treatment (OFF-treatment)

Critical Pitfalls to Avoid

• Do NOT use vemurafenib monotherapy as adjuvant therapy - inferior to combination targeted therapy 1, 7
• Do NOT use anti-PD-1 monotherapy for BRAF-mutant disease without discussing dabrafenib/trametinib as an equally effective option 2, 7
• Do NOT skip baseline staging before adjuvant therapy - must rule out distant metastases with CT chest/abdomen/pelvis and brain MRI 3
• Do NOT use neoadjuvant immunotherapy for microscopic (sentinel node-positive only) disease - this approach is for clinically positive/bulky disease only 1