Mekinist

• Mekinist^®

Contraindications

None

Cautions

New primary malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combination with dabrafenib, and with dabrafenib as a single agent

Hemorrhage, including major hemorrhages, can occur when used in combination with dabrafenib

Venous thromboembolism can occur when used in combination with dabrafenib

Risk of cardiomyopathy when used as a single agent or with dabrafenib; reassess LVEF after 1 month of treatment and then ~ every 2-3 months thereafter

Risk for retinal pigment epithelial detachment (rare); monitor for visual disturbances

Retinal vein occlusion reported; urgently (within 24 hr) perform ophthalmology evaluation for patient-reported vision loss

Interstitial lung disease reported; withhold dose for patients with symptoms (eg, cough, dyspnea, hypoxia, pleural effusion, or infiltrates)

Risk of serious skin toxicity including rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema

Colitis and gastrointestinal perforation can occur; monitor patients closely for colitis and gastrointestinal perforations

Caution with moderate-to-severe hepatic impairment

Serious febrile reactions can occur when trametinib is used in combination with dabrafenib and with dabrafenib as a single agent

Hyperglycemia can occur when trametinib is used in combination with dabrafenib and with dabrafenib as a single agent

Based on its mechanism of action, can cause fetal harm; advise females of reproductive potential of potential risk to a fetus; women with reproductive potential should use highly effective birth control during and at least 4 months following treatment

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using trametinib and call your doctor at once if you have:

• fever, severe diarrhea;
• dry cough, wheezing, feeling short of breath;
• eye pain or swelling, vision changes, seeing halos around lights, seeing color "dots" in your vision;
• severe skin rash, skin pain, redness or warmth, redness and peeling skin on your hands or feet;
• high blood sugar--increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, weight loss;
• dangerously high blood pressure--severe headache, blurred vision, pounding in your neck or ears, nosebleed, anxiety, confusion, severe chest pain, shortness of breath, irregular heartbeats, seizure;
• signs of bleeding (more likely when taking trametinib and dabrafenib together)--weakness, dizziness, headache, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;
• signs of a blood clot (more likely when taking trametinib and dabrafenib together)--chest pain, sudden cough or trouble breathing, pain or swelling in an arm or leg, pale skin or cold feeling in an arm or leg; or
• signs of a heart problem (more likely when taking trametinib and dabrafenib together)--shortness of breath (even with mild exertion), pounding heartbeats, swelling in your feet or ankles.

Common side effects may include:

• diarrhea;
• nausea, vomiting;
• increased blood pressure;
• fever, chills, swollen glands;
• swelling; or
• rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• GlaxoSmithKline LLC

Before you take Mekinist, tell your healthcare provider if you:

• are allergic to Mekinist or to any of its ingredients. 
• have heart problems
• have lung or breathing problems
• have eye problems
• have high blood pressure (hypertension)
• have liver or kidney problems
• have any other medical conditions
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category D. Mekinist can harm your unborn baby. Women who may become pregnant should use effective birth control (contraception) during treatment with Mekinist and for 4 months after stopping treatment. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant during treatment with Mekinist.

Your doctor will perform blood tests to make sure you have the correct tumor type to be treated with trametinib.

Trametinib is usually taken once daily. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take trametinib on an empty stomach, at least 1 hour before or 2 hours after a meal.

Take the medicine at the same time each day.

Your doctor will need to check your skin on a regular basis while you are using trametinib.

Your blood pressure will need to be checked often. Your heart function may need to be checked with an electrocardiograph or ECG (sometimes called an EKG) every 2 or 3 months during your treatment. You may also need regular vision examinations while taking trametinib.

Store in the refrigerator and protect from light. Do not freeze. Keep the tablets in their original container, along with the packet or canister of moisture-absorbing preservative. Do not store trametinib tablets in a pill box.

Formal drug interaction studies not conducted.1

CYP3A4 inducer and CYP2C8 inhibitor in vitro.1

Not a substrate for CYP isoenzymes, P-glycoprotein (P-gp), or breast cancer resistance protein (BCRP).1

Not an inhibitor of CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4.1

Not an inhibitor of organic anion transporter polypeptides (OATP) 1B1 or 1B3, P-gp, or BCRP.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Potential pharmacokinetic interaction (decreased concentrations of substrate drug).1

Substrates of CYP2C8: Potential pharmacokinetic interaction (increased concentrations of substrate drug).1

Specific Drugs

      Patient Selection

Melanoma

Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with Mekinist and dabrafenib [see Clinical Studies (14.1)]. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

NSCLC

Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with Mekinist and dabrafenib [see Clinical Studies (14.2)]. Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

      Recommended Dosing

The recommended dosage regimen is Mekinist 2 mg orally taken once daily at the same time each day as a single agent or with dabrafenib. Continue treatment until disease progression or unacceptable toxicity occurs. 

Take Mekinist at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)]. Do not take a missed dose of Mekinist within 12 hours of the next dose of Mekinist.

      Dose Modifications

Review the Full Prescribing Information for dabrafenib for recommended dose modifications. Dose modifications are not recommended for Mekinist when administered with dabrafenib for the following adverse reactions of dabrafenib: non-cutaneous malignancies and uveitis.

For New Primary Cutaneous Malignancies

No dose modifications are required.

a       National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

b       See Table 1 for recommended dose reductions of Mekinist.

      BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma 

Mekinist as a Single Agent  

The safety and efficacy of Mekinist were evaluated in an international, multicenter, randomized (2:1), open-label, active-controlled trial (the METRIC study; NCT01245062) in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma.

In the METRIC study, patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. The primary efficacy outcome measure was progression-free survival (PFS). Patients were randomized to receive Mekinist 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1,000 mg/m2 intravenously every 3 weeks or paclitaxel 175 mg/m2 intravenously every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes versus no) and lactate dehydrogenase level (normal versus greater than upper limit of normal). Tumor tissue was evaluated for BRAF mutations at a central testing site using a clinical trial assay. Tumor samples from 289 patients (196 patients treated with Mekinist and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID™-BRAF assay.

The median age for randomized patients was 54 years, 54% were male, greater than 99% were White, and all patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were Stage M1c (64%), had elevated LDH (36%), had no history of brain metastasis (97%), and received no prior chemotherapy for advanced or metastatic disease (66%). The distribution of BRAF V600 mutations was BRAF V600E (87%), V600K (12%), or both (less than 1%). The median durations of follow-up prior to initiation of alternative treatment were 4.9 months for patients treated with Mekinist and 3.1 months for patients treated with chemotherapy. Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease progression to receive Mekinist.

The METRIC study demonstrated a statistically significant increase in progression-free survival in the patients treated with Mekinist. Table 9 and Figure 1 summarize the PFS results.

†       CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached.

a       Pike estimator.

Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival (ITT Population) in the METRIC Study

In supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results were consistent with those of the primary efficacy analysis.

Mekinist with Dabrafenib

The safety and efficacy of Mekinist administered with dabrafenib were evaluated in an international, randomized, double-blind, active-controlled trial (the COMBI-d study; NCT01584648). The COMBI-d study compared dabrafenib plus Mekinist to dabrafenib plus placebo as first-line treatment for patients with unresectable (Stage IIIc) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive Mekinist 2 mg once daily plus dabrafenib 150 mg twice daily or dabrafenib 150 mg twice daily plus matching placebo. Randomization was stratified by lactate dehydrogenase (LDH) level (greater than the upper limit of normal (ULN) vs. ≤ ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR).

In the COMBI-d study, 423 patients were randomized to Mekinist plus dabrafenib (n = 211) or dabrafenib plus placebo (n = 212). The median age was 56 years (range: 22 to 89 years), 53% were male, >99% were White, 72% had ECOG performance status of 0, 4% had Stage IIIc, 66% had M1c disease, 65% had a normal LDH, and 2 patients had a history of brain metastases. All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing with the FDA-approved companion diagnostic test; 85% had BRAF V600E mutation-positive melanoma and 15% had BRAF V600K mutation-positive melanoma. 

The COMBI-d study demonstrated statistically significant improvements in PFS and OS (see Table 10 and Figure 2).

†       CI = Confidence interval; HR = Hazard ratio; CR = Complete response; PR = Partial response; NR = Not reached.

a       PFS and ORR were assessed by investigator.

b       Based on stratified log-rank test.

Figure 2. Kaplan Meier Curves of Overall Survival in the COMBI-d Study

      BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) 

In Study BRF113928 (NCT01336634), the safety and efficacy of dabrafenib alone or administered with Mekinist were evaluated in a multicenter, three-cohort, non-randomized, activity-estimating, open-label trial. Key eligibility criteria were locally confirmed BRAF V600E mutation-positive metastatic NSCLC, no prior exposure to BRAF or MEK inhibitor, and absence of EGFR mutation or ALK rearrangement (unless patients had progression on prior tyrosine kinase inhibitor therapy). Patients enrolled in Cohorts A and B were required to have received at least one previous platinum-based chemotherapy regimen with demonstrated disease progression but no more than three prior systemic regimens. Patients in Cohort C could not have received prior systemic therapy for metastatic disease. Patients in Cohort A received dabrafenib 150 mg twice daily. Patients in Cohorts B and C received Mekinist 2 mg once daily and dabrafenib 150 mg twice daily. The major efficacy outcome was overall response rate (ORR) per RECIST v1.1 as assessed by independent review committee (IRC) and duration of response.

There were a total of 171 patients enrolled, which included 78 patients enrolled in Cohort A, 57 patients enrolled in Cohort B, and 36 patients enrolled in Cohort C. The characteristics of the population were: a median age of 66 years; 48% male; 81% White, 14% Asian, 3% Black and 2% Hispanic; 60% former smokers, 32% never smokers, and 8% current smokers; 27% had ECOG performance status (PS) of 0, 63% had ECOG PS of 1, and 11% had ECOG PS of 2; 99% had metastatic disease of which 6% had brain metastasis at baseline and 14% had liver metastasis at baseline; 11% had systemic anti-cancer therapy in the adjuvant setting, 58% of the 135 previously treated patients had only one line of prior systemic therapy for metastatic disease; 98% had non-squamous histology.

Efficacy results are summarized in Table 11.

Table 11. Efficacy Results Based on Independent Review in Study BRF113928

aConfidence interval

bNot estimable

In a subgroup analysis of patients with retrospectively centrally confirmed BRAF V600E mutation-positive NSCLC with the Oncomine™ Dx Target Test, the ORR results were similar to those presented in Table 11.

      Lack of Clinical Activity in Metastatic Melanoma Following BRAF-Inhibitor Therapy

The clinical activity of Mekinist as a single agent was evaluated in a single-arm, multicenter, international trial in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor. All patients received Mekinist at a dose of 2 mg orally once daily until disease progression or unacceptable toxicity.

The median age was 58 years, 63% were male, all were White, 98% had baseline ECOG PS of 0 or 1, and the distribution of BRAF V600 mutations was V600E (83%), V600K (10%), and the remaining patients had multiple V600 mutations (5%), or unknown mutational status (2%). No patient achieved a confirmed partial or complete response as determined by the clinical investigators.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Other drugs may interact with trametinib, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

Trametinib is embryotoxic and abortifacient in rabbits at exposures 0.3 times the human clinical exposure at the recommended dose. There are no controlled data in human pregnancy. FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Trametinib can cause fetal harm. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. FDA pregnancy category: D Comments: Female patients of reproductive potential should use a highly effective method of contraception during treatment and for 4 months after treatment.