What is the recommended treatment approach for patients with metastatic melanoma, particularly those with BRAF V600E or V600K mutations, using dabrafenib (dabrafenib) and trametinib (trametinib) and immunotherapy?

Treatment Approach for Metastatic Melanoma with BRAF V600E/K Mutations

First-Line Treatment Selection

For patients with BRAF V600E/K-mutant metastatic melanoma, both BRAF/MEK inhibitor combinations and immune checkpoint inhibitors are equally valid first-line options, but the choice depends critically on disease tempo and symptomatology. 1

Choose BRAF/MEK Inhibitors First When:

• Disease is symptomatic or rapidly progressing 1
• Patient's overall health is deteriorating 1
• High tumor burden requiring rapid response 1
• Patient has active autoimmune disease or high risk of triggering autoimmunity 1

Choose Immunotherapy First When:

• Disease is asymptomatic with low tumor burden 1
• Time is available for durable immune response to develop 1
• Patient has no contraindications to immune checkpoint inhibitors 1

Recommended BRAF/MEK Inhibitor Regimens (Category 1)

All three combinations are FDA-approved and equally recommended: 1

• Dabrafenib 150 mg twice daily + Trametinib 2 mg once daily 1
• Vemurafenib 960 mg twice daily + Cobimetinib 60 mg once daily 1
• Encorafenib 450 mg once daily + Binimetinib 45 mg twice daily 1

BRAF/MEK combination therapy is strongly preferred over BRAF monotherapy due to superior progression-free survival, overall survival, and similar or better toxicity profiles demonstrated in COMBI-d, COMBI-v, and CoBRIM trials. 1

Key Efficacy Data for Dabrafenib + Trametinib:

• 3-year progression-free survival: 22% (vs 12% with dabrafenib monotherapy) 2
• 3-year overall survival: 44% (vs 32% with monotherapy) 2
• 12-month overall survival: 72% (vs 65% with vemurafenib) 3
• Median progression-free survival: 11.4 months (vs 7.3 months with vemurafenib) 3

Recommended Immunotherapy Regimens

For BRAF-mutant patients choosing immunotherapy first-line: 1

• Nivolumab 3 mg/kg every 2 weeks 1
• Pembrolizumab 2 mg/kg every 3 weeks 1
• Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg every 3 weeks for 4 doses, then Nivolumab 3 mg/kg every 2 weeks 1
• Nivolumab + Relatlimab 1

Critical Testing Requirements

BRAF mutational status must be tested using FDA-approved test or CLIA-approved facility before initiating targeted therapy. 1

• Companion diagnostics: Cobas 4800 BRAF V600 mutation test (for vemurafenib) or THxID BRAF Kit (for dabrafenib/trametinib) 1
• Tissue source: Biopsy of current metastasis is preferred over archival material 1
• VE1 immunohistochemistry: Positive staining is sufficient to start therapy in symptomatic/rapidly progressing patients, but must be confirmed by sequencing due to false positive/negative risk 1

Treatment for All BRAF V600 Mutation Subtypes

BRAF/MEK combination therapy is appropriate for any activating BRAF V600 mutation (V600E, V600K, V600R, V600D, and others), not just V600E/K. 1

Sequencing After Progression

After progression on anti-PD-1 therapy: Switch to BRAF/MEK inhibitor combination therapy. 1

After progression on BRAF/MEK inhibitors: Switch to anti-PD-1-based immunotherapy. 1

Common Pitfalls to Avoid

Never use trametinib monotherapy - it is no longer recommended due to poor efficacy compared to BRAF inhibitor monotherapy and BRAF/MEK combinations. 1

Never use BRAF inhibitor monotherapy unless combination therapy is absolutely contraindicated and patient is not a candidate for immunotherapy. 1

Avoid cutaneous toxicity paradox: BRAF/MEK combinations cause significantly fewer cutaneous squamous cell carcinomas and keratoacanthomas (1%) compared to BRAF monotherapy (6%) or vemurafenib monotherapy (18%) due to reduced paradoxical MAPK pathway activation. 3, 4

Prognostic Subgroups with Dabrafenib + Trametinib

Most favorable subgroup (normal LDH, <3 organ sites with metastasis): 3-year OS of 62% 2

Unfavorable subgroup (elevated LDH): 3-year OS of only 25% 2

Safety Profile

Dabrafenib + trametinib combination therapy demonstrates consistent safety without new signals with long-term use. 2, 4

Most adverse events are mild to moderate and manageable. 2, 3, 4

58% of patients alive at 3 years remained on dabrafenib + trametinib, demonstrating tolerability for long-term use. 2