Mekinist Drug Information
Generic name: TRAMETINIB
Uses of Mekinist
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma MEKINIST ® is indicated, as a single agent in BRAF-inhibitor treatment-naïve patients or in combination with dabrafenib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.
Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma MEKINIST is indicated, in combination with dabrafenib, 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.
BRAF V600E Mutation-Positive Metastatic NSCLC MEKINIST is indicated, in combination with dabrafenib, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.
BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer MEKINIST is indicated, in combination with dabrafenib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation, as detected by an FDA-approved test, and with no satisfactory locoregional treatment options.
BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors MEKINIST is indicated, in combination with dabrafenib, for the treatment of adult and pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
BRAF V600E Mutation-Positive Low-Grade Glioma MEKINIST is indicated, in combination with dabrafenib, for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.
Limitations of Use MEKINIST is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition.
Dosage & Administration of Mekinist
Patient Selection Melanoma Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST as a single agent or in combination with dabrafenib. 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.
An FDA-approved test for the detection of BRAF V600E mutation in solid tumors other than melanoma and NSCLC is not currently available.
Recommended Dosage MEKINIST Tablets Adult Patients
The recommended dosage for MEKINIST tablets in adult patients is 2 mg orally taken once daily. Pediatric Patients The recommended dosage for MEKINIST tablets in pediatric patients who weigh at least 26 kg is based on body weight (Table 1). A recommended dosage of MEKINIST tablets has not been established in patients who weigh less than 26 kg.
Table 1. Recommended Dosage for MEKINIST Tablets in Pediatric Patients (Weight-based) MEKINIST for Oral Solution Adult and Pediatric Patients The recommended dosage for MEKINIST for oral solution for adult and pediatric patients is based on body weight (Table 2). Table 2.
Recommended Dosage for MEKINIST for Oral Solution in Adult and Pediatric Patients (Weight-based) Duration of Treatment The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity. The recommended duration of treatment in the adjuvant melanoma setting is until disease recurrence or unacceptable toxicity for up to 1 year. Combination Therapy with Dabrafenib Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information.
Administration Take MEKINIST at the same time each day, approximately 24 hours apart. Do not take a missed dose of MEKINIST within 12 hours of the next dose of MEKINIST. If vomiting occurs after MEKINIST administration, do not take an additional dose.
Take the next dose at its scheduled time. MEKINIST Tablets Take MEKINIST tablets on an empty stomach (at least 1 hour before or 2 hours after a meal). Do not crush or break MEKINIST tablets.
MEKINIST for Oral Solution MEKINIST powder for oral solution must be reconstituted by a pharmacist or other healthcare provider prior to dispensing to the patient. MEKINIST for oral solution is intended for administration by a caregiver. Prior to use of the oral solution, ensure caregivers receive training on proper dosing and administration of MEKINIST for oral solution.
When administering MEKINIST for oral solution as a single agent, take the oral solution with a low-fat meal or on an empty stomach. Breastfeeding and/or baby formula may be given on demand if a pediatric patient is unable to tolerate the fasting conditions. Preparation and Administration To prepare MEKINIST for oral solution, tap the bottle until powder flows freely.
Add 90 mL distilled or purified water to the powder in the bottle and invert or gently shake the bottle with re-attached cap for up to 5 minutes until powder is fully dissolved yielding a clear solution. Separate the bottle adapter from the oral syringe. Insert bottle adapter into bottle neck after reconstitution of the solution.
Write the discard after date. Once reconstituted, MEKINIST for oral solution can be used for 35 days. The final concentration of the solution is 0.05 mg/mL.
Administer MEKINIST for oral solution from an oral syringe or feeding tube (4 French gauge or larger). After reconstitution, store in original bottle below 25°C (77°F) and do not freeze.
Dosage Modifications for Adverse Reactions
Dose reductions for adverse reactions associated with MEKINIST are presented in Tables 3 and 4. Table 3. Recommended Dosage Reductions for MEKINIST Tablets for Adverse Reactions Reductions for MEKINIST for Oral Solution for Adverse Reactions Dosage modifications for adverse reactions associated with MEKINIST are presented in Table 5.
Table 5. Recommended Dosage Modifications for MEKINIST for Adverse Reactions Refer to the dabrafenib prescribing information for dose modifications for adverse reactions associated with dabrafenib.
| Body Weight | Recommended Dosage |
|---|---|
| 26 to 37 kg | 1 mg orally once daily |
| 38 to 50 kg | 1.5 mg orally once daily |
| 51 kg or greater | 2 mg orally once daily |
| Body Weight | Recommended Dosage Total Volume of Oral Solution Once Daily (Trametinib Content) |
|---|---|
| 8 kg | 0.3 mg (6 mL) |
| 9 kg | 0.35 mg (7 mL) |
| 10 kg | 0.35 mg (7 mL) |
| 11 kg | 0.4 mg (8 mL) |
| 12 to 13 kg | 0.45 mg (9 mL) |
| 14 to 17 kg | 0.55 mg (11 mL) |
| 18 to 21 kg | 0.7 mg (14 mL) |
| 22 to 25 kg | 0.85 mg (17 mL) |
| 26 to 29 kg | 0.9 mg (18 mL) |
| 30 to 33 kg | 1 mg (20 mL) |
| 34 to 37 kg | 1.15 mg (23 mL) |
| 38 to 41 kg | 1.25 mg (25 mL) |
| 42 to 45 kg | 1.4 mg (28 mL) |
| 46 to 50 kg | 1.6 mg (32 mL) |
| ≥ 51 kg | 2 mg (40 mL) |
| Recommended Dosage | 1 mg orally once daily | 1.5 mg orally once daily | 2 mg orally once daily |
|---|---|---|---|
| First dose reduction | 0.5 mg orally once daily | 1 mg orally once daily | 1.5 mg orally once daily |
| Second dose reduction | N/A | 0.5 mg orally once daily | 1 mg orally once daily |
| Subsequent modification | Permanently discontinue MEKINIST tablets if unable to tolerate a maximum of two dose reductions. | ||
| Body Weight (Recommended dosage once daily) | First Dose Reduction (Administer once daily) | Second Dose Reduction (Administer once daily) |
|---|---|---|
| 8 kg [0.3 mg (6 mL)] | 0.25 mg (5 mL) | 0.15 mg (3 mL) |
| 9 kg [0.35 mg (7 mL)] | 0.25 mg (5 mL) | 0.2 mg (4 mL) |
| 10 kg [0.35 mg (7 mL)] | 0.25 mg (5 mL) | 0.2 mg (4 mL) |
| 11 kg [0.4 mg (8 mL)] | 0.3 mg (6 mL) | 0.2 mg (4 mL) |
| 12 to 13 kg [0.45 mg (9 mL)] | 0.35 mg (7 mL) | 0.25 mg (5 mL) |
| 14 to 17 kg [0.55 mg (11 mL)] | 0.4 mg (8 mL) | 0.3 mg (6 mL) |
| 18 to 21 kg [0.7 mg (14 mL)] | 0.55 mg (11 mL) | 0.35 mg (7 mL) |
| 22 to 25 kg [0.85 mg (17 mL)] | 0.65 mg (13 mL) | 0.45 mg (9 mL) |
| 26 to 29 kg [0.9 mg (18 mL)] | 0.7 mg (14 mL) | 0.45 mg (9 mL) |
| 30 to 33 kg [1 mg (20 mL)] | 0.75 mg (15 mL) | 0.5 mg (10 mL) |
| 34 to 37 kg [1.15 mg (23 mL)] | 0.85 mg (17 mL) | 0.6 mg (12 mL) |
| 38 to 41 kg [1.25 mg (25 mL)] | 0.95 mg (19 mL) | 0.65 mg (13 mL) |
| 42 to 45 kg [1.4 mg (28 mL)] | 1.05 mg (21 mL) | 0.7 mg (14 mL) |
| 46 to 50 kg [1.6 mg (32 mL)] | 1.2 mg (24 mL) | 0.8 mg (16 mL) |
| ≥ 51 kg [2 mg (40 mL)] | 1.5 mg (30 mL) | 1 mg (20 mL) |
| Permanently discontinue MEKINIST for oral solution if unable to tolerate a maximum of two dose reductions. | ||
| a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b See Tables 3 and 4 for recommended dose reductions of MEKINIST. c Dose modifications are not recommended for MEKINIST when administered with dabrafenib for the following adverse reactions of dabrafenib: non-cutaneous malignancies and uveitis. Dose modification of MEKINIST is not required for new primary cutaneous malignancies. | |
| Severity of Adverse Reaction a | Dosage Modification for MEKINIST b |
| Hemorrhage [see Warnings and Precautions (5.2)] | |
| Grade 3 | Withhold MEKINIST. If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. |
| Grade 4 | Permanently discontinue MEKINIST. |
| Venous Thromboembolic Events [see Warnings and Precautions (5.4)] | |
| Uncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE) | Withhold MEKINIST for up to 3 weeks. If improved to Grade 0-1, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. |
| Life-threatening PE | Permanently discontinue MEKINIST. |
| Cardiomyopathy [see Warnings and Precautions (5.5)] | |
| Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of 10% or greater from baseline that is below the institutional lower limit of normal (LLN) | Withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume MEKINIST at lower dose. If not improved to normal LVEF value, permanently discontinue MEKINIST. |
| Symptomatic cardiomyopathy Absolute decrease in LVEF of greater than 20% from baseline that is below the institutional LLN | Permanently discontinue MEKINIST. |
| Ocular Toxicities [see Warnings and Precautions (5.6)] | |
| Retinal pigment epithelial detachments (RPED) | Withhold MEKINIST for up to 3 weeks. If improved, resume MEKINIST at same or lower dose. If not improved, permanently discontinue MEKINIST or resume MEKINIST at lower dose. |
| Retinal vein occlusion (RVO) | Permanently discontinue MEKINIST. |
| Pulmonary [see Warnings and Precautions (5.7)] | |
| Interstitial lung disease (ILD)/pneumonitis | Permanently discontinue MEKINIST. |
| Febrile Reactions [see Warnings and Precautions (5.8)] | |
| Fever of 100.4°F to 104°F (or first symptoms in case of recurrence) | Withhold MEKINIST until fever resolves, then resume MEKINIST at same or lower dose. |
| Fever higher than 104°F Fever complicated by rigors, hypotension, dehydration, or renal failure | Withhold MEKINIST until febrile reactions resolve for at least 24 hours, then resume MEKINIST at lower dose. Or Permanently discontinue MEKINIST. |
| Skin Toxicities [see Warnings and Precautions (5.9)] | |
| Intolerable Grade 2 Grade 3 or 4 | Withhold MEKINIST for up to 3 weeks. If improved, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. |
| Severe cutaneous adverse reactions (SCARs) | Permanently discontinue MEKINIST. |
| Other Adverse Reactions c | |
| Intolerable Grade 2 Any Grade 3 | Withhold MEKINIST. If improved to Grade 0-1, resume MEKINIST at lower dose. If not improved, permanently discontinue MEKINIST. |
| First occurrence of any Grade 4 | Withhold MEKINIST until improves to Grade 0-1, then resume MEKINIST at lower dose. Or Permanently discontinue MEKINIST. |
| Recurrent Grade 4 | Permanently discontinue MEKINIST. |
Side Effects of Mekinist
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Safety Pools The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to MEKINIST 2 mg orally, once daily as a single agent in 329 patients with various solid tumors enrolled in METRIC, MEK113583, and MEK111054. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to MEKINIST 2 mg orally, once daily, administered in combination with dabrafenib 150 mg orally, twice daily, in 1087 patients enrolled in COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma, or NSCLC.
Pediatric Safety Pool The pediatric pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to weight-based MEKINIST orally, once daily administered in combination with dabrafenib in 166 pediatric patients across two trials: a multi-center, open-label, multi-cohort study in pediatric patients with BRAF V600E mutation-positive glioma requiring systemic therapy (Study G2201; n = 123) and a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors with MAPK pathway activation (Study X2101; n = 43). Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart failure (New York Heart Association) were excluded. The median duration of treatment with MEKINIST was 4.3 months.
In this study, 9% of patients who received MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication. The most frequent adverse reactions resulting in permanent discontinuation of MEKINIST were decreased LVEF, pneumonitis, renal failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with MEKINIST.
Rash and decreased LVEF were the most frequent reasons cited for dose reductions of MEKINIST. Table 6 and Table 7 present adverse reactions and laboratory abnormalities, respectively, of MEKINIST as a single agent in the METRIC study. Table 6.
Laboratory Abnormalities Occurring at a Higher Incidence in Patients Who Received 3 Other clinically important adverse reactions for MEKINIST in a pool of MEKINIST monotherapy clinical studies observed in less than 10% of patients who received MEKINIST were: Cardiac: Bradycardia, atrioventricular block, bundle branch block Gastrointestinal: Dry mouth Infections and Infestations: Folliculitis, rash pustular, cellulitis Musculoskeletal and Connective Tissue: Rhabdomyolysis Nervous System: Dizziness, dysgeusia, peripheral neuropathy Ocular: Blurred vision, dry eye MEKINIST with Dabrafenib The safety of MEKINIST when administered with dabrafenib was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600 mutation-positive melanoma who received MEKINIST in two trials, the COMBI-d study (n = 209), a multi-center, double-blind, randomized (1:1), active-controlled trial and the COMBI-v study (n = 350), a multi-center, open-label, randomized (1:1), active-controlled trial. In both trials, patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. Both trials excluded patients with abnormal LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of RVO or RPED, QTcB interval ≥ 480 msec, uncontrolled hypertension, uncontrolled arrhythmias, active brain metastases, or known history of glucose-6-phosphate dehydrogenase deficiency.
The most common adverse reactions (≥ 20%) for MEKINIST in patients who received MEKINIST plus dabrafenib in the COMBI-d and COMBI-v studies were: pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema. The demographics and baseline tumor characteristics of patients enrolled in the COMBI-d study are summarized in Clinical Studies. Patients who received MEKINIST plus dabrafenib had a median duration of exposure of for > 1 year.
In the COMBI-d study, adverse reactions leading to discontinuation of MEKINIST occurred in 11% of patients who received MEKINIST plus dabrafenib; the most frequent were pyrexia (1.4%) and decreased ejection fraction (1.4%). Table 8 and Table 9 present selected adverse reactions and laboratory abnormalities, respectively, of MEKINIST observed in the COMBI-d study. Table 8.
Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Who Received MEKINIST with Dabrafenib and at a Higher Incidence* Than in Patients Who Received Single-Agent Dabrafenib in COMBI-d a 0 7 0 Other clinically important adverse reactions for MEKINIST across the COMBI-d and COMBI-v studies (N = 559) observed in less than 10% of patients who received MEKINIST in combination with dabrafenib were: Cardiac: Bradycardia, atrioventricular block, bundle branch block Immune System: Sarcoidosis Musculoskeletal and Connective Tissue: Rhabdomyolysis Nervous System: Peripheral neuropathy, Guillain-Barré syndrome Skin and Subcutaneous Tissue: Photosensitivity Table 9. Laboratory Abnormalities Worsening from Baseline Occurring at ≥ 10% (All Grades) of Patients Who Received MEKINIST with Dabrafenib and at a Higher Incidence* Than in Patients Who Received Single-Agent Dabrafenib in COMBI-d 0K Mutation-Positive Melanoma The safety of MEKINIST when administered with dabrafenib was evaluated in 435 patients with Stage III melanoma with BRAF V600E or V600K mutations following complete resection who received at least one dose of study therapy in the COMBI-AD study. Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily for 12 months.
The trial excluded patients with abnormal LVEF; history of acute coronary syndromes, coronary angioplasty, or stenting within 6 months; Class II or greater congestive heart failure (New York Heart Association); QTc interval ≥ 480 msec; treatment refractory hypertension; uncontrolled arrhythmias; or history of RVO. Patients who received MEKINIST in combination with dabrafenib had a median duration of exposure of 11 months (range: 0 to 12) to MEKINIST. Among the 435 patients who received MEKINIST in combination with dabrafenib, 72% were exposed to MEKINIST for > 6 months.
The most common adverse reactions (≥ 20%) in patients who received MEKINIST in combination with dabrafenib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia. Adverse reactions resulting in discontinuation and dose interruptions of MEKINIST occurred in 24% and 54% of patients, respectively; the most frequent for each were pyrexia and chills. Adverse reactions leading to dose reductions of MEKINIST occurred in 23% of patients; the most frequent were pyrexia and decreased ejection fraction.
The laboratory abnormalities are summarized in Table 11. Table 11. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ Management Study COMBI-APlus evaluated the impact of pyrexia-related outcomes of a revised pyrexia management algorithm in patients who received dabrafenib administered with trametinib in the adjuvant treatment of BRAF V600 mutation-positive melanoma after complete resection.
The pyrexia management algorithm interrupted both dabrafenib and trametinib when patient’s temperature is ≥ 100.4°F. Grade 3-4 pyrexia occurred in 4.3% of patients, hospitalizations due to pyrexia occurred in 5.1% of patients, pyrexia with complications (dehydration, hypotension, renal dysfunction, syncope, severe chills) occurred in 2.2% of patients, and treatment discontinuation due to pyrexia occurred in 2.5% of patients. Metastatic, BRAF V600E Mutation-Positive Non-Small Cell Lung Cancer The safety of MEKINIST when administered with dabrafenib was evaluated in 93 patients with previously untreated (n = 36) and previously treated (n = 57) metastatic BRAF V600E mutation-positive NSCLC in a multi-center, multi-cohort, non-randomized, open-label trial (Study BRF113928).
Among these 93 patients, and dabrafenib for ≥ 1 year. The most common adverse reactions (≥ 20%) in these 93 patients were: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea. Table 12 and Table 13 present adverse reactions and laboratory abnormalities, respectively, of MEKINIST in combination with dabrafenib in Study BRF 5 Other clinically important adverse reactions for MEKINIST in Study BRF113928 observed in less than 20% of patients who received MEKINIST administered with dabrafenib were: Cardiac: Atrioventricular block Nervous System: Peripheral neuropathy Table 13.
Treatment-Emergent Laboratory Abnormalities Occurring in ≥ when administered with dabrafenib was evaluated in a multi-cohort, multi-center, non-randomized, open-label study in adult patients with cancers with the BRAF V600E mutation (Study BRF117019). Serious adverse reactions occurred in 45% of patients who received MEKINIST in combination with dabrafenib. Serious adverse reactions in > 5% of patients included pyrexia (11%) and pneumonia (6%).
Fatal adverse reactions occurred in 3.9% of patients who received MEKINIST in combination with dabrafenib. Fatal adverse reactions that occurred in > 1% of patients included sepsis (1.9%). Permanent treatment discontinuation due to an adverse reaction occurred in 13% of patients.
Adverse reactions which resulted in permanent treatment discontinuation in > 1% of patients included nausea (1.5%). Dosage interruptions due to an adverse reaction occurred in 55% of patients. Dose reductions due to an adverse reaction occurred in 44% of patients.
The most common (≥ 20%) adverse reactions, including laboratory abnormalities, are listed in Table 14 and Table 15. Table 14 summarizes the adverse reactions in Study BRF Clinically relevant adverse reactions for MEKINIST in Study BRF117019 observed in less than 20% of patients who received MEKINIST in combination with dabrafenib were: peripheral neuropathy (9%), decreased ejection fraction (8%), atrioventricular block summarizes the laboratory abnormalities in Study BRF117019. Table 15.
Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Adult Patients Treated with 0E Mutation-Positive Solid Tumors in Pediatric Patients Study CTMT212X2101 (X2101) The safety of MEKINIST when administered with dabrafenib was evaluated in Study X2101, a multi-center, open-label, multi-cohort study in pediatric patients (n = 48) with refractory or recurrent solid tumors activation. The median duration of exposure to MEKINIST in Parts C (dose escalation) and D (cohort expansion) was 20.8 and 24.4 months, respectively. The median duration of exposure to dabrafenib in Parts C and D was 20.8 and 24.9 months, respectively.
The median age of pediatric patients who received MEKINIST with dabrafenib was 9 years (range: 1 to 17). Serious adverse reactions in > 5% of patients included pyrexia (25%) and decreased ejection fraction (6%). Adverse reactions which required dose reductions in > 5% of patients included pyrexia (13%).
The most common (≥ 20%) adverse reactions, including laboratory abnormalities, are listed in Table 16 and Table 17. Table 16 summarizes the adverse reactions in Study X 0 Clinically relevant adverse reactions for MEKINIST in Study X2101 observed in less than 20% of patients (N=48) who received MEKINIST in combination with dabrafenib were: atrioventricular block (2.1%). Table 17 summarizes the laboratory abnormalities in Study X2101.
Table 17. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Pediatric Patients Treated with 0E Mutation-Positive Low-Grade Glioma in Pediatric Patients Study CDRB436G2201 (G2201) The safety of MEKINIST in combination with dabrafenib was evaluated in pediatric patients 1 to < 18 years of age in Study G2201. Patients with low-grade glioma (LGG) who required first systemic therapy were randomized (2:1) to MEKINIST plus dabrafenib (n = 73) or carboplatin plus vincristine (n = 33).
Nine patients crossed over from the carboplatin plus vincristine arm to the MEKINIST and dabrafenib arm. Pediatric patients received weight-based MEKINIST orally once daily administered in combination with dabrafenib until disease progression or intolerable toxicity. Patients in the control arm received carboplatin and vincristine at doses of, respectively in 10-week induction course followed by eight 6-week cycles of maintenance therapy or until disease progression or intolerable toxicity.
Serious adverse reactions occurred in 40% of these patients. Serious adverse reactions in > 3% of patients included pyrexia (14%) and vomiting (4%). Permanent discontinuation of MEKINIST due to an adverse reaction occurred in 4% of patients.
Adverse reactions which resulted in permanent discontinuation of MEKINIST included chills, fatigue, pyrexia, weight increased, and headache. Adverse reactions which required a dosage interruption in > 5% of patients included pyrexia (52%). Adverse reactions which required dose reductions in > 2% of patients included weight increased ( %) laboratory abnormalities that worsened from baseline were leukopenia summarizes the adverse reactions in Study G2201.
Table 18. Adverse Reactions (≥ 15%) in Pediatric LGG Patients Who Received MEKINIST in Combination with Dabrafenib in Study G summarizes the laboratory abnormalities in Study G2201. Table 19.
Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Pediatric LGG Patients Who Received MEKINIST in Combination with Dabrafenib in Study G 6
Postmarketing Experience
The following adverse reactions have been identified during post approval use of MEKINIST in combination with dabrafenib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac: Atrioventricular block complete.
This adverse reaction was also observed with MEKINIST monotherapy. Immune System: Hemophagocytic lymphohistiocytosis (HLH) Skin and Subcutaneous Tissue: SCAR (including DRESS and SJS)
| a NCI CTCAE version 4.0. b Grade 4 adverse reactions limited to rash (n = 1) in trametinib arm and diarrhea (n = 1) in chemotherapy arm. c Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation. d Includes abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness. e Includes lymphedema, edema, and peripheral edema. f Includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, and conjunctival hemorrhage. | ||||
| Adverse Reactions | MEKINIST | Chemotherapy | ||
| N = 211 | N = 99 | |||
| All Grades a (%) | Grades 3 and 4 b (%) | All Grades a (%) | Grades 3 and 4 b (%) | |
| Skin and subcutaneous tissue | ||||
| Rash | 57 | 8 | 10 | 0 |
| Acneiform dermatitis | 19 | < 1 | 1 | 0 |
| Dry skin | 11 | 0 | 0 | 0 |
| Pruritus | 10 | 2 | 1 | 0 |
| Paronychia | 10 | 0 | 1 | 0 |
| Gastrointestinal | ||||
| Diarrhea | 43 | 0 | 16 | 2 |
| Stomatitis c | 15 | 2 | 2 | 0 |
| Abdominal pain d | 13 | 1 | 5 | 1 |
| Vascular | ||||
| Lymphedema e | 32 | 1 | 4 | 0 |
| Hypertension | 15 | 12 | 7 | 3 |
| Hemorrhage f | 13 | < 1 | 0 | 0 |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a Only Grade 3 adverse reactions were reported in either treatment arm. | ||||
| Laboratory Abnormality | MEKINIST | Chemotherapy | ||
| N = 211 | N = 99 | |||
| All Grades (%) | Grades 3 and 4 (%) | All Grades (%) | Grades 3 and 4 (%) | |
| Increased AST | 60 | 2 | 16 | 1 |
| Hypoalbuminemia | 42 | 2 | 23 | 1 |
| Increased ALT | 39 | 3 | 20 | 3 |
| Anemia | 38 | 2 | 26 | 3 |
| Increased alkaline phosphatase | 24 | 2 | 18 | 3 |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. ≥ 5% for All Grades or ≥ 2% for Grades 3–4 incidence in patients who received MEKINIST with dabrafenib compared with patients who received dabrafenib as a single agent. a For these laboratory tests, the denominator is 556. b For these laboratory tests, the denominator is 208 for the combination arm, 207-209 for the dabrafenib arm. c Grade 4 adverse reactions limited to lymphopenia and hyperglycemia (each n = 4), increased ALT and increased AST (each n = 3), neutropenia (n = 2), and hyponatremia (n = 1) in the pooled combination arm; neutropenia, lymphopenia, increased ALT, increased AST, and hyperglycemia (each n = 1) in the COMBI-d study combination arm; neutropenia, thrombocytopenia, increased ALT, and increased AST (each n = 1) in the dabrafenib arm. | ||||||
| Laboratory Abnormality | Pooled MEKINIST plus Dabrafenib N = 559 a | COMBI-d Study | ||||
| MEKINIST plus Dabrafenib N = 209 b | Dabrafenib N = 211 b | |||||
| All Grades (%) | Grades 3 and 4 c (%) | All Grades (%) | Grades 3 and 4 c (%) | All Grades (%) | Grades 3 and 4 c (%) | |
| Chemistry | ||||||
| Hyperglycemia | 60 | 4.7 | 65 | 6 | 57 | 4.3 |
| Hypoalbuminemia | 48 | 1.1 | 53 | 1.4 | 27 | 0 |
| Hyponatremia | 25 | 8 | 24 | 6 | 14 | 2.9 |
| Hepatic | ||||||
| Increased AST | 59 | 4.1 | 60 | 4.3 | 21 | 1.0 |
| Increased blood alkaline phosphatase | 49 | 2.7 | 50 | 1.0 | 25 | 0.5 |
| Increased ALT | 48 | 4.5 | 44 | 3.8 | 28 | 1.0 |
| Hematology | ||||||
| Neutropenia | 46 | 7 | 50 | 6 | 16 | 1.9 |
| Anemia | 43 | 2.3 | 43 | 2.4 | 38 | 4.3 |
| Lymphopenia | 32 | 8 | 38 | 9 | 28 | 7 |
| Thrombocytopenia | 21 | 0.7 | 19 | 0.5 | 10 | 0.5 |
| a NCI CTCAE version 4.0. b Includes pyrexia and hyperpyrexia. c Includes fatigue, asthenia, and malaise. d Includes headache and tension headache. e Includes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular. f Includes myalgia, musculoskeletal pain, and musculoskeletal chest pain. | ||||
| Adverse Reactions | MEKINIST plus Dabrafenib N = 435 | Placebo N = 432 | ||
| All Grades (%) | Grades 3 and 4 (%) | All Grades (%) | Grades 3 and 4 (%) | |
| General | ||||
| Pyrexia b | 63 | 5 | 11 | < 1 |
| Fatigue c | 59 | 5 | 37 | < 1 |
| Chills | 37 | 1 | 4 | 0 |
| Gastrointestinal | ||||
| Nausea | 40 | < 1 | 20 | 0 |
| Diarrhea | 33 | < 1 | 15 | < 1 |
| Vomiting | 28 | < 1 | 10 | 0 |
| Nervous system | ||||
| Headache d | 39 | 1 | 24 | 0 |
| Skin and subcutaneous tissue | ||||
| Rash e | 37 | < 1 | 16 | < 1 |
| Musculoskeletal and connective tissue | ||||
| Arthralgia | 28 | < 1 | 14 | 0 |
| Myalgia f | 20 | < 1 | 14 | 0 |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement: MEKINIST plus Dabrafenib (range: 429 to 431) and Placebo arm (range: 426 to 428). | ||||
| Laboratory Abnormality | MEKINIST plus Dabrafenib a N = 435 | Placebo a N = 432 | ||
| All Grades (%) | Grades 3 and 4 (%) | All Grades (%) | Grades 3 and 4 (%) | |
| Chemistry | ||||
| Hyperglycemia | 63 | 3 | 47 | 2 |
| Hypophosphatemia | 42 | 7 | 10 | < 1 |
| Hypoalbuminemia | 25 | < 1 | < 1 | 0 |
| Hepatic | ||||
| Increased AST | 57 | 6 | 11 | < 1 |
| Increased ALT | 48 | 5 | 18 | < 1 |
| Increased blood alkaline phosphatase | 38 | 1 | 6 | < 1 |
| Hematology | ||||
| Neutropenia | 47 | 6 | 12 | < 1 |
| Lymphopenia | 26 | 5 | 6 | < 1 |
| Anemia | 25 | < 1 | 6 | < 1 |
| a NCI CTCAE version 4.0. b Includes fatigue, malaise, and asthenia. c Includes peripheral edema, edema, and generalized edema. d Includes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular. e Includes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage. | ||
| Adverse Reactions | MEKINIST plus Dabrafenib N = 93 | |
| All Grades (%) | Grades 3 and 4 (%) | |
| General | ||
| Pyrexia | 55 | 5 |
| Fatigue b | 51 | 5 |
| Edema c | 28 | 0 |
| Chills | 23 | 1.1 |
| Gastrointestinal | ||
| Nausea | 45 | 0 |
| Vomiting | 33 | 3.2 |
| Diarrhea | 32 | 2.2 |
| Decreased appetite | 29 | 0 |
| Skin and subcutaneous tissue | ||
| Dry skin | 31 | 1.1 |
| Rash d | 28 | 3.2 |
| Vascular | ||
| Hemorrhage e | 23 | 3.2 |
| Respiratory system | ||
| Cough | 22 | 0 |
| Dyspnea | 20 | 5 |
| a NCI CTCAE version 4.0. b Includes fatigue, asthenia, and malaise. c Includes peripheral edema and peripheral swelling. d Includes rash, rash maculo-papular, rash erythematous, rash pustular, and rash papular. e Includes epistaxis, hematuria, contusion, hematoma, hemoptysis, conjunctival hemorrhage, hematochezia, rectal hemorrhage, hemorrhoidal hemorrhage, melaena, purpura, eye contusion, eye hemorrhage, gastric hemorrhage, gingival bleeding, hematemesis, hemorrhage intracranial, hemorrhagic stroke, hemothorax, increased tendency to bruise, large intestinal hemorrhage, mouth hemorrhage, petechiae, pharyngeal hemorrhage, prothrombin time prolonged, pulmonary hematoma, retinal hemorrhage, vaginal hemorrhage, and vitreous hemorrhage. f Includes cough and productive cough. g Includes myalgia, musculoskeletal chest pain, and musculoskeletal pain. | ||
| Adverse Reactions | MEKINIST plus Dabrafenib a (N = 206) | |
| All Grades (%) | Grade 3 or 4 (%) | |
| General | ||
| Pyrexia | 55 | 4.95 |
| Fatigue b | 50 | 5 |
| Chills | 30 | 0.5 |
| Peripheral edema c | 22 | 0 |
| Gastrointestinal | ||
| Nausea | 40 | 1.5 |
| Constipation | 27 | 0 |
| Vomiting | 27 | 1.5 |
| Diarrhea | 26 | 2.93 |
| Skin and subcutaneous tissue | ||
| Rash d | 40 | 2.4 |
| Nervous system | ||
| Headache | 30 | 1.5 |
| Vascular | ||
| Hemorrhage e | 29 | 4.4 |
| Respiratory system | ||
| Cough f | 29 | 0 |
| Musculoskeletal and connective tissue | ||
| Myalgia g | 24 | 0.5 |
| Arthralgia | 23 | 0.5 |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 199 to 202 based on the number of patients with a baseline value and at least one post-treatment value. | ||
| Laboratory Abnormality | MEKINIST plus Dabrafenib a | |
| All Grades (%) | Grade 3 or 4 (%) | |
| Chemistry | ||
| Hyperglycemia | 61 | 8 |
| Decreased sodium | 35 | 10 |
| Decreased magnesium | 24 | 0 |
| Increased creatinine | 21 | 1.5 |
| Hepatic | ||
| Increased alkaline phosphatase | 51 | 5 |
| Increased AST | 51 | 4.6 |
| Increased ALT | 39 | 3 |
| Hematology | ||
| Decreased hemoglobin | 44 | 9 |
| a NCI CTCAE version 4.0. b Includes fatigue, asthenia, and malaise. c Includes rash, rash maculo-papular, rash erythematous, rash papular, rash pustular, and rash macular. d Includes dermatitis acneiform and acne. e Includes abdominal pain and abdominal pain upper. f Includes epistaxis, hematuria, contusion, hematoma, petechiae, rectal hemorrhage, and red blood cell count decreased. | ||
| Adverse Reactions | MEKINIST plus Dabrafenib a (N = 48) | |
| All Grades (%) | Grade 3 or 4 (%) | |
| General | ||
| Pyrexia | 75 | 17 |
| Fatigue b | 48 | 0 |
| Skin and subcutaneous tissue | ||
| Rash c | 73 | 2.1 |
| Dry skin | 48 | 0 |
| Dermatitis acneiform d | 40 | 0 |
| Gastrointestinal | ||
| Vomiting | 52 | 4.2 |
| Diarrhea | 42 | 2.1 |
| Abdominal pain e | 33 | 4.2 |
| Nausea | 33 | 2.1 |
| Constipation | 23 | 0 |
| Respiratory system | ||
| Cough | 44 | 0 |
| Nervous system | ||
| Headache | 35 | 0 |
| Vascular | ||
| Hemorrhage f | 33 | 0 |
| Infections and infestations | ||
| Paronychia | 23 | 0 |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 39 to 48 based on the number of patients with a baseline value and at least one post-treatment value. | ||
| Laboratory Abnormality | MEKINIST plus Dabrafenib a | |
| All Grades (%) | Grade 3 or 4 (%) | |
| Chemistry | ||
| Hyperglycemia | 65 | 2.2 |
| Hypoalbuminemia | 48 | 2.1 |
| Hypocalcemia | 40 | 2.1 |
| Decreased phosphate | 38 | 0 |
| Decreased magnesium | 33 | 2.1 |
| Hypernatremia | 27 | 0 |
| Hypokalemia | 21 | 2.1 |
| Hepatic | ||
| Increased AST | 55 | 4.2 |
| Increased ALT | 40 | 6 |
| Increased alkaline phosphatase | 28 | 6 |
| Increased total bilirubin | 21 | 2.1 |
| Hematology | ||
| Decreased hemoglobin | 60 | 6 |
| Decreased neutrophils | 49 | 28 |
| a NCI CTCAE version 4.03. b Includes diarrhea, colitis, enterocolitis, and enteritis. c Includes abdominal pain and upper abdominal pain. d Includes stomatitis, cheilitis, mouth ulceration, aphthous ulcer, and glossitis. e Includes pyrexia and body temperature increased. f Includes fatigue and asthenia. g Includes headache and migraine with aura. h Includes dizziness and vertigo. i Includes peripheral neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia, neuralgia, hypoaesthesia, and peripheral sensory neuropathy. j Includes epistaxis, post-procedural hemorrhage, hematuria, upper gastrointestinal hemorrhage, and hemorrhage intracranial. k Includes rash, rash macular, rash maculo-papular, rash pustular, rash papular, rash erythematous, eczema, erythema multiforme, dermatitis, dermatitis exfoliative, skin exfoliation, palmar-plantar erythrodysaesthesia syndrome, and dermatitis bullous. l Includes dermatitis acneiform, acne, and acne pustular. m Includes back pain, myalgia, pain in extremity, arthralgia, bone pain, non-cardiac chest pain, neck pain, and musculoskeletal stiffness. | ||||
| Adverse Reactions | MEKINIST plus Dabrafenib N = 73 | Carboplatin plus Vincristine N = 33 | ||
| All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | |
| Gastrointestinal | ||||
| Vomiting | 34 | 1 | 48 | 3 |
| Diarrhea b | 29 | 0 | 18 | 6 |
| Nausea | 25 | 0 | 45 | 0 |
| Abdominal pain c | 25 | 0 | 24 | 0 |
| Constipation | 12 | 0 | 36 | 0 |
| Stomatitis d | 10 | 0 | 18 | 0 |
| General | ||||
| Pyrexia e | 68 | 8 | 18 | 3 |
| Fatigue f | 33 | 0 | 39 | 0 |
| Nervous system | ||||
| Headache g | 47 | 1 | 33 | 3 |
| Dizziness h | 15 | 0 | 9 | 3 |
| Peripheral neuropathy i | 7 | 0 | 45 | 6 |
| Vascular | ||||
| Hemorrhage j | 25 | 0 | 12 | 0 |
| Skin and subcutaneous tissue | ||||
| Rash k | 51 | 2.7 | 18 | 3 |
| Dry skin | 26 | 0 | 3 | 0 |
| Dermatitis acneiform l | 22 | 0 | 0 | 0 |
| Alopecia | 3 | 0 | 24 | 0 |
| Musculoskeletal and connective tissue | ||||
| Musculoskeletal pain m | 34 | 0 | 30 | 0 |
| Pain in jaw | 1.4 | 0 | 18 | 0 |
| Metabolism and nutrition | ||||
| Decreased appetite | 5 | 0 | 24 | 0 |
| Respiratory, thoracic and mediastinal | ||||
| Oropharyngeal pain | 11 | 0 | 18 | 0 |
| Psychiatric | ||||
| Anxiety | 1.4 | 0 | 15 | 3 |
| Immune system | ||||
| Hypersensitivity | 0 | 0 | 15 | 3 |
| Infections and infestations | ||||
| Upper respiratory tract infection | 15 | 0 | 6 | 0 |
| Injury, poisoning and procedural complications | ||||
| Infusion-related reaction | 0 | 0 | 15 | 3 |
| Investigations | ||||
| Weight increased | 15 | 7 | 0 | 0 |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 70 to 73 in D + T arm and 9 to 33 in C + V arm based on the number of patients with a baseline value and at least one post-treatment value. | ||||
| Laboratory Abnormality | MEKINIST plus Dabrafenib N = 73 | Carboplatin plus Vincristine N = 33 | ||
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Hepatic | ||||
| Increased alkaline phosphatase | 55 | 0 | 13 | 0 |
| Increased AST | 37 | 1.4 | 55 | 0 |
| Increased ALT | 29 | 3 | 61 | 9 |
| Chemistry | ||||
| Decreased magnesium | 34 | 4.1 | 76 | 6 |
| Increased magnesium | 32 | 0 | 24 | 3 |
| Increased potassium | 15 | 4.2 | 21 | 6 |
| Decreased calcium | 14 | 4.1 | 22 | 9 |
| Decreased potassium | 8 | 1.4 | 70 | 0 |
| Decreased phosphate | 7 | 2.7 | 33 | 3 |
| Decreased sodium | 5 | 1.4 | 27 | 6 |
| Increased serum fasting glucose | 0 | 0 | 44 | 0 |
| Hematology | ||||
| Decreased leukocytes | 59 | 0 | 91 | 18 |
| Decreased hemoglobin | 46 | 0 | 94 | 36 |
| Decreased neutrophils | 44 | 17 | 84 | 75 |
| Decreased platelets | 30 | 0 | 73 | 18 |
| Increased lymphocytes | 24 | 0 | 13 | 3.1 |
| Decreased lymphocytes | 16 | 1.4 | 56 | 6 |
Warnings & Cautions for Mekinist
New Primary Malignancies Cutaneous Malignancies MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population, cutaneous squamous cell carcinomas (cuSCCs) and keratoacanthomas occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and < 1% of patients, respectively. MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, new primary melanoma occurred in < 1% of patients.
Perform dermatologic evaluations prior to initiation of MEKINIST when used with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination. Non-Cutaneous Malignancies Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms; refer to the prescribing information for dabrafenib. In the pooled safety population of MEKINIST administered with dabrafenib, non-cutaneous malignancies occurred in 1% of patients.
Monitor patients receiving MEKINIST and dabrafenib closely for signs or symptoms of non-cutaneous malignancies. No dose modification is required for MEKINIST in patients who develop non-cutaneous malignancies.
Hemorrhage
Hemorrhages, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with MEKINIST. Fatal cases have been reported. MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population, hemorrhagic events occurred in 17% of patients; gastrointestinal hemorrhage occurred in 3% of patients; intracranial hemorrhage occurred in 0.6% of patients; fatal hemorrhage occurred in 0.5% of patients.
The fatal events were cerebral hemorrhage and brainstem hemorrhage. MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, hemorrhagic events occurred in 25% of patients; the most common type of bleeding was epistaxis (16%). Permanently discontinue MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve.
Withhold MEKINIST for Grade 3 hemorrhagic events; if improved, resume MEKINIST at the next lower dose level.
Colitis and Gastrointestinal Perforation Colitis and gastrointestinal perforation, including fatal outcomes, have been reported in patients taking: MEKINIST Monotherapy and Administered with Dabrafenib (Adult): In the pooled safety population, colitis occurred in < 1% of patients and gastrointestinal perforation occurred in < 1% of patients. MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, colitis events occurred in < 1% of patients. Monitor patients closely for colitis and gastrointestinal perforations.
Venous Thromboembolic Events MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population, deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue MEKINIST for life-threatening PE.
Withhold MEKINIST for uncomplicated DVT and PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose level.
Cardiomyopathy
Cardiomyopathy, including cardiac failure, can occur with MEKINIST. MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population, cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥ 10% from baseline and below the institutional lower limit of normal (LLN), occurred in 6% of patients. Development of cardiomyopathy resulted in dose interruption or discontinuation of MEKINIST in 3% and < 1% of patients, respectively.
Cardiomyopathy resolved in 45 of 50 patients who received MEKINIST administered with dabrafenib. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of MEKINIST as a single agent or with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. For an asymptomatic absolute decrease in LVEF of 10% or greater from baseline that is below the institutional LLN, withhold MEKINIST for up to 4 weeks.
If improved to normal LVEF value, resume MEKINIST at a lower dose. If no improvement to normal LVEF value within 4 weeks, permanently discontinue MEKINIST. For symptomatic cardiomyopathy or an absolute decrease in LVEF of greater than 20% from baseline that is below the institutional LLN, permanently discontinue MEKINIST.
Ocular Toxicities Retinal Vein Occlusion In the pooled safety population of MEKINIST monotherapy, the incidence of retinal vein occlusion (RVO) was 0.6%. In the pooled safety population of MEKINIST administered with dabrafenib, there were no cases of RVO. RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.
Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. Retinal Pigment Epithelial Detachment Retinal pigment epithelial detachment (RPED) can occur with MEKINIST.
Retinal detachments may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina. MEKINIST Administered with Dabrafenib (Adult): In a clinical trial of 131 patients treated with MEKINIST in combination with dabrafenib that included ophthalmological monitoring with optical coherence tomography (OCT), RPED occurred in 5% of patients, including 1 patient with visual field defect symptoms. Perform ophthalmological evaluation periodically and at any time a patient reports visual disturbances.
Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at same or reduced dose. If no improvement after 3 weeks, resume MEKINIST at reduced dose or permanently discontinue MEKINIST.
Interstitial Lung Disease/Pneumonitis In the pooled safety population of MEKINIST monotherapy, interstitial lung disease or pneumonitis occurred in 2% of patients. In the pooled safety population of MEKINIST administered with dabrafenib, ILD or pneumonitis occurred in 1% of patients. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings, including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations.
Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.
Serious Febrile Reactions
Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when MEKINIST is administered with dabrafenib. MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population, fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration or renal failure occurred in 5% of patients.
MEKINIST Administered with Dabrafenib (Pediatric): In the pooled safety population, pyrexia occurred in 66% of patients. Withhold MEKINIST when used as monotherapy, and both MEKINIST and dabrafenib when used in combination, if the patient’s temperature is ≥ 100.4°F. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia.
Fever may be complicated by hypotension, rigors or chills, dehydration, or renal failure. Evaluate for signs and symptoms of infection and monitor serum creatinine and other evidence of renal function during and following severe pyrexia. If appropriate, MEKINIST, or both MEKINIST and dabrafenib when used in combination, may be restarted if the patient has recovered from the febrile reaction for at least 24 hours, either at same or lower dose.
Administer antipyretics as secondary prophylaxis when resuming MEKINIST if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., prednisone 10 mg daily) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia, or for pyrexia associated with complications, such as dehydration, hypotension, renal failure, or severe chills/rigors, and there is no evidence of active infection.
Serious Skin Toxicities
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with MEKINIST administered with dabrafenib. MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population, other serious skin toxicity occurred in < 1% of patients. Monitor for new or worsening serious skin reactions.
Permanently discontinue MEKINIST for SCARs. For other skin toxicities, withhold MEKINIST for intolerable or severe skin toxicity. Resume MEKINIST at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks.
Permanently discontinue MEKINIST if skin toxicity has not improved in 3 weeks.
Hyperglycemia MEKINIST Administered with Dabrafenib (Adult): In the pooled safety population, 15% of patients with a history of diabetes who had received MEKINIST with dabrafenib required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia occurred in 2% of patients. Monitor serum glucose levels upon initiation and as clinically appropriate when MEKINIST is administered with dabrafenib in patients with preexisting diabetes or hyperglycemia.
Initiate or optimize anti-hyperglycemic medications as clinically indicated.
Risks Associated with Combination Treatment MEKINIST is indicated for use in combination with dabrafenib. Review the prescribing information for dabrafenib for information on the serious risks of dabrafenib prior to initiation of MEKINIST with dabrafenib.
Hemophagocytic Lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) has been observed in the post-marketing setting when MEKINIST was administered with dabrafenib. If HLH is suspected, interrupt treatment. If HLH is confirmed, discontinue treatment and initiate appropriate management of HLH.
Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended adult clinical dose. Advise pregnant women of the potential risk to a fetus.
Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after treatment.
Drug Interactions with Mekinist
MEKINIST is indicated for use in combination with dabrafenib. Refer to the dabrafenib prescribing information for additional risk information that applies to combination use treatment.
Pregnancy Safety for Mekinist
Pregnancy Risk Summary Based on its mechanism of action and findings from animal reproduction studies, MEKINIST can cause fetal harm when administered to a pregnant woman. There is insufficient data in pregnant women exposed to MEKINIST to assess the risks. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended adult clinical dose (see Data).
Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day.
In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended adult dose, there was maternal toxicity and an increase in post-implantation loss. In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended adult dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended adult dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.
Pediatric Use of Mekinist
Pediatric Use BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors and LGG The safety and effectiveness of MEKINIST in combination with dabrafenib have been established in pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options; or with LGG with BRAF V600E mutation who require systemic therapy. The safety and effectiveness of MEKINIST in combination with dabrafenib have not been established for these indications in pediatric patients less than 1 year old. The safety and effectiveness of MEKINIST as a single agent in pediatric patients have not been established.
Juvenile Animal Toxicity Data In a repeat-dose toxicity study in juvenile rats, decreased bone length and corneal dystrophy were observed at doses resulting in exposures as low as 0.3 times the human exposure at the recommended adult dose based on AUC. Additionally, a delay in sexual maturation was noted at doses resulting in exposures as low as 1.6 times the human exposure at the recommended adult dose based on AUC.
Overdosage Information for Mekinist
In seven patients treated on one of these two schedules, there were two cases of RPEDs for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST.
Clinical Studies 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, multi-center, 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. Treatment continued until disease progression or unacceptable toxicity.
Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes vs. no) and LDH level (normal vs. greater than ULN). 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 major efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. 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 PFS in the patients treated with MEKINIST. Table 20 and Figure 1 summarize the PFS results.
Table 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 COMBI-d Study 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. Randomization was stratified by LDH level (> ULN vs. ≤ ULN) and BRAF mutation subtype (V600E vs. V600K).
The major efficacy outcome measure 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). 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. Table 21 and Figure 2 summarize the efficacy results. Table 21.
Efficacy Results in the COMBI-d Study in the COMBI-d Study COMBI-MB Study The activity of MEKINIST with dabrafenib for the treatment of BRAF V600E or V600K mutation-positive melanoma, metastatic to the brain, was evaluated in a non-randomized, open-label, multi-center, multi-cohort trial (the COMBI-MB study; NCT02039947). Eligible patients were required to have at least one measurable intracranial lesion and to have no leptomeningeal disease, parenchymal brain metastasis greater than 4 cm in diameter, ocular melanoma, or primary mucosal melanoma. Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity.
The major efficacy outcome measure was intracranial response rate, defined as the percentage of patients with a confirmed intracranial response per RECIST v1.1, modified to allow up to five intracranial target lesions at least 5 mm in diameter, as assessed by independent review. The COMBI-MB study enrolled 121 patients with a BRAF V600E (85%) or V600K (15%) mutation. The intracranial response rate was with a complete response rate of 4.1% and a partial response rate of 46%.
The median duration of intracranial response was 6.4 months (range: 1 to 31). Of the patients with an intracranial response, 9% had stable or progressive disease as their best overall response.
Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma The efficacy of MEKINIST administered with dabrafenib was evaluated in an international, multi-center, randomized, double-blind, placebo-controlled trial (COMBI-AD; NCT01682083) that enrolled patients with Stage III melanoma with BRAF V600E or V600K mutations as detected by the THxID ® -BRAF assay and pathologic involvement of regional lymph node(s). Enrollment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomization. The trial excluded patients with mucosal or ocular melanoma, unresectable in-transit metastases, distant metastatic disease, or prior systemic anti-cancer treatment, including radiotherapy.
Randomization was stratified by BRAF mutation status (V600E or V600K) and American Joint Committee on Cancer (AJCC; 7 th Edition) Stage (IIIA, IIIB, or IIIC). The major efficacy outcome measure was relapse-free survival (RFS), 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 underwent imaging for tumor recurrence every 3 months for the first two years and every 6 months thereafter.
In COMBI-AD, a total of 870 patients were randomized: 438 to MEKINIST in combination with dabrafenib and 432 to placebo. The median duration of follow-up at the time of the primary analysis was 2.8 years. COMBI-AD showed a statistically significant improvement in RFS in patients randomized to MEKINIST in combination with dabrafenib compared to those randomized to placebo.
Efficacy results are presented in Table 22 and Figure 3. Table 22. Efficacy Results in COMBI-AD in the Adjuvant Figure 3.
Kaplan-Meier Curves for Investigator-Assessed Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma The median duration of follow-up at the time of the final overall survival analysis was 8.0 years. Median overall survival was not estimable in both arms.
BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer The safety and efficacy of dabrafenib alone or administered with MEKINIST were evaluated in a multi-center, three-cohort, non-randomized, activity-estimating, open-label trial (Study BRF113928; NCT01336634). 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 for NSCLC 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 NSCLC. 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 measure was overall response rate (ORR) per RECIST v1.1 as assessed by independent review committee (IRC) and duration of response (DoR). Efficacy results are summarized in Table 23. Table 23.
Efficacy Results Based on Independent Review in Study BRF113928.2 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 23.
BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer The safety and efficacy of MEKINIST administered with dabrafenib was evaluated in an activity-estimating, nine-cohort, multi-center, non-randomized, open-label trial (Study BRF117019; NCT02034110) in patients with rare cancers with the BRAF V600E mutation, including locally advanced, unresectable, or metastatic ATC with no standard locoregional treatment options. Trial BRF117019 excluded patients who could not swallow or retain the medication; who received prior treatment with BRAF or MEK inhibitors; with symptomatic or untreated CNS metastases; or who had airway obstruction. Thirty-six patients were enrolled and were evaluable for response in the ATC cohort.
Prior anti-cancer treatments included surgery and external beam radiotherapy (83% each), and systemic therapy (67%). Efficacy results are summarized in Table 24. Table 24.
Efficacy Results in the ATC Cohort Based on Independent Review of Study BRF117019.5 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, multi-center, 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. No patient achieved a confirmed partial or complete response as determined by the clinical investigators.
BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors The safety and efficacy of MEKINIST in combination with dabrafenib for the treatment of BRAF V600E mutation-positive unresectable or metastatic solid tumors were evaluated in Trials BRF117019, NCI-MATCH, and CTMT212X2101, and supported by results in COMBI-d, COMBI-v, and BRF113928. In adult studies, patients received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily. The major efficacy outcome measures were ORR per RECIST v1.1, RANO or modified RANO criteria and duration of response (DoR).
BRF117019 Study and NCI-MATCH Study Study BRF117019 (NCT02034110) is a multi-cohort, multi-center, non-randomized, open-label trial in adult patients with selected tumors with the BRAF V600E mutation, including high-grade glioma (HGG) (n = 45), biliary tract cancer (BTC) (n = 43), low-grade glioma (LGG) (n = 13), adenocarcinoma of small intestine (ASI) (n = 3), gastrointestinal stromal tumor (GIST) (n = 1), and anaplastic thyroid cancer. Patients were enrolled based on local assessments of BRAF V600E mutation status; a central laboratory confirmed the BRAF V600E mutation in 93 of 105 patients. Arm H (EAY131-H) of the NCI-MATCH study (NCT02465060) is a single-arm, open-label study that enrolled patients with a BRAF V600E mutation.
Patients with melanoma, thyroid cancer, or CRC were excluded. BRAF V600E mutation status for enrollment was determined either by central or local laboratory test. Of the 131 patients, 90% received prior systemic therapy.
Efficacy results in patients with solid tumors are summarized in Table 25. Table 25. Efficacy Results Based on Independent Review in Study BRF117019 and NCI-MATCH Arm H CTMT212X2101 (X2101) Study Study X2101 (NCT02124772) was a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors.
Part C was a dose escalation of MEKINIST in combination with dabrafenib in patients with a BRAF V600E mutation. Part D was a cohort expansion phase of MEKINIST in combination with dabrafenib in patients with LGG with a BRAF V600E mutation. The major efficacy outcome measure was ORR as assessed by independent review committee per RANO criteria.
The efficacy of MEKINIST in combination with dabrafenib was evaluated in 48 pediatric patients, including 34 patients with LGG and 2 patients with HGG. Prior anti-cancer treatments included surgery (83%), external beam radiotherapy (2.8%), and systemic therapy (92%). The ORR was CDRB436G2201 (G2201) Study – High-Grade Glioma Cohort Study G2201 (NCT02684058) was a multi-center, randomized, open-label, Phase II study of dabrafenib and trametinib in chemotherapy-naïve pediatric patients with BRAF V600E mutant low-grade glioma (LGG) and patients with relapsed or progressive BRAF V600E mutant HGG.
Patients with HGG were enrolled in a single-arm cohort. The efficacy of MEKINIST in combination with dabrafenib was evaluated in 41 pediatric patients with relapsed or progressive HGG. Prior anti-cancer treatments included surgery (98%), radiotherapy (90%), and chemotherapy (81%).
The ORR was The median DoR was not reached (95% CI: 9.2, NE). For the 23 patients who responded in the HGG cohort, DoR was ≥ 6 months for 78% of patients, ≥ 12 months for 48% of patients, and ≥ 24 months for 22% of patients.
BRAF V600E Mutation-Positive Low-Grade Glioma CDRB436G2201 (G2201) Study – Low-Grade Glioma Cohort The safety and efficacy of MEKINIST in combination with dabrafenib for the treatment of BRAF V600E mutation-positive low-grade glioma (LGG) in pediatric patients aged 1 to < 18 years of age were evaluated in the multi-center, open-label trial (Study CDRB436G2201; NCT02684058). Patients with LGG (WHO grades 1 and 2) who required first systemic therapy were randomized in a 2:1 ratio to dabrafenib plus trametinib (D + T) or carboplatin plus vincristine (C + V). BRAF mutation status was identified prospectively via a local assessment or a central laboratory test.
In addition, retrospective testing of available tumor samples by the central laboratory was performed to evaluate BRAF V600E mutation status. Patients received age- and weight-based dosing of MEKINIST and dabrafenib until loss of clinical benefit or until unacceptable toxicity. Carboplatin and vincristine were dosed based on body surface area at doses mg/kg for patients < 12 kg, respectively, as one 10-week induction course followed by eight 6-week cycles of maintenance therapy.
The major efficacy outcome measure was overall response rate (ORR) by independent review based on RANO LGG criteria. The primary analysis was performed when all patients had completed at least 32 weeks of therapy. In the LGG cohort, 110 patients were randomized to D + T (n = 73) or C + V (n = 37).
Study G2201 showed a statistically significant improvement in ORR and PFS in patients with LGG randomized to D + T compared to those randomized to C + V. Efficacy results are shown in Table 26. Table 26.
Efficacy Results Based on Independent Review in Study G2 1 (LGG cohort) At the time of the interim analysis of overall survival (OS), conducted when all patients had completed at least 32 weeks of treatment or had discontinued earlier, there was one death on the C + V arm. The OS results at interim analysis did not reach statistical significance.
| Abbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached. a Pike estimator. | ||
| Investigator - A ssessed Endpoints | MEKINIST N = 214 | Chemotherapy N = 108 |
| P rogression- F ree S urvival | ||
| Number of events (%) | 117 (55%) | 77 (71%) |
| Progressive disease | 107 (50%) | 70 (65%) |
| Death | 10 (5%) | 7 (6%) |
| Median, months (95% CI) | 4.8 (4.3, 4.9) | 1.5 (1.4, 2.7) |
| HR a (95% CI) | 0.47 (0.34, 0.65) | |
| P -value (log-rank test) | < 0.0001 | |
| Confirmed Tumor Responses | ||
| Overall response rate (95% CI) | 22% (17%, 28%) | 8% (4%, 15%) |
| Complete response, n (%) | 4 (2%) | 0 |
| Partial response, n (%) | 43 (20%) | 9 (8%) |
| Duration of Response | ||
| Median DoR, months (95% CI) | 5.5 (4.1, 5.9) | NR (3.5, NR) |
| Abbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached; ORR, overall response rate. a PFS and ORR were assessed by investigator. b Based on stratified log-rank test. | ||
| Endpoint | MEKINIST plus D abrafenib N = 211 | Placebo plus Dabrafenib N = 212 |
| Progression-Free Survival a | ||
| Number of events (%) | 102 (48%) | 109 (51%) |
| Median, months (95% CI) | 9.3 (7.7, 11.1) | 8.8 (5.9, 10.9) |
| HR (95% CI) | 0.75 (0.57, 0.99) | |
| P -value b | 0.035 | |
| Overall Survival | ||
| Number of deaths (%) | 99 (47%) | 123 (58%) |
| Median, months (95% CI) | 25.1 (19.2, NR) | 18.7 (15.2, 23.1) |
| HR (95% CI) | 0.71 (0.55, 0.92) | |
| P -value b | 0.01 | |
| Overall Response Rate a | ||
| ORR (95% CI) | 66% (60%, 73%) | 51% (44%, 58%) |
| P -value | < 0.001 | |
| Complete response | 10% | 8% |
| Partial response | 56% | 42% |
| Median DoR, months (95% CI) | 9.2 (7.4, NR) | 10.2 (7.5, NR) |
| Abbreviations: HR, hazard ratio; CI, confidence interval; NE, not estimable. a Pike estimator obtained from the stratified log-rank test. b Log-rank test stratified by disease stage (IIIA vs. IIIB vs. IIIC) and BRAF V600 mutation type (V600E vs. V600K). | ||
| Investigator-Assessed Endpoint | MEKINIST plus Dabrafenib N = 438 | Placebo N = 432 |
| Relapse-Free Survival | ||
| Number of events (%) | 166 (38) | 248 (57) |
| Median, months (95% CI) | NE (44.5, NE) | 16.6 (12.7, 22.1) |
| HR (95% CI) a | 0.47 (0.39, 0.58) | |
| P -value b | < 0.0001 | |
| Abbreviations: CI, confidence interval; DoR, duration of response; ORR, overall response rate. a Represents final analysis results (cutoff date of 24 Feb 2021) for the primary analysis responder cohorts. | |||
| Treatment | Dabrafenib | MEKINIST plus Dabrafenib | |
| Population | Previously Treated N = 78 | Previously Treated N = 57 | Treatment Naïve N = 36 |
| Overall Response Rate a | |||
| ORR (95% CI) | 27% (18%, 38%) | 61% (48%, 74%) | 61% (44%, 77%) |
| Complete response | 1% | 5% | 8% |
| Partial response | 26% | 56% | 53% |
| Duration of Response a | n = 21 | n = 35 | n = 22 |
| Median DoR, months (95% CI) | 18.0 (4.2, 40.1) | 9.0 (5.8, 26.2) | 15.2 (7.8, 23.5) |
| Abbreviations: ATC, anaplastic thyroid cancer; CI, confidence interval; DoR, duration of response; NE, not estimable; ORR, overall response rate. | |
| ATC Cohort Population | N = 36 |
| Overall Response Rate | |
| ORR (95% CI) | 53% (35.5%, 69.6%) |
| Complete response | 6% |
| Partial response | 47% |
| Duration of Response | n = 19 |
| Median DoR, months (95% CI) | 13.6 (3.8, NE) |
| % with DoR ≥ 6 months | 68% |
| % with DoR ≥ 12 months | 53% |
| Abbreviations: NA, not applicable; PR, partial response. a Excludes NSCLC (n = 6) and ATC (n = 36) (previously approved tumor types for MEKINIST in combination with dabrafenib). b Median DoR 9.8 months (95% CI: 5.3, 20.4). c Median DoR 13.6 months (95% CI: 5.5, 26.7). d Denotes a right-censored DoR. | ||||
| Tumor Type a | N | Objective Response Rate | Duration of Response | |
| % | 95% CI | Range (months) | ||
| Biliary tract cancer b | 48 | 46 | (31, 61) | 1.8 d, 40 d |
| High-grade glioma c | 48 | 33 | (20, 48) | 3.9, 44 |
| Glioblastoma | 32 | 25 | (12, 43) | 3.9, 27 |
| Anaplastic pleomorphic xanthoastrocytoma | 6 | 67 | (22, 96) | 6, 43 |
| Anaplastic astrocytoma | 5 | 20 | (0.5, 72) | 15 |
| Astroblastoma | 2 | 100 | (16, 100) | 15, 23 d |
| Undifferentiated | 1 | PR | (2.5, 100) | 6 |
| Anaplastic ganglioglioma | 1 | 0 | NA | NA |
| Anaplastic oligodendroglioma | 1 | 0 | NA | NA |
| Low-grade glioma | 14 | 50 | (23, 77) | 6, 29 d |
| Astrocytoma | 4 | 50 | (7, 93) | 7, 23 |
| Ganglioglioma | 4 | 50 | (7, 93) | 6, 13 |
| Pleomorphic xanthoastrocytoma | 2 | 50 | (1.3, 99) | 6 |
| Pilocytic astrocytoma | 2 | 0 | NA | NA |
| Choroid plexus papilloma | 1 | PR | (2.5, 100) | 29 d |
| Gangliocytoma/ganglioglioma | 1 | PR | (2.5, 100) | 18 d |
| Low-grade serous ovarian carcinoma | 5 | 80 | (28, 100) | 12, 42 d |
| Adenocarcinoma small intestine | 4 | 50 | (7, 93) | 7, 8 |
| Adenocarcinoma pancreas | 3 | 0 | NA | NA |
| Mixed ductal/adenoneuroendocrine carcinoma | 2 | 0 | NA | NA |
| Neuroendocrine carcinoma of colon | 2 | 0 | NA | NA |
| Ameloblastoma of mandible | 1 | PR | (2.5, 100) | 30 |
| Combined small cell-squamous carcinoma of lung | 1 | PR | (2.5, 100) | 5 |
| Mucinous-papillary serous adenocarcinoma of peritoneum | 1 | PR | (2.5, 100) | 8 |
| Adenocarcinoma of anus | 1 | 0 | NA | NA |
| Gastrointestinal stromal tumor | 1 | 0 | NA | NA |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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