What are dabrafenib and trametinib?

Dabrafenib and Trametinib: Targeted Therapy for BRAF-Mutant Cancers

Dabrafenib and trametinib are FDA-approved targeted therapies used in combination to treat unresectable or metastatic melanoma with BRAF V600E or V600K mutations, with superior efficacy compared to single-agent therapy. 1

Mechanism of Action

• Dabrafenib: An oral selective BRAF inhibitor that targets mutated BRAF V600 protein
• Trametinib: An oral small-molecule inhibitor of MEK1 and MEK2, which are downstream of BRAF in the MAPK signaling pathway

Together, they provide complementary inhibition of the MAPK pathway, which is abnormally activated in approximately 50% of metastatic melanomas due to BRAF V600 mutations 1, 2.

FDA-Approved Indications

1. Metastatic or unresectable melanoma with BRAF V600E or V600K mutations 1
2. Adjuvant treatment for melanoma with BRAF V600E/K mutations in patients with lymph node involvement following complete resection 1
3. Metastatic NSCLC with BRAF V600E mutation 1

Clinical Efficacy in Melanoma

Metastatic/Unresectable Disease

• Improved progression-free survival (PFS): 9.3-13.8 months with combination therapy vs. 7.3-8.8 months with single-agent BRAF inhibitor 1, 3, 4
• Higher objective response rate: 64-69% with combination vs. 45-51% with monotherapy 1, 4
• Improved overall survival: Median OS of 25.1 months with combination therapy 1, 4
• Effective in brain metastases: 61.3% response rate in patients with brain metastases 5

Adjuvant Setting

• Reduced risk of recurrence: In the COMBI-AD trial, adjuvant dabrafenib/trametinib significantly improved relapse-free survival in patients with resected stage III melanoma 1

Dosing

• Dabrafenib: 150 mg orally twice daily
• Trametinib: 2 mg orally once daily

Adverse Effects

Common adverse effects include:

• Pyrexia: More common with combination therapy (51% vs. 28% with dabrafenib alone) 3
• Skin-related toxicity: Less cutaneous squamous cell carcinoma with combination (2%) compared to single-agent BRAF inhibitor (9-18%) 3, 4
• Other common adverse events: Fatigue, nausea, diarrhea, rash, arthralgia, headache, peripheral edema 6, 7

Most adverse events are mild to moderate in severity and generally manageable with dose modifications 6.

Patient Selection

• BRAF testing is mandatory: Treatment requires confirmation of BRAF V600E or V600K mutation using an FDA-approved test or CLIA-approved facility 1, 2
• Preferred over single-agent therapy: The BRAF/MEK inhibitor combination is preferred over BRAF inhibitor monotherapy due to improved efficacy and reduced risk of paradoxical MAPK pathway activation 1

Clinical Pearls

• Combination therapy delays the emergence of resistance compared to BRAF inhibitor monotherapy 3
• Trametinib monotherapy is not recommended due to relatively poor efficacy compared to combination therapy 1
• Regular monitoring for adverse effects is essential, particularly for pyrexia, skin toxicity, and ocular effects
• Patients who progress on prior BRAF inhibitor therapy have limited benefit from subsequent trametinib monotherapy 1, 7

Treatment Algorithm for BRAF-Mutant Melanoma

1. Confirm BRAF V600 mutation status using FDA-approved test
2. Assess disease stage and resectability
3. For unresectable/metastatic disease: Initiate dabrafenib plus trametinib combination therapy
4. For completely resected stage III disease: Consider adjuvant dabrafenib plus trametinib
5. Monitor for response and toxicity every 2-3 months

The combination of dabrafenib and trametinib represents a significant advancement in targeted therapy for BRAF-mutant cancers, offering improved survival outcomes with manageable toxicity compared to single-agent approaches.