On May 4, 2018, dabrafenib (Tafinlar) and trametinib (Mekinist) in combination was granted approval for treatment of patients with locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation and no satisfactory locoregional treatment options.1-3 Dabrafenib is not indicated for use in wild-type BRAF anaplastic thyroid cancer.
On April 30, 2018, dabrafenib and trametinib in combination was granted regular approval for adjuvant treatment of melanoma with BRAF V600E or V600K mutations, as detected by a U.S. Food and Drug Administration (FDA)-approved test, and involvement of lymph node(s) following complete resection.2-4
Supporting Efficacy Data
In Thyroid Cancer: Approval was based on the findings in the anaplastic thyroid cancer cohort included in an activity-estimating 9-cohort trial (BRF117019) in patients with rare cancers with the BRAF V600E mutation.2,3,5 Patients who had received prior treatment with BRAF or MEK inhibitors and those with symptomatic or untreated central nervous system metastases were excluded from the study. Among the 26 patients with anaplastic thyroid cancer enrolled, the median age was 70 years (range = 49–85 years); 50% were female; 50% were white and 46% were Asian; all had an Eastern Cooperative Oncology Group performance status of 0 or 1; 54% had a history of differentiated thyroid cancer; and prior treatments included surgery in 92%, external-beam radiotherapy in 81%, and systemic therapy in 54%.
Patients received dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily. The objective response rate as assessed by independent review committee among the 23 evaluable patients was 61%, including a complete response in 4%. The duration of response was ≥ 6 months in 64% of responders.
In Melanoma: Approval was based on relapse-free survival findings in the international double-blind phase III COMBI-AD trial, in which 870 patients with stage III melanoma with BRAF V600E or V600K mutations and pathologic involvement of regional lymph node(s) were randomized to receive dabrafenib at 150 mg twice daily in combination with trametinib at 2 mg once daily (n = 438) or placebos (n = 432) for up to 1 year.2,3,6 Overall, patients had a median age of 51 years (range = 18–89 years); 55% were male; 99% were white; 91% had an Eastern Cooperative Oncology Group performance status of 0; disease stage was IIIA in 18%, IIIB in 41%, and IIIC in 40%; 91% had BRAF V600E mutation and 9% had BRAF V600K mutation; 65% had macroscopic lymph nodes; and 41% had tumor ulceration.
The median duration of follow-up was 2.8 years. By data cutoff, relapse-free survival events had occurred in 38% of patients in the dabrafenib/trametinib group vs 57% in the placebo group; median relapse-free survival was not reached vs 16.6 months (hazard ratio = 0.47, P < .0001, stratified by disease stage and mutation type).
How They Work
Dabrafenib and trametinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination results in greater growth inhibition of BRAF V600–mutant tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600–mutant tumor xenografts compared with either drug alone.
Both dabrafenib and trametinib carry warnings and precautions for new primary malignancies, hemorrhage, cardiomyopathy, ocular toxicity, serious febrile reactions, serious skin toxicity, and hyperglycemia.
Dabrafenib inhibits some mutated forms of BRAF kinases, including BRAF V600E, BRAF V600K, and BRAF V600D enzymes, as well as wild-type BRAF and CRAF kinases and other kinases (eg, SIK1, NEK11, and LIMK1). Some mutations in BRAF, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases, which may stimulate tumor cell growth. Dabrafenib inhibits cell growth of various BRAF V600–mutant tumors in vitro and in vivo.
Trametinib is a reversible inhibitor of MEK1 and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the ERK pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway, which includes MEK1 and MEK2. Trametinib inhibits cell growth of various BRAF V600 mutation–positive tumors in vitro and in vivo.
How They Are Used
The recommended doses for the current indication are oral dabrafenib at 150 mg twice daily in combination with oral trametinib at 2 mg once daily until disease recurrence or unacceptable toxicity. The presence of BRAF V600E mutation in tumor specimens should be confirmed prior to initiation of therapy.
The dabrafenib dose can be reduced for adverse reactions incrementally to 100, 75, and 50 mg twice daily, with discontinuation if further dose reduction is required. Dabrafenib labeling provides specific instructions for dose modification, withholding of treatment, and treatment discontinuation for the following conditions: new primary noncutaneous RAS mutation–positive malignancies; symptomatic congestive heart failure and absolute decrease in left-ventricular ejection fraction (LVEF) > 20% from baseline that is below the lower limit of normal (LLN); uveitis including iritis and iridocyclitis; febrile drug reactions; intolerable grade 2 and 3 or 4 dermatologic adverse reactions; and any intolerable grade 2, any grade 3, and first occurrence of and recurrent grade 4 adverse reactions.
Dose modifications are not recommended for dabrafenib when administered with trametinib for the following adverse reactions associated with trametinib: retinal vein occlusion, retinal pigment epithelial detachment, interstitial lung disease/pneumonitis, and uncomplicated venous thromboembolism. Dose modification of dabrafenib is not required for new primary cutaneous malignancies.
The trametinib dose can be reduced incrementally to 1.5 and 1 mg daily, with discontinuation if further dose reduction is required. Trametinib labeling provides specific instructions for dose modification, withholding of treatment, and treatment discontinuation for the following conditions: uncomplicated deep vein thrombosis or pulmonary embolism and life-threatening pulmonary embolism; asymptomatic, absolute decrease in LVEF of ≥ 10% from baseline and below LLN, symptomatic congestive heart failure, and absolute decrease in LVEF of > 20% from baseline that is below LLN; retinal pigment epithelial detachment and retinal vein occlusion; interstitial lung disease/pneumonitis; febrile drug reactions; intolerable grade 2 and grade 3 or 4 dermatologic adverse reactions; and any intolerable grade 2, any grade 3, and first occurrence of and recurrent grade 4 adverse reactions.
Dose modifications are not recommended for trametinib when administered with dabrafenib for the following adverse reactions associated with dabrafenib: noncutaneous malignancies and uveitis. Dose modification of trametinib is not required for new primary cutaneous malignancies.
Safety analysis included 100 patients in the BRF117019 trial (including 16 in the anaplastic thyroid cancer cohort); of them, 46% were exposed to dabrafenib plus trametinib for > 6 months and 23% were exposed to the combination for ≥ 1 year. The adverse-event profile among all patients in the trial and in the anaplastic thyroid cancer cohort was similar to that in other approved indications.
The most common adverse events (≥ 20% of patients) for dabrafenib, in combination with trametinib, include the following by indication—unresectable or metastatic melanoma: pyrexia, rash, chills, headache, arthralgia, and cough; adjuvant treatment of melanoma: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia; non–small cell lung cancer (NSCLC): pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.
The most common adverse events (≥ 20% of patients ) for trametinib, in combination with dabrafenib, include the following by indication—unresectable or metastatic melanoma: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema; adjuvant treatment of melanoma: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia; NSCLC: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
In the COMBI-AD trial in melanoma, adverse events resulted in discontinuation, dose reduction, and dose interruption of dabrafenib in 25%, 35%, and 66% of patients, respectively, with the most common reasons for each being pyrexia and chills. Adverse events resulted in discontinuation and dose interruption of trametinib in 24% and 54% of patients, respectively, with the most common reasons for both being pyrexia and chills; adverse events led to dose reduction of trametinib in 23% of patients, with the most common reasons being pyrexia and decreased ejection fraction.
Dabrafenib carries warnings/precautions for new primary malignancies, cutaneous and noncutaneous (can occur with dabrafenib alone or combined with trametinib); tumor promotion in BRAF wild-type tumors; hemorrhage (major events can occur with combination treatment); cardiomyopathy; uveitis; serious febrile reactions (incidence and severity increased with combination treatment); serious skin toxicity; hyperglycemia; glucose-6-phosphate dehydrogenase deficiency; risks associated with combined dabrafenib/trametinib treatment; and embryofetal toxicity.
Trametinib carries warnings/precautions for new primary malignancies, cutaneous and noncutaneous (can occur when trametinib is used with dabrafenib); hemorrhage (major hemorrhagic events can occur); colitis and gastrointestinal perforation; venous thromboembolism; cardiomyopathy; ocular toxicities; interstitial lung disease; serious febrile reactions (can occur with combination treatment); serious skin toxicity; hyperglycemia; risks associated with combined dabrafenib/trametinib treatment; and embryofetal toxicity.
Patients receiving the combination should be monitored for new malignancies prior to and during therapy as well as after discontinuation of treatment. LVEF should be assessed before combination treatment, after 1 month of treatment, and then every 2 to 3 months thereafter. Ophthalmologic evaluation should be performed for any visual disturbances. Serum glucose levels should be monitored in patients with preexisting diabetes or hyperglycemia. Patients should be closely monitored for hemolytic anemia. ■
1. U.S. Food and Drug Administration: FDA approves dabrafenib plus trametinib for anaplastic thyroid cancer with BRAF V600E mutation. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm606708.htm. Accessed May 22, 2018.
2. Tafinlar (dabrafenib) capsules prescribing information, Novartis Pharmaceuticals Corp, May 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/202806s010lbl.pdf. Accessed May 22, 2018.
3. Mekinist (trametinib) tablets prescribing information, Novartis Pharmaceuticals Corp, May 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/204114s009lbl.pdf. Accessed May 22, 2018.
4. U.S. Food and Drug Administration: FDA approves dabrafenib plus trametinib for adjuvant treatment of melanoma with BRAF V600E or V600K mutations. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm606165.htm. Accessed May 22, 2018.
5. 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 36:7-13, 2018.
6. Long GV, Hauschild A, Santinami M, et al: Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 377:1813-1823, 2017.