Side Effects of Dabrafenib and Trametinib Combination Therapy
The combination of dabrafenib and trametinib causes predominantly flu-like symptoms (pyrexia, chills, fatigue), gastrointestinal upset (diarrhea, nausea), and skin toxicities, but importantly reduces the hyperproliferative skin lesions (squamous cell carcinoma, keratoacanthoma) seen with BRAF inhibitor monotherapy. 1
Most Common Side Effects
Flu-Like Symptoms (Most Prominent)
- Pyrexia (fever) occurs in approximately 50% of patients and is significantly more common with combination therapy than monotherapy 1, 2
- Chills affect a substantial proportion of patients 1
- Fatigue and asthenia are very common (any grade: 38-52% of patients) 1, 3, 4
- Headache occurs frequently 1
Gastrointestinal Effects
- Diarrhea is notably more common with BRAF/MEK combination than BRAF monotherapy 1, 3
- Nausea affects 35-52% of patients 1, 4
- Vomiting occurs in a significant subset 1
- Decreased appetite 1
Skin and Subcutaneous Toxicities
- Rash is common with combination therapy 1, 3
- Alopecia affects approximately 36% of patients (5/14 in one series) 1, 5
- Papillomas are the most common skin finding (50% in one series: 7/14 patients) 5
- Palmoplantar hyperkeratosis occurs in approximately 36% of patients 5
- Acneiform eruption specifically associated with trametinib (60% of trametinib-treated patients: 3/5) 5
- Seborrheic dermatitis-like eruption 5
Musculoskeletal Complaints
- Arthralgia is less common with combination therapy compared to BRAF monotherapy 1
- Myalgia similarly reduced with combination versus monotherapy 1
- Patients should be educated to report joint pain and swelling 1
Laboratory Abnormalities
- Hypertension: 6-14% (any grade) 1
- Elevated liver enzymes (ALT, AST, GGT): 1-15% depending on grade 1
- Elevated CPK, alkaline phosphatase, lipase 1
- Anemia 1
- Hyperglycemia (46% with dabrafenib) 6
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
- Cutaneous squamous cell carcinoma: Markedly reduced with combination therapy 1
- Keratoacanthoma: Substantially lower incidence 1
- Hyperkeratosis: Less common with combination 1
- Palmoplantar disorders: Reduced frequency 1
This reduction occurs because MEK inhibition suppresses the paradoxical MAPK activation that causes these proliferative lesions during BRAF inhibition alone 1
Serious but Rare Toxicities
Ocular Toxicities (MEK Inhibitor-Specific)
- Serous retinopathy is the most notable ocular toxicity, specifically from trametinib 7
- Mandatory ophthalmologic surveillance protocol: 7
- Comprehensive dilated fundoscopy at baseline before starting therapy
- Recheck at 2-3 weeks after initiation
- Every 3-4 months during the first year of treatment
- Dabrafenib alone has minimal to no ocular toxicity 7
Cardiovascular
- Decreased ejection fraction (serious adverse event reported) 1
- Deep venous thrombosis (rare, attributed to MEK inhibitors) 1
Other Serious Events
- Neutropenia (grade 3-4) 1
- Hyponatremia (grade 3-4) 1
- Hemoptysis 1
- Intracranial hemorrhage (one grade 5 event reported with encorafenib/binimetinib) 1
- Keratoacanthoma-like squamous cell carcinoma can still occur but is much less common than with monotherapy 5
Clinical Management Pearls
Dermatologic Monitoring
- Regular skin evaluation and dermatology referral are still recommended despite reduced risk, as secondary skin lesions remain a class effect of BRAF inhibition 1
- Skin adverse effects can present as early as 2 weeks, with mean onset at 9 weeks 5
Discontinuation Patterns
- In clinical practice, 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, while very common with combination therapy, are less likely to lead to treatment discontinuation, especially when patients are forewarned 1
Toxicity Management Strategy
- Most adverse events are mild and do not require discontinuation 1
- Dose interruptions and supportive care are effective for managing most side effects 3
- Dose reductions may be necessary in some cases 3