What are the potential eye side effects of dabrafenib (dabrafenib) and trametinib (trametinib) combination therapy?

Eye Side Effects of Dabrafenib and Trametinib Combination Therapy

Trametinib carries significant risk of serous retinopathy and requires mandatory ophthalmologic surveillance, while dabrafenib alone has minimal ocular toxicity—the combination therapy demands pretreatment eye examination and close monitoring at 2-3 weeks after initiation, then every 3-4 months. 1

Primary Ocular Toxicities

Trametinib-Associated Effects

• Serous retinopathy (reversible) is the most notable ocular toxicity of trametinib monotherapy 1
• Requires pretreatment ophthalmologic evaluation before initiating therapy 1
• Recheck ophthalmologic examination 2-3 weeks after initiation is mandatory 1
• Ongoing monitoring every 3-4 months for the first year of treatment 1

Dabrafenib-Associated Effects

• Dabrafenib monotherapy has minimal to no specific ocular toxicity reported in guidelines 1
• Primary toxicities are cutaneous (keratoacanthoma/squamous cell carcinoma), fever, and arthralgias 1

Severe Uveitis with Combination Therapy

Clinical Presentation

The combination of dabrafenib plus trametinib can cause severe bilateral panuveitis with the following features:

• Granulomatous or non-granulomatous anterior uveitis 2, 3
• Vitritis (inflammatory cells in vitreous) 2, 3, 4
• Multiple serous retinal detachments (bullous in severe cases) 2, 3, 5, 4
• Choroidal thickening and chorioretinal folds 3, 4
• Sudden onset of bilateral painless visual loss 3

Incidence and Severity

• This is a rare but vision-threatening complication 4
• Can occur despite discontinuation of one agent (trametinib) while continuing the other (dabrafenib) 3
• Suggests synergistic toxicity from MAPK pathway inhibition 3

Management Algorithm

When Ocular Symptoms Develop:

1. Immediately discontinue both dabrafenib and trametinib 2, 3, 5
2. Initiate topical corticosteroids for anterior uveitis 2, 3
3. Add systemic corticosteroids (intravenous followed by oral with tapering) for severe panuveitis with serous detachments 2, 4
4. Expect good response with visual acuity recovery within 2 weeks in most cases 2
5. Near-complete resolution of serous retinal detachments typically occurs with treatment 3

Reintroduction Considerations:

• If therapy must be restarted due to metastatic disease progression, mild ocular adverse effects may recur 4
• These can be managed with oral corticosteroids while continuing therapy 4
• Patients with history of uveitis are at higher risk for severe ocular toxicity and require especially strict monitoring 6

Monitoring Protocol

Baseline (Before Starting Therapy):

• Comprehensive ophthalmologic examination including dilated fundoscopy 1
• Document baseline visual acuity and retinal anatomy 1

Early Follow-up:

• Ophthalmologic examination at 2-3 weeks after initiation is critical 1
• This catches early serous retinopathy before it becomes symptomatic 1

Ongoing Surveillance:

• Every 3-4 months during the first year of treatment 1
• Continue monitoring every 3 months thereafter 1
• Patients should undergo consecutive eye examinations from the beginning of therapy 5

Critical Pitfalls to Avoid

• Do not assume discontinuing only trametinib is sufficient—the combination appears to have synergistic ocular toxicity requiring cessation of both agents 3
• Do not delay ophthalmologic evaluation when visual symptoms develop—these can progress rapidly 3
• Do not restart therapy without ophthalmologic clearance and consideration of prophylactic corticosteroids 4
• Do not overlook patients with pre-existing uveitis—they require enhanced surveillance as they are at higher risk for choroidal neovascularization and severe complications 6