Dabrafenib and Trametinib in BRAF V600E–Mutant Metastatic NSCLC


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On June 22, 2017, regular approvals were granted to dabrafenib (Tafinlar) and trametinib (Mekinist) given in combination for the treatment of patients with metastatic non–small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by a U.S. Food and Drug Administration (FDA)-approved test.1-3 These approvals are the first specifically for treatment of patients with BRAF V600E–mutant metastatic NSCLC.

The FDA also approved the Oncomine Dx Target Test, a next-generation sequencing test for detecting multiple gene mutations for lung cancer in a single test from a single tissue specimen. The test detects the presence of BRAF, ROS1, and EGFR mutations or alterations in NSCLC tumor tissue. This test can be used to select patients with NSCLC with the BRAF V600E mutation for treatment with the combination of dabrafenib and trametinib. This is the first next-generation sequencing oncology panel test approved for multiple companion diagnostic indications.

Supporting Efficacy Data

The approvals are based on the finding of durable responses in a three-cohort nonrandomized study. Patients in cohorts A (n = 78) and B (n = 57) had to have received at least one previous platinum-based regimen for NSCLC with demonstrated disease progression but no more than three prior systemic regimens, and patients in cohort C (n = 36) had received no prior systemic treatment for metastatic disease. Patients in cohort A received dabrafenib at 150 mg twice daily alone; patients in cohorts B and C (n = 93) received dabrafenib plus trametinib at 2 mg once daily.

OF NOTE

Dabrafenib and trametinib carry warnings/precautions for new primary malignancies, hemorrhage, cardiomyopathy, ocular toxicity, serious febrile reactions, serious skin toxicity, hyperglycemia, and embryofetal toxicity.

Among the 93 patients receiving the combination, the median age was 65 years (range = 41–91 years); 54% were female; 85% were white; 93% had an Eastern Cooperative Oncology Group performance status of 0 or 1; 98% had nonsquamous histology; and 12% were current smokers, 60% were former smokers, and 28% were never smokers.

Objective response rates on independent review in patients receiving the combination were 63% in the previously treated group, including a complete response in 4%, and 61% in the treatment-naive group, including a complete response in 3%. The median duration of response was 2.6 months in the previously treated group and not estimable in the treatment-naive group, with 64% and 59% having a response ≥ 6 months, respectively. The response rate in patients receiving single-agent dabrafenib was 27%, with a median response duration of 9.9 months.

How It Works

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.

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 resulting in BRAF V600E, can result in constitutively activated BRAF kinases that 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 It Is Used

Recommended doses for the current indication are dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily, with treatment continuing until disease progression or unacceptable toxicity. The presence of BRAF V600E mutation in tumor specimens should be confirmed by an FDA-approved test prior to initiation of therapy.

Dose modifications are not recommended for dabrafenib for the following adverse reactions associated with trametinib: retinal vein occlusion, retinal pigment epithelial detachment, interstitial lung disease/pneumonitis, and uncomplicated venous thromboembolism. Dose modifications are not recommended for trametinib for the following adverse reactions associated with dabrafenib: noncutaneous malignancies and uveitis.

Combination Therapy for BRAF V600E–Mutant Metastatic Lung Cancer

  • Regular approvals were granted to dabrafenib (Tafinlar) and trametinib (Mekinist) given in combination for the treatment of patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test.
  • The recommended doses for the current indication are dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily, with treatment continuing until disease progression or unacceptable toxicity.

The dabrafenib dose can be reduced incrementally to 100, 75, and 50 mg twice daily, with treatment discontinuation if a further dose reduction is required. No dose modification is required for new primary cutaneous malignancies. Treatment should be discontinued in patients who develop RAS mutation–positive noncutaneous malignancies. Dabrafenib labeling provides instructions for dosing modification or treatment discontinuation for fever of 101.3°F to 104°F; fever higher than 104°F; fever complicated by rigors, hypotension, dehydration, or renal failure; intolerable grade 2 skin toxicity; grade 3 or 4 skin toxicity; symptomatic congestive heart failure; an absolute decrease in left ventricular ejection fraction (LVEF) of greater than 20% from baseline that is below the lower limit of normal; uveitis including iritis and iridocyclitis; intolerable grade 2 adverse reactions; any grade 3 adverse reactions; and the first occurrence of any grade 4 adverse reaction and recurrent grade 4 adverse reactions.

The trametinib dose can be reduced incrementally to 1.5 and 1 mg daily, with treatment discontinuation if a further dose reduction is required. No dose modification is required for new cutaneous malignancies. Trametinib labeling provides instructions for dosing modification or treatment discontinuation for fever higher than 104°F; fever complicated by rigors, hypotension, dehydration, or renal failure; intolerable grade 2 skin toxicity; grade 3 or 4 skin toxicity; an asymptomatic, absolute decrease in LVEF of 10% or greater from baseline that is below the lower limit of normal; symptomatic congestive heart failure; an absolute decrease in LVEF of > 20% from baseline that is below the lower limit of normal; uncomplicated deep vein thrombosis or pulmonary embolism; life threatening pulmonary embolism; retinal pigment epithelial detachment; retinal vein occlusion; interstitial lung disease/pneumonitis; intolerable grade 2 adverse reactions; any grade 3 adverse reactions; and the first occurrence of any grade 4 adverse reaction and recurrent grade 4 adverse reactions.

Safety Profile

Among the 93 patients receiving combination treatment, the most common adverse events of any grade were pyrexia (55%), fatigue (51%), nausea (45%), vomiting (33%), diarrhea (32%), dry skin (31%), decreased appetite (29%), edema (28%), rash (28%), chills (23%), hemorrhage (23%), cough (22%), and dyspnea (20%). The most common grade 3 or 4 adverse events were pyrexia and fatigue (5% each) and hemorrhage, rash, and vomiting (3.2% each). The most common grade 3 or 4 laboratory abnormalities were hyponatremia (17%), lymphopenia (14%), and anemia (10%).

Adverse events led to dabrafenib dose reduction in 35% of patients, most commonly due to pyrexia (10%), and to dose interruption in 62%, most commonly due to pyrexia (27%) and vomiting (11%). Adverse events led to treatment discontinuation in 18%, most commonly due to pyrexia, decreased ejection fraction, and respiratory distress (2.2% each).

Adverse events led to trametinib dose reduction in 30% of patients, most commonly due to pyrexia (5%), and to dose interruption in 57%, most commonly due to pyrexia (16%) and vomiting (10%). Adverse events led to treatment discontinuation in 19%, most commonly due to pyrexia, decreased ejection fraction, and respiratory distress (2.2% each).

OF NOTE

The recommended doses for the treatment of patients with metastatic NSCLC with BRAFV600E mutaion are dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily, with treatment continuing until disease progression or unacceptable toxicity.

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; 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 (eg, deep vein thrombosis and pulmonary embolism); cardiomyopathy; ocular toxicities; interstitial lung disease; serious febrile reactions (can occur with combination treatment); serious skin toxicity; hyperglycemia; and embryofetal toxicity.

Patients receiving combination treatment should be monitored for new malignancies prior to initiation of therapy, while on therapy, and following discontinuation of treatment; signs/symptoms of bleeding; skin toxicities and secondary infections; and hemolytic anemia. LVEF should be assessed before treatment, at 1 month, and every 2 to 3 months thereafter. Ophthalmologic evaluation should be performed for any visual disturbances. Serum glucose levels should be monitored in patients with diabetes or hyperglycemia. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564331.htm. Accessed November 7, 2017.

2. Tafinlar (dabrafenib) capsules prescribing information, Novartis Pharmaceuticals Corporation, June 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202806s006lbl.pdf. Accessed November 7, 2017.

3. Mekinist (trametinib) tablets prescribing information, Novartis Pharmaceuticals Corporation, June 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204114s005lbl.pdf. Accessed November 7, 2017.


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