What is the standard treatment for stage 4 melanoma?

Standard Treatment for Stage 4 Melanoma

The standard treatment for stage 4 melanoma depends on BRAF mutation status, with first-line options including immune checkpoint inhibitors (nivolumab plus ipilimumab or PD-1 inhibitor monotherapy) for all patients, and BRAF/MEK inhibitor combinations for BRAF-mutated melanoma. 1

Initial Assessment and Staging

• Complete diagnostic workup including:
  • Pathological evaluation
  • Whole-body imaging
  • Serum LDH analysis
  • Genetic mutation analysis (especially BRAF V600)
  • CNS assessment for brain metastases 1
• Surgical evaluation for possible metastasectomy if complete resection is feasible 1

Treatment Algorithm Based on Disease Characteristics

1. Limited Metastatic Disease (Resectable)

• Surgical resection if complete removal is feasible 1
  • Consider observation period or systemic therapy before surgery for solitary visceral metastases to rule out rapid disease progression 1
• Adjuvant therapy options after complete resection:
  • Clinical trial (preferred)
  • Immune checkpoint inhibitors (nivolumab or pembrolizumab)
  • Note: Adjuvant interferon alpha monotherapy is not recommended 1

2. Disseminated Disease (Unresectable) - BRAF Mutation Positive

Good Performance Status:

• First-line options:
  • Nivolumab plus ipilimumab (combination shows median OS of 72.1 months) 2
  • PD-1 inhibitor monotherapy (nivolumab or pembrolizumab)
  • BRAF/MEK inhibitor combination (vemurafenib/cobimetinib, dabrafenib/trametinib, or encorafenib/binimetinib) 1

Poor Performance Status or Uncontrolled CNS Disease:

• First-line: BRAF/MEK inhibitor combination 1
• Second-line: Ipilimumab or chemotherapy 1
• Third-line: Single-agent chemotherapy, clinical trial, or palliative care 1

3. Disseminated Disease (Unresectable) - BRAF Wild Type

Good Performance Status:

• First-line options:
  • Nivolumab plus ipilimumab (preferred if tolerable) 1
  • PD-1 inhibitor monotherapy (nivolumab or pembrolizumab) 1
  • High-dose IL-2 (for selected patients) 1

Poor Performance Status:

• First-line options:
  • Ipilimumab
  • Clinical trial participation
  • Chemotherapy (dacarbazine, temozolomide, or paclitaxel-based) 1

Dosing for Key Immunotherapy Agents

• Ipilimumab:

  • Monotherapy: 3 mg/kg every 3 weeks for a maximum of 4 doses 3
  • With nivolumab: 3 mg/kg immediately following nivolumab 1 mg/kg on the same day, every 3 weeks for 4 doses 3

• PD-1 inhibitors:

  • Nivolumab: 240 mg every 2 weeks or 480 mg every 4 weeks
  • Pembrolizumab: 200 mg every 3 weeks or 400 mg every 6 weeks

Management of Brain Metastases

• Surgical resection for solitary or limited brain metastases 1
• Stereotactic radiosurgery for small lesions
• Whole-brain radiation therapy for multiple symptomatic lesions
• Systemic therapy with agents that cross the blood-brain barrier (ipilimumab, nivolumab, BRAF/MEK inhibitors) 1

Palliative Care Considerations

• Palliative radiation therapy for symptomatic metastases (brain, bone) 1
• Pain management and supportive care
• RT has shown 54% response rate for brain metastases and 77% for nodal/in-transit metastases 1

Treatment Response Monitoring

• Continue treatment until maximum response, confirmed progression, or unacceptable toxicity 1
• For ipilimumab, delayed responses may occur; continue follow-up even after initial progression until clinical deterioration or confirmation of progression on follow-up imaging at least 4 weeks later 1

Important Considerations and Pitfalls

• Immune-related adverse events: Close monitoring is essential with checkpoint inhibitors, especially with combination therapy 1
• BRAF inhibitor resistance: Often develops within 6-8 months; consider immunotherapy before or after progression
• Treatment sequencing: For BRAF-mutated melanoma, consider immunotherapy first for patients with good performance status and controlled disease, as responses may be more durable 1
• Clinical trials: Should always be considered as a priority option at all stages of treatment 1