What are the common adverse effects, monitoring, and management strategies for the dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination in adults with BRAF‑mutated melanoma?

Side Effects of Dabrafenib and Trametinib Combination Therapy

The combination of dabrafenib and trametinib causes predominantly flu-like symptoms (pyrexia, chills, headache), gastrointestinal toxicity (diarrhea, nausea), and mild skin reactions, but critically reduces the dangerous hyperproliferative skin lesions (cutaneous squamous cell carcinoma, keratoacanthoma) seen with BRAF inhibitor monotherapy. 1

Most Common Adverse Effects

Constitutional Symptoms (Flu-like)

• Pyrexia (fever) occurs in approximately 50% of patients and is significantly more common with combination therapy than monotherapy 1, 2
• Fever is often grade 3 in severity (6% of patients) and represents a dabrafenib-specific toxicity 2, 3
• Manage fever with acetaminophen and/or NSAIDs; temporary discontinuation may be necessary 4
• Chills affect 92% of patients in neoadjuvant settings 4
• Headache occurs in 92% of patients 4, 1
• Fatigue and asthenia affect 38-52% of patients 1

Gastrointestinal Toxicity

• Diarrhea is notably more common with BRAF/MEK combination than BRAF monotherapy 1
• Grade 3 diarrhea occurred in 15% of patients in neoadjuvant trials 4
• Nausea affects 35-52% of patients 1, 5
• Vomiting occurs in a significant subset 1
• Decreased appetite is common 1

Dermatologic Effects

• Rash is common but generally mild 1
• Alopecia affects approximately 36% of patients 1
• Regular skin evaluation and dermatology referral remain recommended despite reduced risk, as secondary skin lesions are still a class effect of BRAF inhibition 4, 1

Musculoskeletal Symptoms

• Arthralgia is less common with combination therapy compared to BRAF monotherapy 1
• Myalgia is similarly reduced with combination versus monotherapy 1
• Patients should be educated to report joint pain and swelling 4, 1

Cardiovascular and Laboratory Abnormalities

• Hypertension occurs in 6-14% of patients 1
• Elevated liver enzymes occur in 1-15% of patients depending on grade 1
• Elevated CPK, alkaline phosphatase, and lipase are common laboratory abnormalities 1
• Anemia is a common side effect 1

Critical Advantage: Reduced Hyperproliferative Skin Toxicities

A key benefit of combination therapy is the dramatic reduction in dangerous hyperproliferative skin lesions compared to BRAF inhibitor monotherapy. 1, 6

• Cutaneous squamous cell carcinoma is markedly reduced: 2% with combination versus 9% with dabrafenib alone 2, 1
• Keratoacanthoma has substantially lower incidence with combination therapy (6% with dabrafenib alone) 4, 1, 5
• Hyperkeratosis is less common with combination therapy 1, 5
• Palmoplantar disorders have reduced frequency with combination therapy 1
• This reduction occurs because MEK inhibition prevents paradoxical MAPK pathway activation that causes these lesions 6, 2

Serious but Rare Toxicities

Ocular Toxicity (Trametinib-Specific)

• Serous retinopathy is the most notable ocular toxicity, specifically from trametinib 1, 7
• Mandatory ophthalmologic surveillance protocol: comprehensive dilated fundoscopy at baseline, recheck at 2-3 weeks, and every 3-4 months during the first year of treatment 1, 7
• Dabrafenib alone has minimal ocular toxicity 7

Other Serious Events

• Decreased ejection fraction is a serious adverse event 1
• Deep venous thrombosis is a rare event attributed to MEK inhibitors 1
• Neutropenia, hyponatremia, hemoptysis, and intracranial hemorrhage are rare but serious 1

Overall Toxicity Profile and Treatment Discontinuation

• All-grade adverse events occur in 97-99% of patients 1
• Grade 3-5 adverse events occur in 48-50% of patients with combination therapy, similar to monotherapy rates 1, 2
• The overall risk of toxicity is similar between combination and monotherapy, but the type of toxicities differs significantly 1
• Most adverse events are mild and do not require discontinuation 4, 1
• Treatment discontinuation rate was 26% in COMBI-AD, higher than with anti-PD-1 therapy (8-10%) 4
• Dose modifications occur more frequently with combination therapy than monotherapy 2

Clinical Management Strategy

Proactive Monitoring

• The shift from BRAF monotherapy to BRAF/MEK combinations has resulted in lower discontinuation rates due to hyperproliferative skin toxicities and musculoskeletal complaints 1
• Flu-like symptoms are less likely to lead to treatment discontinuation, especially when patients are forewarned 1

Alternative Combinations

• Other BRAF/MEK inhibitor combinations (vemurafenib/cobimetinib or encorafenib/binimetinib) can be considered in the event of unacceptable toxicities to dabrafenib/trametinib or based on side effect profiles 4

Common Pitfall to Avoid

• Do not use BRAF inhibitor monotherapy when combination therapy is available, as resistance develops rapidly and cutaneous malignancies are significantly more common 1, 2