What are the initial treatment recommendations for a patient with advanced melanoma, considering their disease characteristics, medical history, and potential BRAF V600E or V600K (B-Raf proto-oncogene, serine/threonine kinase) mutations?

Advanced Melanoma Management

First-Line Treatment Selection

For patients with advanced melanoma, initiate treatment with immune checkpoint inhibitors (anti-PD-1 monotherapy or nivolumab/ipilimumab combination) for all patients, reserving BRAF/MEK inhibitor combinations specifically for BRAF V600-mutant patients with rapidly progressive or symptomatic disease. 1

Mandatory Initial Testing

• All patients must undergo BRAF mutation testing using an FDA-approved test or CLIA-approved facility before treatment selection to identify any BRAF V600 mutation (V600E, V600K, V600R, V600D, or others). 1
• Positive VE1 immunohistochemistry is sufficient to start targeted therapy in symptomatic or rapidly progressing patients, but all VE1 results (positive and negative) require confirmation by sequencing due to false positive/negative risk. 2
• Tissue should be obtained from biopsy of a current metastasis (preferred) or archival material. 2

Treatment Algorithm by BRAF Status

BRAF Wild-Type Melanoma

Recommended first-line options (all Category 1/Strong recommendations): 1

• Nivolumab 3 mg/kg IV every 2 weeks 2
• Pembrolizumab 2 mg/kg IV every 3 weeks 2
• Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg IV every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks 2, 1

BRAF V600-Mutant Melanoma

Treatment selection depends critically on disease tempo and symptomatology: 1

For rapidly progressive or symptomatic disease:

• BRAF/MEK inhibitor combinations are preferred due to rapid response (median time to response ≈1.5 months vs. 2.1-3.5 months for immunotherapy) and high initial response rates. 2, 1

Approved BRAF/MEK combinations: 1

• Dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily
• Encorafenib 450 mg PO once daily plus binimetinib 45 mg PO twice daily
• Vemurafenib 960 mg PO twice daily plus cobimetinib 60 mg PO once daily (21 days on, 7 days off)

For low-volume, asymptomatic metastatic disease:

• Immunotherapy is preferred (same options as BRAF wild-type above) as checkpoint inhibitors are effective regardless of BRAF mutation status and may provide more durable responses. 2, 1

Choosing Between Anti-PD-1 Monotherapy vs. Nivolumab/Ipilimumab Combination

Selection should be based on the following factors: 2, 1

• Patient's overall health and comorbidities: Patients with autoimmune disease history or significant comorbidities favor anti-PD-1 monotherapy. 2
• Ability to comply with proactive monitoring: Combination therapy requires intensive monitoring for immune-related adverse events. 2, 1
• Tolerance for toxicity: Nivolumab/ipilimumab has grade ≥3 adverse events in 65% vs. 32% for anti-PD-1 monotherapy. 2, 1
• Disease burden: Higher disease burden or more aggressive disease tempo may warrant combination therapy despite higher toxicity. 3

Key consideration: Although nivolumab/ipilimumab combination provides somewhat better progression-free survival, there is currently no evidence of improvement in overall survival compared to anti-PD-1 monotherapy. 2

Critical Treatment Pitfalls to Avoid

Never use the following approaches: 1

• Ipilimumab monotherapy as first-line treatment - CheckMate 067 trial showed superior outcomes with anti-PD-1 monotherapy or combination therapy. 2
• BRAF inhibitor monotherapy unless combination therapy is absolutely contraindicated - combination therapy has superior response rate, PFS, and OS with similar or better toxicity profile. 2, 1
• MEK inhibitor monotherapy - poor efficacy with response rate of only 22% and median PFS of 2.8 months. 1

Second-Line Treatment After Progression

After progression on anti-PD-1 therapy in BRAF-mutant patients:

• Switch to BRAF/MEK inhibitor combination therapy, or alternatively offer ipilimumab or ipilimumab-containing regimens. 1

After progression on BRAF/MEK inhibitors:

• Switch to anti-PD-1-based immunotherapy. 1
• Important caveat: Patients who progressed rapidly on first-line BRAF inhibitors derive minimal benefit from second-line BRAF/MEK combinations. 1

BRAF/MEK Combination Efficacy Data

The superiority of BRAF/MEK combinations over monotherapy is established by multiple phase III trials: 2

• COMBI-d trial: Dabrafenib/trametinib showed 69% response rate, median response duration 12.9 months, median PFS 11.0 months, and median OS 25.1 months. 2
• Vemurafenib/cobimetinib trial: 68% response rate vs. 45% for vemurafenib alone, median PFS 9.9 months vs. 6.2 months, with significant OS benefit (81% vs. 73% at specified timepoint, p=0.046). 2

Treatment Duration Considerations

For immunotherapy: 1

• Treatment may continue beyond 2 years based on clinical trials, though pembrolizumab was limited to 24 months maximum in KEYNOTE-002. 2
• Discontinuation is common (45-77% in trials with median follow-up <2 years), and clinical experience beyond 1 year is currently limited. 2
• No high-quality melanoma-specific data exist on optimal duration. 1

For BRAF/MEK inhibitors:

• Continue until disease progression or unacceptable toxicity. 2

Special Populations

Brain metastases:

• Both BRAF/MEK inhibitors and checkpoint inhibitors (including ipilimumab/nivolumab) can be safely used in patients with symptomatic brain metastases and have shown significant efficacy. 2
• Stereotactic irradiation of progressive brain metastases is reasonable if systemic therapy achieves partial disease control. 2

Injectable lesions:

• For patients with injectable cutaneous/subcutaneous/nodal lesions, talimogene laherparepvec (T-VEC) may be offered as primary therapy if patients are not eligible for or decline systemic therapies, or for disease control in limited stage IV disease. 1