What is the recommended treatment for a patient with stage 4B melanoma?

Treatment for Stage 4B Melanoma

For stage 4B melanoma, initiate anti-PD-1 checkpoint inhibitor monotherapy with pembrolizumab or nivolumab as first-line treatment, or consider the combination of nivolumab plus ipilimumab for patients with symptomatic, bulky, or rapidly progressive disease, recognizing that combination therapy offers superior response rates (approximately 70%) but with significantly increased toxicity. 1, 2

First-Line Treatment Algorithm

BRAF Mutation Testing Required

• Immediately test for BRAF V600 mutations to determine eligibility for targeted therapy versus immunotherapy-only approaches 2
• If BRAF-mutated: Choose between anti-PD-1 therapy or BRAF/MEK inhibitor combination (dabrafenib/trametinib, vemurafenib/cobimetinib, or encorafenib/binimetinib) based on individual patient factors and toxicity profiles 3
• If BRAF wild-type (including triple wild-type): Anti-PD-1 therapy is the only recommended first-line option 1, 2

Immunotherapy Options

Anti-PD-1 Monotherapy (Preferred for Most Patients):

• Pembrolizumab or nivolumab as single agents 1, 2, 4
• Superior efficacy compared to ipilimumab monotherapy 2
• Better tolerated than combination regimens 1
• Effective regardless of NRAS, c-KIT, or NF1 mutation status 1

Nivolumab Plus Ipilimumab Combination (For Select Patients):

• Consider for symptomatic, bulky metastases or rapidly progressive disease 1, 2
• Overall response rate approximately 70% 2
• Significantly higher toxicity than monotherapy—requires careful patient selection 1, 2
• Can be safely used in patients with symptomatic brain metastases 1, 2

BRAF/MEK Inhibitor Combinations (If BRAF-Mutated)

• Dabrafenib/trametinib, vemurafenib/cobimetinib, or encorafenib/binimetinib 3
• No direct comparison exists between these three combinations 3
• Rapid response induction compared to immunotherapy 3
• Consider when rapid disease control is critical 3

Special Clinical Scenarios

Limited/Resectable Metastatic Disease

• Complete surgical resection should be strongly considered first if technically feasible 1, 2, 5
• Following complete resection, adjuvant pembrolizumab or nivolumab is recommended 1, 2, 5
• Nivolumab plus ipilimumab combination showed HR 0.23 (95% CI 0.13-0.41) for recurrence-free survival in resected stage IV disease 5
• Observation alone is no longer recommended even for very limited disease 3

Brain Metastases

• Checkpoint inhibitors (including nivolumab plus ipilimumab) can be safely used and have shown significant efficacy 1, 2
• Stereotactic radiotherapy is preferred over whole brain irradiation 1, 2
• Treatment of CNS disease usually takes priority to prevent intratumoral hemorrhage, seizures, or neurologic dysfunction 3

Symptomatic/Bulky Disease

• Anti-PD-1 based therapy remains preferred even in symptomatic disease 1
• Consider nivolumab plus ipilimumab for more aggressive disease 1, 2
• Palliative radiotherapy for symptomatic brain or localized painful bone metastases 1, 2
• Palliative resection for gastrointestinal bleeding, obstruction, or ulcerated soft tissue metastases 3

Second-Line and Subsequent Treatment

After Anti-PD-1 Monotherapy Failure

• Switch to nivolumab plus ipilimumab combination with overall response rate of 21% and 12-month overall survival of 55% 2
• Prioritize clinical trial enrollment given limited standard options 2

After Immunotherapy Failure

• Clinical trial enrollment is preferred 3, 1, 2
• If trials unavailable, cytotoxic chemotherapy options include dacarbazine (reference drug for palliative chemotherapy), temozolomide, taxanes, fotemustine, or platinum derivatives 1
• Chemotherapy has limited role and dramatically inferior outcomes compared to immunotherapy 1, 2

After BRAF/MEK Inhibitor Failure (If BRAF-Mutated)

• Switch to anti-PD-1 therapy 3
• Consider clinical trial 3

Treatment Duration and Monitoring

• Continue treatment until maximum response is reached, confirmed progression, or unacceptable adverse effects occur 2
• Stopping anti-PD-1 therapy should be considered after 2 years in case of partial response 2
• Delayed responses have been reported with ipilimumab—follow patients until clinical deterioration or confirmation of progression by repeat imaging at least 4 weeks after initial progression 3

Critical Monitoring for Immune-Related Adverse Events

Monitor for the following immune-related toxicities:

• Colitis 1, 2, 5
• Hepatitis 1, 2, 5
• Pneumonitis 1, 2, 5
• Endocrinopathies 1, 2, 5
• Dermatologic toxicities 1, 2, 5

Infection Risk:

• Pembrolizumab and nivolumab significantly increase susceptibility to severe infections, particularly tuberculosis and bacterial infections 1, 5
• PD-1 blockade impairs normal immune responses to pathogens 5

Ipilimumab-Specific Monitoring:

• Close monitoring of potentially lethal immune-related events is essential 3
• Strong recommendation for participation in risk evaluation and mitigation strategy (REMS) program during ipilimumab treatment 3

Common Pitfalls to Avoid

Do NOT:

• Delay immunotherapy initiation—starting treatment promptly after diagnosis optimizes outcomes 1, 2, 5
• Rely on chemotherapy as first-line treatment—immunotherapy has dramatically superior outcomes 1, 2
• Use single-agent ipilimumab in the modern era—it has lower efficacy and higher toxicity compared to anti-PD-1 therapy 3, 5
• Fail to obtain BRAF mutation testing—this is mandatory in stage IV melanoma to guide treatment selection 2
• Perform observation alone for resected stage IV disease—modern evidence strongly supports active adjuvant treatment given high recurrence risk 3, 5

Multidisciplinary Management

• All stage IV melanoma patients should be managed by Specialist Skin Cancer Multidisciplinary Teams 3
• Treatment should be discussed in an interdisciplinary tumor board at centers with broad experience in melanoma 1, 2
• Multidisciplinary tumor board consultation is encouraged 3

Additional Molecular Testing Considerations

• Retesting for BRAF mutations should be considered if disease progresses, as false-negative results can rarely occur 2
• Expanded molecular profiling may identify rare actionable alterations such as KIT mutations or NTRK fusions 2
• Mutation testing for BRAF, NRAS, and KIT is mandatory in patients with unresectable stage III or stage IV melanoma 2