What is the recommended treatment for unresectable metastatic melanoma?

Treatment of Unresectable Metastatic Melanoma

For unresectable metastatic melanoma, first-line treatment should be either immune checkpoint inhibitors (anti-PD-1 monotherapy with nivolumab or pembrolizumab, or nivolumab/ipilimumab combination) for all patients, or BRAF/MEK inhibitor combinations specifically for patients with BRAF V600 mutations who have rapidly progressive or symptomatic disease. 1

Initial Diagnostic Requirement

• All patients must undergo BRAF mutation testing using an FDA-approved test or CLIA-approved facility before treatment selection 1, 2
• Testing should identify any BRAF V600 mutation (V600E, V600K, V600R, V600D, or others) 1, 2
• Companion diagnostics include the Cobas 4800 BRAF V600 mutation test or THxID BRAF Kit 2

Treatment Algorithm Based on BRAF Status

For BRAF Wild-Type Patients

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

• Nivolumab 3 mg/kg IV every 2 weeks (or 240 mg every 2 weeks, or 480 mg every 4 weeks) 1
• Pembrolizumab 2 mg/kg IV every 3 weeks (or 200 mg every 3 weeks, or 400 mg every 6 weeks) 1
• 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 1, 3

For BRAF V600-Mutant Patients

Treatment selection depends on disease tempo and symptomatology: 1, 2

Choose BRAF/MEK inhibitor combinations first when: 1, 2

• Disease is rapidly progressing (time to progression anticipated <6 months) 1, 2
• Patient has symptomatic metastatic disease requiring rapid response 1, 2
• High tumor burden necessitating quick disease control 2
• Patient's overall health is deteriorating 2
• Active autoimmune disease or high risk of triggering autoimmunity 2

Choose immunotherapy first when: 1

• Low-volume, asymptomatic metastatic disease where time exists for durable immune response to develop 1
• Patient can tolerate potential immune-related adverse events 1

Approved BRAF/MEK inhibitor combinations (all Category 1): 1, 2

• Dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily 1, 2
• Encorafenib 450 mg PO once daily plus binimetinib 45 mg PO twice daily 1, 2
• Vemurafenib 960 mg PO twice daily plus cobimetinib 60 mg PO once daily (21 days on, 7 days off) 1, 2

Immunotherapy options for BRAF-mutant patients (same as wild-type): 1

• Nivolumab monotherapy, pembrolizumab monotherapy, or nivolumab/ipilimumab combination as detailed above 1

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

Key decision factors: 1

• Nivolumab/ipilimumab combination provides somewhat better progression-free survival but significantly higher risk of serious immune-mediated toxicities (grade ≥3 adverse events: 65% for combination vs. 32% for monotherapy) 1
• No evidence of overall survival improvement with combination therapy over monotherapy 1
• Descriptive analyses suggest patients with low PD-L1 expression may benefit more from combination therapy, while high PD-L1 expressors may do equally well on monotherapy 1
• Consider patient's comorbidities, ability to comply with proactive monitoring for immune-related adverse events, and tolerance for toxicity 1

Critical Evidence on BRAF/MEK Combinations vs. Monotherapy

BRAF/MEK combination therapy is strongly preferred over BRAF inhibitor monotherapy based on superior outcomes: 1, 2

• COMBI-d trial: dabrafenib/trametinib showed 69% response rate vs. historical BRAF monotherapy, with median PFS 11.0 months 1
• CoBRIM trial: vemurafenib/cobimetinib showed 68% response rate with median PFS 9.9 months vs. 6.2 months for vemurafenib alone 1
• Never use trametinib or other MEK inhibitor monotherapy due to poor efficacy (response rate 22%, median PFS 2.8 months) 1, 2

Second-Line Treatment After Progression

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

• Switch to BRAF/MEK inhibitor combination therapy 1
• Alternatively, ipilimumab or ipilimumab-containing regimens may be offered 1

After progression on BRAF/MEK inhibitors: 1, 4

• Switch to anti-PD-1-based immunotherapy 1
• Patients who progressed rapidly on first-line BRAF inhibitors (<6 months) derive minimal benefit from second-line BRAF/MEK combinations (response rate 0% vs. 25% for those progressing after ≥6 months) 1

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

• Ipilimumab or ipilimumab-containing regimens may be offered 1
• T-VEC therapy for injectable lesions 1

Special Considerations for Injectable Lesions

For patients with injectable cutaneous/subcutaneous/nodal lesions: 1

• Talimogene laherparepvec (T-VEC) may be offered as primary therapy if patients are not eligible for or decline systemic therapies 1
• T-VEC can be used for disease control in limited stage IV disease 1

Treatment Duration

For immunotherapy: 1

• Nivolumab can be continued beyond 2 years in clinical trials 1
• Pembrolizumab was limited to 2 years in pivotal trials 1
• Shorter courses (as brief as 1 year) may be reasonable, though no high-quality melanoma-specific data exist on optimal duration 1

Common Pitfalls to Avoid

• Never use ipilimumab monotherapy as first-line treatment due to CheckMate 067 trial showing superior outcomes with anti-PD-1 monotherapy or combination therapy 1
• Never use BRAF inhibitor monotherapy unless combination therapy is absolutely contraindicated 2
• Never use MEK inhibitor monotherapy 1, 2
• Never switch between different BRAF/MEK combinations after failure as no data support efficacy of this approach 1
• Hold BRAF/MEK inhibitors 3 days before and after fractionated radiation therapy, and 1 day before and after stereotactic radiosurgery to avoid increased toxicity 1