May 4, 2018–Dabrafenib (TAFINLAR®, Novartis Pharmaceuticals Corp.) and trametinib (MEKINIST®, Novartis Pharmaceuticals Corp.) in combination for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options. (With Pharmacist's Applications to Practice)
April 30, 2018–Dabrafenib (TAFINLAR®, Novartis Pharmaceuticals Corp.) and Trametinib (MEKINIST®, Novartis Pharmaceuticals Corp.) in combination for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.
May 4, 2018, with PAP
On May 4, 2018, the Food and Drug Administration approved dabrafenib (TAFINLAR®, Novartis Pharmaceuticals Corp.) and trametinib (MEKINIST®, Novartis Pharmaceuticals Corp.) in combination for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options.
Approval was based on a nine-cohort, non-randomized trial, BRF117019 (NCT02034110) enrolling patients with rare cancers with the BRAF V600E mutation, including locally advanced, unresectable, or metastatic ATC with no locoregional treatment options. The overall response rate was 61% (95% CI: 39%, 80%) in 23 patients with ATC who were evaluable for response. The complete and partial response rates were 4% and 57%, respectively. Response duration was at least 6 months in 64% of responding patients.
The adverse reaction profile among all patients in the trial and among patients in the ATC cohort was similar to that observed in other approved indications.
The recommended doses for ATC are 150 mg of dabrafenib orally twice daily and 2 mg of trametinib orally once daily. Full prescribing information is available at:
FDA granted this application priority review. FDA also granted breakthrough designation and orphan drug designation for the combination of dabrafenib and trametinib in the anaplastic thyroid cancer with BRAF V600 mutation indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
Pharmacist’s Applications to Practice
Dabrafenib and Trametinib for the Treatment of Patients with Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer
Author: Catherine Gawronski, PharmD
PGY-1 Pharmacy Resident
Vanderbilt University Medical Center
What is the potential role for dabrafenib and trametinib in the treatment of B-Raf kinase (BRAF) V600-mutant anaplastic thyroid cancer (ATC)?
- Dabrafenib is an inhibitor of mutated BRAF kinases and wild-type BRAF and C-Raf (CRAF) kinases.1 Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and MEK1 and MEK2 kinase activity.2
- The lifetime risk of being diagnosed with thyroid cancer is 1.2% in the United States. ATC is a rare thyroid cancer that constitutes 1%-2% of all thyroid cancers. The BRAF V600 mutation is present in 20%–50% of ATCs. Tumors with the BRAF mutation have increased tumorgenicity. The combination of a BRAF and MEK inhibitor has been shown to delay or prevent drug resistance pathways compared to a BRAF inhibitor alone.3,4
- On May 4, 2018, dabrafenib and trametinib in combination were approved by the U.S. Food and Drug Administration for treating locally advanced or metastatic ATC with BRAF V600E mutation and no satisfactory locoregional treatment options based on the results of the BRF117019 trial. Breakthrough and orphan drug designations were also granted for this combination in ATC with BRAF V600 mutation.5
- BRF117019 was a phase 2 open-label trial that evaluated the safety and efficacy of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) in nine cohorts with BRAF V600E-mutated rare malignancies. Patients with ATC (N = 16) were included if they were BRAF or MEK treatment naive, had an Eastern Cooperative Oncology Group performance status of 0–2, and had not been treated with radiotherapy within 7 days of enrollment. Patients in which cure by surgical excision was possible and those who did not receive standard-of-care treatment were also excluded from this study. The primary end point was overall response rate, and secondary end points included duration of response, progression-free survival, overall survival, and safety. At an interim analysis of data available as of August 26, 2016, the overall response rate was 69% (complete response [n = 1] plus partial response [n = 10]) in the intent-to-treat population. Response was durable in 7 of the 11 patients, with response continuing at the time of cutoff. Because of this, median duration of response, progression-free survival, and overall survival were not reached but were estimated to be 90%, 79%, and 80%, respectively, at 12 months. The most common adverse events in the ATC cohort were fatigue (all grades, 44%), pyrexia (all grades, 31%), nausea (all grades, 31%), hyperglycemia (all grades, 31%), chills (all grades, 25%), vomiting (all grades, 25%), diarrhea (all grades, 25%), anemia (all grades, 25%), rash (all grades, 25%), and constipation (25%). The most common grade 3–4 adverse event was anemia (13%).3
- The National Comprehensive Cancer Network (NCCN) recognizes the combination of dabrafenib and trametinib as a category 2A recommendation for systemic therapy for treatment of locally advanced or metastatic ATC with BRAF V600E mutation based on the results of the BRF117019 trial. This is the first BRAF/MEK combination approved for this indication. Other therapies recommended by the NCCN in this setting include paclitaxel/carboplatin, docetaxel/doxorubicin, paclitaxel monotherapy, and doxorubicin monotherapy.4
What role can the pharmacist play in the management of patients on dabrafenib and trametinib?
- Dabrafenib is dosed 150 mg by mouth twice daily in combination with trametinib 2 mg by mouth once daily. Both medications should be taken at least 1 hour before or 2 hours after a meal.1,2
- No dose modifications are identified for hepatic or renal impairment for either medication.1,2
- Dose modifications or interruptions of dabrafenib are recommended for new primary malignancies, cardiac toxicities, uveitis, febrile drug reactions, dermatologic toxicities, intolerable grade-2 reactions, and any grade-3-or-higher reaction.1
- First dose reduction is to 100 mg by mouth twice daily.
- Second dose reduction is to 75 mg by mouth twice daily.
- Third dose reduction is to 50 mg by mouth twice daily.
- Dabrafenib should be discontinued if further modifications are required.
- Dose modifications or interruptions of trametinib are recommended for venous thromboembolism, cardiac toxicities, ocular toxicities, pulmonary toxicities, febrile drug reactions, dermatologic toxicities, intolerable grade-2 reactions, and any grade-3-or higher reaction.2
- First dose reduction is to 1.5 mg by mouth once daily.
- Second dose reduction is to 1 mg by mouth once daily.
- Trametinib should be discontinued if further modifications are required.
- Dabrafenib is metabolized by cytochrome P450 2C8 (CYP2C8) and CYP3A4 enzymes. Strong inhibitors of CYP2C8 or CYP3A4 may increase concentrations and should be substituted during treatment. If dabrafenib is to be used with a strong inhibitor, then patients should be monitored for adverse reactions.1
- Trametinib has not been evaluated for CYP enzyme–mediated interactions. The package insert recommends following labeling information that applies to dabrafenib treatment, because they are used in combination.2
- The Novartis Oncology Universal Co-Pay Program allows patients to pay no more than $25/month and will pay the remaining co-pay, up to $15,000/year. Medicare, Medicaid, and other patients insured through federal or state programs are ineligible.6
- Dabrafenib is supplied as a 50-mg or 75-mg capsule stored at room temperature.1 Trametinib is supplied as a 0.5-mg or 2-mg tablet stored at a refrigerated temperature and should be kept in the original bottle.2
- Other indications for this combination include unresectable or metastatic melanoma with BRAF V600E or V600K mutation, adjuvant treatment in patients with melanoma with BRAF V600E or V600K mutation and involvement of lymph node(s) following resection, and metastatic non-small-cell lung cancer with BRAF V600E mutation. Dosing is consistent across all indications.1,2
- The adverse events observed in ATC patients receiving dabrafenib and trametinib were similar to adverse events seen with other indications.1,2
- Left ventricular ejection fraction (LVEF) should be monitored by echocardiogram or multigated acquisition (MUGA) scan before initiation of dabrafenib and trametinib, 1 month after initiation, and then at 2- or 3-month intervals.1,2 Electrocardiograms should be used to monitor for prolonged QTc, particularly if dabrafenib and trametinib are used in combination with other drugs that may cause QTc prolongation.
- Cutaneous squamous cell carcinomas occur with single-agent dabrafenib but are seen less commonly when dabrafenib is used in combination with trametinib.1,2
- After a febrile reaction, antipyretics may be administered for secondary prophylaxis upon the resumption of dabrafenib and trametinib. For a second or subsequent febrile reaction, corticosteroids should be given for at least 5 days if the patient’s temperature does not return to baseline within 3 days of onset of pyrexia or for fever associated with noninfectious complications.1,2
- Dabrafenib carries a risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency because of a sulfonamide moiety in the drug structure.1
- Tafinlar (dabrafenib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018.
- Mekinist (trametinib) [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; 2018.
- Subbiah V, Kreitman RJ, Wainberg ZA, 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.
- National Comprehensive Cancer Network. Thyroid Carcinoma (Version 1.2018). Available at https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Accessed August 27, 2018.
- U.S. Food and Drug Administration. FDA Hematology/Oncology (Cancer) Approvals and Safety Notifications. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Accessed August 27, 2018.
- Universal Co-pay Card. Available at https://www.copay.novartisoncology.com. Accessed August 30, 2018.
April 30, 2018
On April 30, 2018, the Food and Drug Administration granted regular approval to dabrafenib (TAFINLAR®, Novartis Pharmaceuticals Corp.) and trametinib (MEKINIST®, Novartis Pharmaceuticals Corp.) in combination for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.
Approval was based on COMBI-AD (NCT01682083), an international, multi-center, randomized, double-blind, placebo-controlled trial in 870 patients with Stage III melanoma with BRAF V600E or V600K mutations, and pathologic involvement of regional lymph node(s). Patients were randomly allocated (1:1) to receive dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily or two placebos for up to 1 year.
The major efficacy outcome was relapse-free survival (RFS). RFS was defined as the time from randomization to disease recurrence (local, regional, or distant metastasis), new primary melanoma, or death from any cause, whichever occurred first as assessed by the investigator. Patients who received the combination treatment had a statistically significant improvement in RFS compared with those receiving placebo. Patients in the combination arm experienced fewer recurrences/deaths at the time of data-cutoff: 38% (n=166), compared with 57% (n=248) in the placebo arm (hazard ratio 0.47; 95% confidence interval 0.39, 0.58; p<0.0001). The estimated median RFS was not reached for patients who received the combination therapy, compared with 16.6 months (95% CI: 12.7, 22.1) for those receiving placebo.
The most common adverse reactions in at least 20% of patients receiving the combination in the COMBI-AD trial were pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. Adverse reactions resulting in discontinuation, dose reduction, or dose interruption of dabrafenib occurred in 25%, 35%, and 66% of patients, respectively; the most common for each were pyrexia and chills. Adverse reactions resulting in discontinuation and dose interruption of trametinib occurred in 24% and 54% of patients respectively; the most common for each were pyrexia and chills. Adverse reactions leading to dose reduction of trametinib occurred in 23% of patients; the most common were pyrexia and decreased ejection fraction.
The recommended doses for the adjuvant treatment of melanoma are 150 mg of dabrafenib orally twice daily and 2 mg of trametinib orally once daily until disease recurrence or unacceptable toxicity, for up to one year.
Full prescribing information is available at:
Dabrafenib PI: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202806s008lbl.pdf
Trametinib PI: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204114s007lbl.pdf
FDA granted this application priority review. Dabrafenib in combination with trametinib was granted breakthrough therapy designation and orphan drug designation for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).