Generic Name: TRAMETINIB
Brand Name: Mekinist
- Substance Name(s):
- TRAMETINIB DIMETHYL SULFOXIDE
DRUG INTERACTIONS
7 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.
OVERDOSAGE
10 The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily.
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.
DESCRIPTION
11 Trametinib dimethyl sulfoxide is a kinase inhibitor.
The chemical name is acetamide, N-[3-[3-cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-, compound with 1,1’-sulfinylbis[methane] (1:1).
It has a molecular formula C 26 H 23 FIN 5 O 4 •C 2 H 6 OS with a molecular mass of 693.53 g/mol.
Trametinib dimethyl sulfoxide has the following chemical structure: Trametinib dimethyl sulfoxide is a white to almost white powder.
It is practically insoluble in the pH range of 2 to 8 in aqueous media.
MEKINIST (trametinib) tablets for oral use are supplied as 0.5 mg and 2 mg tablets for oral administration.
Each 0.5 mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-solvated parent.
Each 2 mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated parent.
The inactive ingredients of MEKINIST tablets are: Tablet Core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate (vegetable source), mannitol, microcrystalline cellulose, and sodium lauryl sulfate.
Coating: hypromellose, iron oxide red (2 mg tablets), iron oxide yellow (0.5 mg tablets), polyethylene glycol, polysorbate 80 (2 mg tablets), and titanium dioxide.
MEKINIST (trametinib) for oral solution is a white or almost white powder which produces a clear colorless solution when reconstituted with water.
Each bottle contains 4.7 mg of trametinib equivalent to 5.3 mg trametinib dimethyl sulfoxide.
Each mL of reconstituted trametinib solution contains 0.05 mg of trametinib non-solvated parent.
The inactive ingredients of MEKINIST for oral solution are betadex sulfobutyl ether sodium, citric acid monohydrate, dibasic sodium phosphate, methylparaben, potassium sorbate, sucralose, and strawberry flavor.
Trametinib Structure-01
CLINICAL STUDIES
14 Figure 1.
Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival (ITT Population) in the METRIC Study Figure 2.
Kaplan-Meier Curves of Overall Survival in the COMBI-d Study Figure 3.
Kaplan-Meier Curves for Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma Figure 4.
Kaplan-Meier Curves for Progression-Free Survival in Study G2201 (LGG cohort) 14.1 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.
Patients were randomized to receive MEKINIST 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1000 mg/m 2 intravenously every 3 weeks or paclitaxel 175 mg/m 2 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 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).
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%), had M1c disease (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 PFS in the patients treated with MEKINIST.
Table 20 and Figure 1 summarize the PFS results.
Table 20.
Efficacy Results in the METRIC Study 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) 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.
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 LDH level (> ULN vs.
≤ ULN) and BRAF mutation subtype (V600E vs.
V600K).
The major efficacy outcome was investigator-assessed 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), 53% were male, > 99% were White, 72% had ECOG performance status of 0, 4% had Stage IIIC, 66% had M1c disease, 65% had 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.
Table 21 and Figure 2 summarize the efficacy results.
Table 21.
Efficacy Results in the COMBI-d Study 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) Figure 2.
Kaplan-Meier Curves of Overall Survival 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 median age was 54 years (range: 23 to 84), 58% were male, 100% were White, 8% were from the United States, 65% had normal LDH at baseline, and 97% had an ECOG performance status of 0 or 1.
Intracranial metastases were asymptomatic in 87% and symptomatic in 13% of patients, 22% received prior local therapy for brain metastases, and 87% also had extracranial metastases.
The intracranial response rate was 50% (95% CI: 40, 60), 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.
14.2 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma The safety and efficacy of MEKINIST administered with dabrafenib were 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.
Patients were randomized (1:1) to receive MEKINIST 2 mg once daily in combination with dabrafenib 150 mg twice daily or two placebos for up to 1 year.
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 the MEKINIST in combination with dabrafenib and 432 to placebo.
Median age was 51 years (range: 18 to 89), 55% were male, 99% were White, and 91% had an ECOG performance status of 0.
Disease characteristics were AJCC Stage IIIA (18%), Stage IIIB (41%), Stage IIIC (40%), stage unknown (1%); BRAF V600E mutation (91%), BRAF V600K mutation (9%); macroscopic lymph nodes (65%); and tumor ulceration (41%).
The median duration of follow-up (time from randomization to last contact or death) was 2.8 years.
COMBI-AD showed a statistically significant improvement in RFS in patients randomized to MEKINIST in combination with dabrafenib arm 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 Treatment of Melanoma 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).
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 Figure 3.
Kaplan-Meier Curves for Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma 14.3 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 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 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 23.
Table 23.
Efficacy Results Based on Independent Review in Study BRF113928 Abbreviations: CI, confidence interval; DoR, duration of response.
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) 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 16.
14.4 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.
Patients received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily.
The major efficacy outcome measure was ORR per RECIST v1.1 as assessed by independent review committee (IRC) and duration of response (DoR).
Thirty-six patients were enrolled and were evaluable for response in the ATC cohort.
The median age was 71 years (range: 47 to 85); 44% were male, 50% White, 44% Asian; and 94% had ECOG performance status of 0 or 1.
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 Abbreviations: ATC, anaplastic thyroid cancer; CI, confidence interval; DoR, duration of response; ORR, overall response rate; NE, not estimable.
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% 14.5 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.
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.
14.6 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 [see Clinical Studies (14.2)] , and BRF113928 [see Clinical Studies (14.4)] .
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 [HGG] or modified RANO [LGG] criteria and duration of response (DoR).
BRF117019 Study and NCI-MATCH Study Study BRF117019 (NCT02034110) [see Clinical Studies (14.5)] 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 [see Clinical Studies (14.5)] .
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 mutation status for enrollment was determined either by central or local laboratory test.
The study included adult patients with solid tumors including gastrointestinal tumors (n = 14), lung tumors (n = 7), gynecologic or peritoneal tumors (n = 6), CNS tumors (n = 4), and ameloblastoma of mandible (n = 1).
Among the 131 patients enrolled in BRF117019 and NCI-MATCH with the tumor types shown in Table 21, the baseline characteristics were: median age of 51 years with 20% age 65 or older; 56% female; 85% White, 9% Asian, 3% Black, 3% other; and 37% ECOG 0, 56% ECOG 1, and 6% ECOG 2.
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 Abbreviations: 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 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.
For patients with BRAF V600E mutant LGG and HGG in Parts C and D, the median age was 10 years (range: 1 to 17); 50% were male, 75% White, 8% Asian, 3% Black; and 58% had Karnofsky/Lansky performance status of 100.
Prior anti-cancer treatments included surgery (83%), external beam radiotherapy (2.8%), and systemic therapy (92%).
The ORR was 25% (95% CI: 12%, 42%).
For the 9 patients who responded, DoR was ≥ 6 months for 78% of patients and ≥ 24 months for 44% of patients.
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 major efficacy outcome measure for the HGG cohort was ORR as assessed by independent review committee per RANO 2010 criteria.
The efficacy of MEKINIST in combination with dabrafenib was evaluated in 41 pediatric patients with relapsed or progressive HGG.
For patients with BRAF V600E mutant HGG enrolled in the HGG cohort, the median age was 13 years (range: 2 to 17); 56% were female, 61% White, 27% Asian, 2.4% Black, and 37% had Karnofsky/Lansky performance status of 100.
Prior anti-cancer treatments included surgery (98%), radiotherapy (90%), and chemotherapy (81%).
The ORR was 56% (95% CI: 40, 72).
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.
14.7 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 175 mg/m 2 and 1.5 mg/m 2 (0.05 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 (2017) criteria.
Additional efficacy outcome measures were progression-free survival and overall survival.
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).
Median age was 9.5 years (range: 1 to 17); 60% were female.
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 G2201 (LGG cohort) Abbreviations: CI, confidence interval; NE, not estimable.
a Based on Clopper-Pearson exact confidence interval b Based on Kaplan-Meier method c Based on proportional hazards model MEKINIST plus Dabrafenib N = 73 Carboplatin plus Vincristine N = 37 Overall Response Rate ORR% (95% CI) a 46.6 (34.8, 58.6) 10.8 (3.0, 25.4) P value < 0.001 Complete response, n (%) 2 (2.7) 1 (2.7) Partial response, n (%) 32 (44) 3 (8) Duration of Response Median (95% CI) b , months 23.7 (14.5, NE) NE (6.6, NE) % with observed DoR ≥ 12 months 56 50 % with observed DoR ≥ 24 months 15 25 Progression-Free Survival Median (95% CI) b , months 20.1 (12.8, NE) 7.4 (3.6, 11.8) Hazard ratio (95% CI) c 0.31 (0.17, 0.55) P value < 0.001 Figure 4.
Kaplan-Meier Curves for Progression-Free Survival in Study G2201 (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.
HOW SUPPLIED
16 /STORAGE AND HANDLING MEKINIST Tablets : 0.5 mg tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’ on the opposing face and are available in bottles of 30 (NDC 0078-0666-15).
0.5 mg tablets: Yellow, ovaloid, biconvex, unscored film-coated tablets with beveled edges and with the Novartis logo debossed on one side and ‘TT’ on the other side; available in bottles of 30 (NDC 0078-1105-15).
2 mg tablets: Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the opposing face and are available in bottles of 30 (NDC 0078-0668-15).
2 mg tablets: Pink, round, biconvex, unscored film-coated tablets with beveled edges and with the Novartis logo debossed on one side and ‘LL’ on the other side; available in bottles of 30 (NDC 0078-1112-15).
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].
Dispense in original bottle.
Do not remove desiccant.
Protect from moisture and light.
Do not place medication in pill boxes.
MEKINIST for Oral Solution : White or almost white powder in amber glass bottles, co-packaged with a press-in bottle adapter and an oral syringe.
Each bottle contains 4.7 mg of trametinib equivalent to 5.3 mg trametinib dimethyl sulfoxide.
Each mL of reconstituted strawberry flavored trametinib solution contains 0.05 mg of trametinib non-solvated parent.
(NDC 0078-1161-47).
Store refrigerated at 2°C to 8°C (36°F to 46°F).
Store in the original carton to protect from light and moisture.
After reconstitution, store in the original bottle below 25°C (77°F) and do not freeze.
Discard any unused solution 35 days after reconstitution.
GERIATRIC USE
8.5 Geriatric Use Of the 214 patients with melanoma who received single agent MEKINIST in the METRIC study, 27% were aged 65 years and older and 4% were over 75 years old [see Clinical Studies (14.1)] .
This study of single agent MEKINIST in melanoma did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger adults.
Of the 994 patients with melanoma who received MEKINIST plus dabrafenib in the COMBI-d, COMBI-v, and COMBI-AD studies [see Clinical Studies (14.1, 14.2)] , 21% were aged 65 years and older and 5% were aged 75 years and older.
No overall differences in the effectiveness of MEKINIST plus dabrafenib were observed in geriatric patients as compared to younger adults across these melanoma studies.
The incidences of peripheral edema (26% vs.
12%) and anorexia (21% vs.
9%) increased in geriatric patients as compared to younger adults in these studies.
Of the 93 patients with NSCLC who received MEKINIST in Study BRF113928, there were insufficient numbers of geriatric patients aged 65 and older to determine whether they respond differently from younger adults [see Clinical Studies (14.4)] .
Of the 26 patients with ATC who received MEKINIST in Study BRF117019, 77% were aged 65 years and older and 31% were aged 75 years and older [see Clinical Studies (14.4)] .
This study in ATC did not include sufficient numbers of younger adults to determine whether they respond differently compared to geriatric patients.
MECHANISM OF ACTION
12.1 Mechanism of Action Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity.
MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.
BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2.
Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.
Trametinib and dabrafenib target two different kinases in the RAS/RAF/MEK/ERK pathway.
Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation-positive tumor xenografts compared with either drug alone.
In the setting of BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors [see Indications and Usage (1.7)] .
INDICATIONS AND USAGE
1 MEKINIST is a kinase inhibitor indicated as a single agent for the treatment of BRAF-inhibitor treatment-naïve patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.
( 1.1 , 2.1 ) MEKINIST is indicated, 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.
( 1.1 , 2.1 ) 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.
( 1.2 , 2.1 ) the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.
( 1.3 , 2.1 ) the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options.
( 1.4 , 2.1 ) 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).
( 1.5 , 2.1 ) 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.
( 1.6 , 2.1 ) Limitations of Use : MEKINIST is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition.
( 1.7 , 12.1 ) 1.1 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 [see Dosage and Administration (2.1)] .
1.2 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 [see Dosage and Administration (2.1)].
1.3 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 [see Dosage and Administration (2.1)] .
1.4 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 and with no satisfactory locoregional treatment options [see Dosage and Administration (2.1)] .
1.5 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 [see Dosage and Administration (2.1)] .
This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.6)] .
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
1.6 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 [see Dosage and Administration (2.1)] .
1.7 Limitations of Use MEKINIST is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition [see Indications and Usage (1.5), Clinical Pharmacology (12.1)] .
PEDIATRIC USE
8.4 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.
Use of MEKINIST in combination with dabrafenib for these indications is supported by evidence from studies X2101 and G2201 that enrolled 171 patients (1 to < 18 years) with BRAF V600 mutation-positive advanced solid tumors, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (23%) patients were 2 to < 6 years of age, 54 (32%) patients were 6 to < 12 years of age, and 74 (43%) patients were 12 to < 18 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6, 14.7)] .
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.
PREGNANCY
8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1)] 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 2% to 4% and 15% to 20%, 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 [approximately 0.3 times the human exposure at the recommended adult dose based on area under the curve (AUC)].
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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS New Primary Malignancies, Cutaneous and Non-Cutaneous : Can occur when MEKINIST is used with dabrafenib.
Monitor patients for new malignancies prior to, or while on therapy, and following discontinuation of treatment.
( 5.1 ) Hemorrhage : Major hemorrhagic events can occur.
Monitor for signs and symptoms of bleeding.
( 5.2 ) Colitis and Gastrointestinal Perforation : Colitis and gastrointestinal perforation can occur in patients receiving MEKINIST.
( 5.3 ) Venous Thromboembolic Events : Deep vein thrombosis (DVT) and pulmonary embolism (PE) can occur in patients receiving MEKINIST.
( 5.4 , 2.4 ) Cardiomyopathy : Assess left ventricular ejection fraction (LVEF) before treatment, after one month of treatment, then every 2 to 3 months thereafter.
( 5.5 , 2.4 ) Ocular Toxicities : Perform ophthalmological evaluation for any visual disturbances.
For Retinal Vein Occlusion (RVO), permanently discontinue MEKINIST.
( 5.6 , 2.4 ) Interstitial Lung Disease (ILD)/Pneumonitis : Withhold MEKINIST for new or progressive unexplained pulmonary symptoms.
Permanently discontinue MEKINIST for treatment-related ILD or pneumonitis.
( 5.7 , 2.4 ) Serious Febrile Reactions : Can occur when MEKINIST is used with dabrafenib.
( 5.8 , 2.4 ) Serious Skin Toxicities : Monitor for skin toxicities and for secondary infections.
Permanently discontinue MEKINIST for intolerable Grade 2 or for Grade 3 or 4 rash not improving within 3 weeks despite interruption of MEKINIST.
Permanently discontinue for severe cutaneous adverse reactions (SCARs).
( 5.9 , 2.4 ) Hyperglycemia : Monitor serum glucose levels in patients with preexisting diabetes or hyperglycemia.
( 5.10 ) Hemophagocytic Lymphohistiocytosis (HLH) : Interrupt treatment for suspected HLH.
Discontinue treatment if HLH is confirmed.
( 5.12 ) Embryo-Fetal Toxicity : Can cause fetal harm.
Advise females of reproductive potential of potential risk to a fetus and to use effective contraception.
( 5.13 , 8.1 , 8.3 ) 5.1 New Primary Malignancies Cutaneous Malignancies MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , 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.
5.2 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 [see Adverse Reactions (6.1)] , 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%).
Serious events of bleeding occurred in 3.6% of patients and included gastrointestinal hemorrhage (1.2%), cerebral hemorrhage (0.6%) uterine hemorrhage (0.6%), post-procedural hemorrhage (0.6%), and epistaxis (0.6%).
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.
5.3 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 [see Adverse Reactions (6.1)] , 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.
5.4 Venous Thromboembolic Events MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients.
MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, embolism events occurred in < 1% 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 [see Dosage and Administration (2.4)] .
5.5 Cardiomyopathy Cardiomyopathy, including cardiac failure, can occur with MEKINIST.
MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , 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.
MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, cardiomyopathy, defined as a decrease in LVEF ≥ 10% from baseline and below the institutional LLN, occurred in 9% of patients.
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 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 LLN, permanently discontinue MEKINIST [see Dosage and Administration (2.4)] .
5.6 Ocular Toxicities Retinal Vein Occlusion In the pooled safety population [see Adverse Reactions (6.1)] of MEKINIST monotherapy, the incidence of retinal vein occlusion (RVO) was 0.6%.
In the pooled safety population [see Adverse Reactions (6.1)] 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 [see Dosage and Administration (2.4)] .
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.
In melanoma and NSCLC trials, routine monitoring of patients to detect asymptomatic RPED was not conducted; therefore, the true incidence of this finding is unknown.
MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, RPED events occurred in < 1% of patients.
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 [see Dosage and Administration (2.4)] .
5.7 Interstitial Lung Disease/Pneumonitis In the pooled safety population [see Adverse Reactions (6.1)] of MEKINIST monotherapy, interstitial lung disease or pneumonitis occurred in 2% of patients.
In the pooled safety population [see Adverse Reactions (6.1)] 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 [see Dosage and Administration (2.4)] .
5.8 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 [see Adverse Reactions (6.1)] , 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.
Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in < 1% of patients.
MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population [see Adverse Reactions (6.1)] , 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 [see Adverse Reactions (6.1)] .
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 [see Dosage and Administration (2.4)] .
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.
5.9 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 [see Adverse Reactions (6.2)] .
MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , other serious skin toxicity occurred in < 1% of patients.
MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, serious adverse events of skin and subcutaneous tissue disorders occurred in 1.8% of patients.
Monitor for new or worsening serious skin reactions.
Permanently discontinue MEKINIST for SCARs [see Dosage and Administration (2.4)] .
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 [see Dosage and Administration (2.4)] .
5.10 Hyperglycemia MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , 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.
MEKINIST Administered with Dabrafenib (Pediatric) : In the pooled safety population, Grade 3 and Grade 4 hyperglycemia events occurred in < 1% 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.
5.11 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.
5.12 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.
5.13 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 [see Use in Specific Populations (8.1, 8.3)] .
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
New Primary Cutaneous and Non-cutaneous Malignancies Advise patients that MEKINIST administered with dabrafenib can result in the development of new primary cutaneous and non-cutaneous malignancies.
Advise patients to contact their healthcare provider immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)] .
Hemorrhage Advise patients that MEKINIST administered with dabrafenib increases the risk of intracranial and gastrointestinal hemorrhage.
Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.2)] .
Colitis and Gastrointestinal Perforation Advise patients that MEKINIST can cause colitis and gastrointestinal perforation and to contact their healthcare provider for signs or symptoms of colitis or gastrointestinal perforation [see Warnings and Precautions (5.3)] .
Venous Thromboembolic Events Advise patients that MEKINIST administered with dabrafenib increases the risks of PE and DVT.
Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)] .
Cardiomyopathy Advise patients that MEKINIST can cause cardiomyopathy and to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)] .
Ocular Toxicities Advise patients that MEKINIST can cause severe visual disturbances that can lead to blindness and to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)] .
Interstitial Lung Disease/Pneumonitis Advise patients that MEKINIST can cause ILD (or pneumonitis).
Advise patients to contact their healthcare provider as soon as possible if they experience signs, such as cough or dyspnea [see Warnings and Precautions (5.7)] .
Serious Febrile Reactions Advise patients that MEKINIST administered with dabrafenib can cause serious febrile reactions.
Instruct patients to contact their healthcare provider if they develop a fever while taking MEKINIST with dabrafenib [see Warnings and Precautions (5.8)] .
Serious Skin Toxicities Advise patients that MEKINIST can cause serious skin toxicities, which may require hospitalization, and to contact their healthcare provider for progressive or intolerable rash.
Advise patients to contact their healthcare provider immediately if they develop signs and symptoms of a severe skin reaction [see Warnings and Precautions (5.9)] .
Hypertension Advise patients that MEKINIST can cause hypertension and that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension, such as severe headache, blurry vision, or dizziness [see Adverse Reactions (6.1)] .
Diarrhea Advise patients that MEKINIST often causes diarrhea which may be severe in some cases.
Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment [see Adverse Reactions (6.1)] .
Embryo-Fetal Toxicity Advise pregnant women and males of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.13), Use in Specific Populations (8.1, 8.3)] .
Advise females to contact their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after the last dose.
Advise male patients with female partners of reproductive potential to use condoms during treatment with MEKINIST and for 4 months after the last dose.
Lactation Advise women not to breastfeed during treatment with MEKINIST and for 4 months after the last dose [see Use in Specific Populations (8.2)] .
Infertility Advise females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)] .
Administration Instruct patients to take MEKINIST at least 1 hour before or at least 2 hours after a meal [see Dosage and Administration (2.3)] .
THxID ® BRAF assay is a trademark of bioMérieux.
Oncomine ™ Dx Target Test is a trademark of Life Technologies Corporation, a part of Thermo Fisher Scientific Inc.
Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2024-71
DOSAGE AND ADMINISTRATION
2 The recommended dosage of MEKINIST in adult patients is 2 mg orally once daily.
The recommended dosage for MEKINIST in pediatric patients is based on body weight.
Take MEKINIST at least 1 hour before or at least 2 hours after a meal.
( 2 ) 2.1 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 [see Clinical Studies (14.1, 14.2)] .
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 (14.3)] .
Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics .
ATC Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.4)] .
An FDA-approved test for the detection of BRAF V600E mutation in ATC is not currently available.
Solid Tumors Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.6)] .
An FDA-approved test for the detection of BRAF V600E mutation in solid tumors other than melanoma and NSCLC is not currently available.
Low-Grade Glioma Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.7)] .
An FDA-approved test for the detection of BRAF V600E mutation in LGG is not currently available.
2.2 Recommended Dosage MEKINIST Tablets Adult Patients The recommended dosage for MEKINIST tablets in adult patients is 2 mg orally taken once daily [see Dosage and Administration (2.3)] .
Pediatric Patients The recommended dosage for MEKINIST tablets in pediatric patients who weigh at least 26 kg is based on body weight (Table 1) [see Dosage and Administration (2.3)] .
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) 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 MEKINIST for Oral Solution The recommended dosage for MEKINIST for oral solution is based on body weight (Table 2) [see Dosage and Administration (2.3)] .
Table 2.
Recommended Dosage for MEKINIST for Oral Solution (Weight-based) 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) 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.
The recommended duration of treatment for pediatric patients with LGG is until disease progression or until unacceptable toxicity.
Refer to the dabrafenib prescribing information for recommended dabrafenib dosing information.
2.3 Administration Take MEKINIST at the same time each day, approximately 24 hours apart.
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.
If vomiting occurs after MEKINIST administration, do not take an additional dose.
Take the next dose at its scheduled time.
MEKINIST Tablets Do not crush or break MEKINIST tablets.
MEKINIST for Oral Solution 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.
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.
2.4 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 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.
Table 4.
Recommended Dosage Reductions for MEKINIST for Oral Solution for Adverse Reactions 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.
Dosage modifications for adverse reactions associated with MEKINIST are presented in Table 5.
Table 5.
Recommended Dosage Modifications for MEKINIST for Adverse Reactions 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 and is below institutional lower limit of normal (LLN) from pretreatment value 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 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.
Refer to the dabrafenib prescribing information for dose modifications for adverse reactions associated with dabrafenib.