A. Systemic therapy for
metastatic or unresectable disease:
A. Recommended first-line therapy (metastatic
or unresectable disease):
• Anti–programmed cell death protein 1 (PD1)
monotherapy: Pembrolizumab, nivolumab.
• Combination targeted therapy for BRAF V600–activating
mutation (preferred if clinically necessary for early response):
Dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib.
• Useful in certain circumstances:
Nivolumab/ipilimumab.
2. Recommended second-line or subsequent
therapy (disease progression or maximum clinical benefit from BRAF-targeted therapy):
• Preferred regimens: Anti-PD1 monotherapy
(pembrolizumab, nivolumab); nivolumab/ipilimumab; combination targeted therapy
for BRAF V600–activating
mutation (dabrafenib/trametinib, vemurafenib/cobimetinib,
encorafenib/binimetinib).
• Other regimens: Ipilimumab; high-dose IL-2.
• Useful in certain circumstances:
Ipilimumab/intralesional talimogene laherparepvec (T-VEC); cytotoxic agents;
imatinib for tumors with activating mutations of KIT; larotrectinib
for NTRK gene
fusion–positive tumors.
B. Recommended adjuvant
systemic therapies:
1. For stage III (sentinel lymph node
positive) disease:
• Primary treatment: Wide local excision of
primary lesion and sentinel lymph node biopsy, followed by complete lymph node
dissection or nodal ultrasound surveillance.
• Recommended options: Observation, nivolumab,
pembrolizumab, combination dabrafenib/trametinib.
2. For stage III (clinically positive nodes
[no in-transit or satellite metastases]) disease:
• Primary treatment: Wide local excision of
primary lesion and complete lymph node dissection.
• Recommended options: Observation, nivolumab,
pembrolizumab, combination dabrafenib/trametinib.
3. For stage III (clinical or microscopic
satellite/in-transit) disease:
• Primary treatment: Complete surgical
excision to clear margins.
• Recommended options: Observation, nivolumab,
pembrolizumab, combination dabrafenib/trametinib.
4. For stage IV resectable disease:
• Primary treatment: Complete resection.
• Recommended options: Observation, high-dose
ipilimumab (recommended only if patient has prior exposure to anti-PD1
therapy), nivolumab, pembrolizumab.
5. For local satellite/in-transit disease
recurrence:
• Primary treatment: Complete surgical
excision to clear margins.
• Recommended options: Observation, nivolumab,
pembrolizumab, combination dabrafenib/trametinib.
6. For nodal recurrence:
• Primary treatment: Excise nodal metastasis
and complete lymph node dissection (if incomplete or no prior complete lymph
node dissection).
• Recommended options: Observation, high-dose
ipilimumab (recommended only if patient has prior exposure to anti-PD1
therapy), nivolumab, pembrolizumab, combination dabrafenib/trametinib.
