What Is Dabrafenib (Tafinlar)? FDA Approval, Licensing and Reimbursement in Turkey

• FDA Approved: Yes (Initial approval date: May 29, 2013)
• Brand Name: Tafinlar
• Active Ingredient: Dabrafenib
• Route of Administration: Oral
• Class: Signal transduction inhibitor, BRAF inhibitor
• Category: Targeted agent
• Manufacturer: Novartis
• Distribution in Turkey: Novartis Sağlık, Gıda ve Tarım Ürünleri San. Ve Tic. A.Ş.
• Approved Cancers: With a BRAF V600E mutation: melanoma, non-small cell lung cancer, anaplastic thyroid cancer, low-grade glioma and advanced tumor-agnostic solid tumors carrying this mutation.

What Is Dabrafenib (Tafinlar) and How Does It Work?

Dabrafenib is an oral kinase inhibitor that prevents cell proliferation by inhibiting the MAPK signaling pathway in cancer cells with a BRAF V600 mutation.

What Is a BRAF Inhibitor?

BRAF inhibitors are drugs targeting the BRAF protein, which transmits growth signals in cancer cells. By inhibiting mutated BRAF, they stop cell division and cause cancer cell death.

How Does It Work?

• Dabrafenib targets and inhibits the mutant BRAF serine-threonine kinase enzyme, particularly the BRAF V600E mutation.
• It stops cell growth by blocking mitogen-activated protein kinase (MAPK) signaling.
• It can inhibit wild-type BRAF and CRAF kinases, although its inhibitory activity against wild-type BRAF is limited.

Through these mechanisms, dabrafenib inhibits cancer cell growth and slows disease progression.

FDA (US Food and Drug Administration) Approval History

• May 29, 2013: The FDA approved Tafinlar (dabrafenib) for advanced melanoma.
• January 9, 2014: GSK received accelerated FDA approval for Mekinist (trametinib) in combination with Tafinlar (dabrafenib).
• June 22, 2017: Novartis's targeted combination therapy Tafinlar + Mekinist received FDA approval for metastatic non-small cell lung cancer with a BRAF V600E mutation.
• April 30, 2018: Novartis received FDA approval for Tafinlar + Mekinist as adjuvant treatment for BRAF V600-mutated melanoma.
• May 4, 2018: The FDA approved Tafinlar + Mekinist for BRAF-positive anaplastic thyroid cancer.
• June 23, 2022: Novartis received the first FDA approval for Tafinlar + Mekinist in tumor-agnostic solid tumors carrying a BRAF V600E mutation.
• March 19, 2023: Novartis received FDA approval for Tafinlar + Mekinist in pediatric patients with BRAF V600E-mutated low-grade glioma.

Licensing in Turkey

Tafinlar's licensed uses and therapeutic indications in Turkey are listed as follows:

Therapeutic Indications:

• TAFİNLAR is indicated alone or with trametinib until progression in patients with relapsed or metastatic BRAF V600 mutation-positive malignant melanoma who have not previously received a RAF pathway inhibitor, have an ECOG performance score of 0-1, have relapsed after local treatments and do not receive further local treatment.
• TAFİNLAR is used with trametinib for a maximum of 12 months as adjuvant treatment following complete resection in adult patients with stage III melanoma and a BRAF V600 E mutation. Treatment is stopped if progression occurs during this period. Tafinlar may not be used alone.
• Indicated with trametinib until progression in patients with locally advanced or metastatic lung adenocarcinoma who have a BRAF V600 E mutation identified in an accredited laboratory; absent or unknown EGFR or ALK mutation status; an ECOG performance status of 0-1; adequate bone marrow reserve (neutrophil count above 1500 and platelet count above 100000); adequate liver and kidney function (ALT, AST, bilirubin and serum creatinine no more than 1.5 times normal); and a left ventricular ejection fraction within normal limits. Tafinlar may not be used alone.

Is Tafinlar Reimbursed in Turkey?

Tafinlar is covered by Turkey's Social Security Institution (SGK) in the following treatment settings:

• Reimbursement is provided for treatment of patients with relapsed or metastatic BRAF V600 mutation-positive malignant melanoma who have not previously received a RAF pathway inhibitor, have an ECOG performance score of 0-1, have relapsed after local treatments and do not receive further local treatment.
• SGK covers up to 12 months of adjuvant treatment after complete resection in adult patients with stage III melanoma carrying a BRAF V600 E mutation.

What Is Tafinlar's Status on the List of Off-Label Drugs That May Be Used Without Additional TİTCK Approval?

1. STAGE IV COLORECTAL CANCER:
   In BRAF-V600E-positive disease, dabrafenib and trametinib may be used with cetuximab or panitumumab in the 2nd line and beyond.
2. GBM:
   Its use is appropriate in BRAF-V600E mutation-positive patients whose disease has progressed after CRT and temozolomide.
3. STAGE IV BILIARY TRACT CANCER:
   Its use is appropriate in the 2nd line and beyond when a BRAF-V600E mutation is present.

Price: Tafınlar 50 mg, 120 capsules: 78335.28 TL, Tafınlar 75 mg, 120 capsules: 117447.95 TL respectively. 

Mechanisms of Resistance

• Increased MAPK signaling: Overactivity of the MAPK signaling pathway in cancer cells may lead to dabrafenib resistance.
• Gene mutations: Mutations in MAP2K1, encoding the MEK1 kinase, and MAP2K2, encoding MEK2, activate intracellular MAPK signaling independently of BRAF and reduce the drug's effect.
• BRAF amplification: Extra copies of the BRAF gene in cancer cells (amplification) may reduce the drug's efficacy.
• NRAS mutations: Changes in the NRAS gene may contribute to dabrafenib resistance.
• Activation of alternative signaling pathways: Activation of other signaling pathways, such as fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and PI3K/Akt, may allow cancer cells to evade dabrafenib.
• Reactivation of Ras/Raf signaling: Reactivation of Ras and Raf signaling in cancer cells may reduce the drug's effect and lead to resistance.

Absorption

Oral bioavailability is approximately 95%. Absorption is rapid, with peak plasma concentrations reached within 2 hours. High-fat food reduces both maximum concentration (Cmax) and area under the curve (AUC).

Distribution

Dabrafenib is more than 99% bound to plasma proteins.

Metabolism

Dabrafenib is metabolized mainly in the liver by the microsomal enzymes CYP2C8 and CYP3A4, producing hydroxy-dabrafenib. This metabolite is then converted by CYP3A4 to carboxy-dabrafenib. The hydroxy metabolite and other metabolites may also be clinically active. Elimination is mainly hepatic: approximately 70% is excreted in feces and 25% through the kidneys in urine. The average terminal half-life is approximately 8 hours.

Dose Range

1. The recommended adult dose, alone or in combination, is 150 mg orally twice daily (bid). It should be taken at least 1 hour before or 2 hours after food.
2. The recommended pediatric dose is adjusted by body weight and specified in the product information.

Drug Interactions

1. Drugs such as ketoconazole, itraconazole and erythromycin may reduce dabrafenib metabolism, increasing drug levels and potential toxicity.
2. Drugs such as rifampin and phenytoin may increase dabrafenib metabolism and reduce its efficacy.
3. Dabrafenib may increase warfarin's anticoagulant effect; PT and INR should be checked regularly.

Precautions

1. Because of the risk of skin cancer, skin examinations should be performed at baseline and every 2 months during treatment, continuing for up to 6 months after treatment ends.
2. Dabrafenib may cause febrile drug reactions, so body temperature should be monitored. If fever exceeds 38.5°C, the drug should be stopped and the risk of infection assessed.
3. Serum glucose should be monitored regularly in patients with diabetes or hyperglycemia.
4. Patients should undergo eye examinations for conditions such as uveitis and iritis because of the risk of ocular reactions.
5. The presence of a BRAF-V600E mutation should be confirmed using an FDA-approved diagnostic test before treatment begins.
6. No dose adjustment is needed in mild hepatic impairment. Caution is required in moderate or severe hepatic impairment.
7. No dose adjustment is needed in mild or moderate renal impairment, but caution is required in severe renal impairment.
8. Consumption of citrus fruits and their products, such as Seville oranges, grapefruit, pomelo and star fruit, should be avoided during treatment.
9. Dabrafenib may harm the fetus. Women of reproductive potential should use effective contraception during treatment and for a specified period after the last dose: at least 2 weeks when used alone and at least 4 months when combined with trametinib.

Side Effects

Side effects have been reported as follows, from most to least common:

• Skin cancers (squamous cell cancers and keratoacanthoma), generally appearing 6-8 weeks after treatment starts.
• Skin reactions, hyperkeratosis, hand-foot syndrome and rash.
• Fever.
• Hyperglycemia.
• Joint pain (arthralgia) and muscle pain (myalgia).
• Ophthalmologic adverse effects (uveitis, iritis, photophobia).
• Constipation.
• Fatigue.