Introduction
Dabrafenib (trade name Tafinlar®) is an oral targeted anticancer agent classified as a BRAF kinase inhibitor. It represents a significant advancement in precision oncology for treating specific molecular subtypes of cancer. Dabrafenib received initial FDA approval in 2013 and has since become an essential component of targeted therapy regimens for patients with BRAF V600 mutation-positive malignancies.
Mechanism of Action
Dabrafenib selectively inhibits mutant forms of BRAF kinases, particularly the V600E mutation. BRAF is a serine/threonine protein kinase in the RAS-RAF-MEK-ERK signaling pathway, which regulates cell division, differentiation, and apoptosis. The V600 mutation causes constitutive activation of this pathway, leading to uncontrolled cellular proliferation. Dabrafenib binds to the ATP-binding site of mutant BRAF, inhibiting its kinase activity and downstream signaling, thereby suppressing tumor growth and promoting apoptosis in cancer cells with this specific mutation.
Indications
FDA-approved indications include:
- Treatment of unresectable or metastatic melanoma with BRAF V600E mutation (as detected by an FDA-approved test)
- Adjuvant treatment of melanoma with BRAF V600E or V600K mutations following complete resection
- Treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation
- Treatment of locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation with no satisfactory locoregional treatment options
- Treatment of solid tumors with BRAF V600E mutation that have progressed following prior treatment (with no satisfactory alternative treatment options)
Dabrafenib is commonly used in combination with trametinib (a MEK inhibitor) for these indications to enhance efficacy and reduce resistance.
Dosage and Administration
Standard dosing: 150 mg orally twice daily (approximately every 12 hours) with or without food Special populations:- Renal impairment: No dosage adjustment necessary for mild to moderate impairment. Use with caution in severe renal impairment.
- Hepatic impairment: No dosage adjustment necessary for mild impairment. Reduce dose to 100 mg twice daily in moderate to severe hepatic impairment.
- Pediatric patients: Safety and effectiveness not established in children
- Geriatric patients: No dosage adjustment required, but monitor closely due to potentially increased susceptibility to adverse effects
- Swallow capsules whole with water; do not crush, chew, or open
- If a dose is missed, take it as soon as remembered unless the next dose is due within 6 hours
- Do not take two doses at the same time to make up for a missed dose
Pharmacokinetics
Absorption: Median time to peak concentration (Tmax) is 2 hours post-dose. Oral bioavailability is approximately 95%. Food does not significantly affect absorption. Distribution: Mean volume of distribution is 70.3 L. Protein binding is approximately 99.7%, primarily to albumin and alpha-1 acid glycoprotein. Metabolism: Primarily metabolized by CYP2C8 and CYP3A4 enzymes to hydroxyl-dabrafenib, which is further metabolized to carboxy-dabrafenib and desmethyl-dabrafenib. These metabolites are further metabolized through glucuronidation. Elimination: Mean elimination half-life is approximately 8 hours. Excretion is primarily fecal (71%) with renal elimination accounting for approximately 23% of the dose.Contraindications
- Hypersensitivity to dabrafenib or any component of the formulation
- Use with strong CYP3A4 or CYP2C8 inhibitors when alternative therapies are unavailable (due to risk of increased toxicity)
Warnings and Precautions
Boxed Warning: Risk of new primary malignancies (cutaneous and non-cutaneous), including squamous cell carcinoma, keratoacanthoma, and new primary melanoma. Perform dermatologic evaluations prior to treatment, every 2 months during therapy, and for up to 6 months after discontinuation. Additional important precautions:- Hemorrhage: Serious hemorrhagic events can occur; permanently discontinue for severe hemorrhage
- Cardiomyopathy: Assess LVEF before treatment, after 1 month, then every 2-3 months
- Ocular toxicity: Perform ophthalmologic evaluations for any visual disturbances
- Serious febrile reactions and fever: Monitor for fever and manage with antipyretics; withhold or discontinue based on severity
- Serious skin toxicity: Monitor for severe dermatologic reactions
- Hyperglycemia: Monitor blood glucose levels at baseline and during treatment
- Embryo-fetal toxicity: Can cause fetal harm; advise women of reproductive potential of risk and need for contraception
Drug Interactions
Clinically significant interactions:- Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): Increase dabrafenib exposure → reduce dabrafenib dose to 75 mg BID
- Strong CYP3A4 inducers (e.g., rifampin, carbamazepine): Decrease dabrafenib exposure → avoid concomitant use
- Strong CYP2C8 inhibitors (e.g., gemfibrozil): Increase dabrafenib exposure → reduce dabrafenib dose to 75 mg BID
- Sensitive CYP substrates: Dabrafenib induces CYP3A4 and CYP2C9 → may reduce efficacy of drugs metabolized by these enzymes (e.g., midazolam, warfarin)
- P-gp substrates: Dabrafenib may decrease concentrations of drugs that are P-gp substrates
Adverse Effects
Very common (≥10%):- Hyperkeratosis (37%)
- Headache (32%)
- Pyrexia (28%)
- Arthralgia (27%)
- Papilloma (27%)
- Alopecia (22%)
- Fatigue (19%)
- Rash (17%)
- Nausea (16%)
- Dermatitis acneiform (11%)
- New primary cutaneous malignancies (11%)
- Hemorrhage (5%)
- Cardiomyopathy (7%)
- Severe febrile reactions (3%)
- Severe dermatologic reactions (2%)
- Ocular toxicity (1%)
- Hyperglycemia requiring medication (6%)
Monitoring Parameters
Baseline assessment:- Confirm BRAF V600 mutation status with validated test
- Complete dermatologic exam
- LVEF assessment (ECHO or MUGA scan)
- Fasting blood glucose and HbA1c
- Liver function tests
- Renal function tests
- Complete blood count
- Dermatologic evaluations every 2 months during treatment and for 6 months post-treatment
- LVEF assessment at 1 month, then every 2-3 months
- Blood glucose monitoring regularly, especially in diabetic patients
- Temperature monitoring for febrile reactions
- Liver function tests monthly for first 3 months, then as clinically indicated
- Visual symptoms assessment at each visit
- Signs and symptoms of hemorrhage
Patient Education
Key points to discuss with patients:- Importance of genetic testing to confirm BRAF mutation before treatment
- Take exactly as prescribed; do not change dose or stop without discussing with healthcare provider
- Report any new skin lesions, changes in existing moles, or skin abnormalities immediately
- Monitor for fever (≥38.5°C or 101.3°F) and report promptly; may require temporary treatment interruption
- Report any unusual bleeding or bruising, shortness of breath, chest pain, or visual changes
- Use effective contraception during treatment and for 2 weeks after final dose (4 months for women taking hormonal contraceptives)
- Do not breastfeed during treatment and for 2 weeks after final dose
- Potential for photosensitivity; use sun protection including sunscreen (SPF ≥30), protective clothing, and avoid sun exposure
- Common side effects include skin changes, joint pain, fever, and fatigue; most are manageable
- Maintain all scheduled appointments for monitoring and laboratory tests
- Inform all healthcare providers about dabrafenib use due to potential drug interactions
References
1. FDA Prescribing Information: Tafinlar (dabrafenib) capsules. Revised 2023. 2. Hauschild A, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-365. 3. Long GV, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444-451. 4. Planchard D, et al. Dabrafenib plus trametinib in patients with previously treated BRAF V600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17(7):984-993. 5. NCCN Guidelines: Melanoma Version 3.2023. 6. Subbiah V, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018;36(1):7-13. 7. Salama AKS, et al. Dabrafenib and trametinib in patients with tumors with BRAF V600E mutations: results of the NCI-MATCH trial subprotocol H. J Clin Oncol. 2020;38(33):3895-3904.