Trametinib, an inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2 in cells with b-Raf serine-threonine kinase ( BRAF ) V600E or V600K mutations, is an antineoplastic agent.1
Trametinib, alone or in combination therapy, is used for the treatment of unresectable or metastatic melanoma in selected patients; the drug also is used in combination therapy for the adjuvant treatment of melanoma in selected patients.1
Trametinib, as a single agent, is not indicated for use in patients with melanoma who have experienced disease progression following treatment with a b-Raf serine-threonine kinase (BRAF) inhibitor.1
Trametinib is used in combination with dabrafenib as adjuvant therapy following complete resection of melanoma with BRAF V600E or V600K mutation and nodal involvement.1 An FDA-approved diagnostic test (e.g., THxID® BRAF kit) is required to confirm the presence of the BRAF V600E or V600K mutation prior to initiation of therapy.1, 6
The current indication for trametinib in combination with dabrafenib as adjuvant therapy following complete resection of melanoma with BRAF V600E or V600K mutation and nodal involvement is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (COMBI-AD) in patients who had undergone complete resection of stage III melanoma with BRAF V600E or V600K mutation (as detected by the bioMerieux THxID® BRAF V600 mutation test) and involvement of regional lymph nodes.1, 4 In this study, 870 patients were randomized (stratified by disease stage and BRAF mutation status) in a 1:1 ratio to receive trametinib 2 mg once daily with dabrafenib 150 mg twice daily or placebo for up to 12 months.1, 4 Patients enrolled in this study had undergone complete resection of melanoma with complete lymphadenectomy within 12 weeks of randomization.1 The primary measure of efficacy was relapse-free survival.1, 4 Secondary outcomes included overall survival and freedom from relapse.4 The median age of patients was 51 years; 99% were white, 55% were male, 91% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0, 65% had macroscopic lymph node involvement, 41% had tumor ulceration, 41% had stage IIIb disease, and 40% had stage IIIc disease.1 The majority (91%) of patients had a BRAF V600E mutation and 9% had a V600K mutation.1 Patients who had mucosal or ocular melanoma, unresectable in-transit metastases, or distant metastatic disease and those who had previously received systemic therapy (including radiation therapy) were not eligible to enroll in the study.1
After a median follow-up of 2.8 years, median relapse-free survival had not been reached in patients receiving trametinib in combination with dabrafenib and was 16.6 months in those receiving placebo.1, 4 In an updated analysis of this study at a median follow-up of 44 months, 3- or 4-year relapse-free rates were 59 or 54%, respectively, for dabrafenib plus trametinib.16 At a median of 42 months for those receiving placebo, 3- or 4-year relapse-free survival rates were 40 or 38%, respectively.16
Unresectable or Metastatic Melanoma
Trametinib is used as monotherapy, in BRAF-inhibitor treatment-naive patients, for the treatment of unresectable or metastatic melanoma harboring BRAF V600E or V600K mutations.1, 2 Trametinib has been designated an orphan drug by the FDA as monotherapy for the treatment of this cancer.3 An FDA-approved diagnostic test (e.g., THxID® BRAF kit) is required to confirm the presence of the BRAF V600E or V600K mutation prior to initiation of therapy.1, 6
The current indication for trametinib monotherapy in patients with unresectable or metastatic melanoma positive for V600E or V600K BRAF mutations is based principally on the results of a randomized, open-label, phase 3 study (METRIC study).1, 2 Trametinib improved progression-free survival and overall survival when compared with conventional chemotherapy.1, 2 A total of 322 adults (median 54 years of age, 54% male, more than 99% white, 36% with elevated lactate dehydrogenase [LDH]) were randomized in a 2:1 ratio to receive oral trametinib 2 mg daily or investigator's choice of chemotherapy (dacarbazine 1 g/m2 or paclitaxel 175 mg/m2) every 3 weeks.1, 2 In this study, 87% of patients with unresectable or metastatic melanoma had BRAF V600E mutations and 12% had V600K mutations.1, 2 The majority of patients (66%) had not received prior chemotherapy for advanced melanoma; prior use of MEK inhibitors, BRAF inhibitors, or ipilimumab was not allowed.1, 2 Once disease progression occurred, patients originally randomized to conventional chemotherapy were allowed to cross over to trametinib treatment.2 The primary measure of efficacy was progression-free survival.1 Median progression-free survival was 4.8 months in patients randomized to trametinib versus 1.5 months in patients randomized to conventional chemotherapy.1 The overall response rate was 22% in the trametinib group and 8% in the conventional chemotherapy group.1 Complete response was seen in 2 or 0% of patients given trametinib or conventional chemotherapy; partial response rates were 20 or 8%, respectively.1 Median duration of response was 5.5 months for patients randomized to trametinib and was not reached for those randomized to conventional chemotherapy.1
Trametinib is not indicated for use in patients with melanoma who have experienced disease progression following treatment with a BRAF inhibitor.1 In an open-label, phase 2 study in patients with unresectable or metastatic melanoma with BRAF mutations, no confirmed objective responses were observed in the cohort of 40 patients who had previously received treatment with a BRAF inhibitor.1, 7 The median progression-free survival among these patients was 1.8 months.7
Trametinib is used in combination with dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation.1 Trametinib has been designated an orphan drug by the FDA when used in combination with dabrafenib for the treatment of this cancer.3 An FDA-approved diagnostic test (e.g., THxID® BRAF kit) is required to confirm the presence of the BRAF V600E or V600K mutation prior to initiation of therapy.1, 6
The current indication for trametinib in combination with dabrafenib in the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation is based principally on the results of a randomized phase 3 study (COMBI-d) in patients with previously untreated stage IIIc or IV cutaneous melanoma with BRAF V600E or V600K mutation.1, 18 In this study, 423 patients were randomized in a 1:1 ratio to receive either trametinib (2 mg once daily) in combination with dabrafenib (150 mg twice daily) or dabrafenib in combination with placebo.1, 18 Treatment was continued until disease progression or unacceptable toxicity occurred, or the patient withdrew from the study; however, patients with disease progression could continue receiving treatment if they met prespecified criteria for continuation.18
A total of 423 patients were enrolled, with a median age of 56 years; more than 99% were white, 72% had an ECOG performance status of 0, 66% had stage M1c disease, 65% had normal LDH concentrations, and 2 patients had a history of brain metastases.1, 18, 18 Most patients (85%) had a BRAF V600E mutation and 15% had a V600K mutation.1, 18 The primary outcome was progression-free survival with secondary outcomes of overall survival, response rate, and response duration.18
At a median follow-up of 9 months, median progression-free survival was 9.3 or 8.8 months in patients receiving trametinib plus dabrafenib or placebo plus dabrafenib, respectively.1, 18 The overall response rates were 67 (10% as complete response) or 51% (9% as complete response) in patients given trametinib plus dabrafenib or placebo plus dabrafenib, respectively.1 The median duration of response was 9.2 and 10.2 months for trametinib plus dabrafenib versus placebo plus dabrafenib, respectively.1, 18
The COMBI-d trial was continued after analysis of the primary outcome to assess the secondary endpoint of overall survival.18, 30 A final analysis for overall survival estimated a prolonged median overall survival (25.1 versus 18.7 months) and a reduction in the risk of death (29%) in patients receiving trametinib in combination with dabrafenib.30 The 1-year overall survival estimates were 74 or 68% for trametinib plus dabrafenib versus placebo plus dabrafenib, respectively.30 The corresponding 2-year overall survival estimates were 51 or 42%, respectively.30 In addition, patients receiving trametinib and dabrafenib had higher overall response rates (66 versus 51%) compared with those receiving placebo and dabrafenib; complete responses were achieved in 10 or 8% of patients receiving trametinib in combination with dabrafenib or placebo in combination with dabrafenib, respectively.1 The median duration of response was 9.2 months in patients receiving trametinib in combination with dabrafenib and 10.2 months in those receiving dabrafenib alone.1 Results of a subgroup analysis (based on age, gender, disease stage, baseline ECOG performance status, baseline serum LDH concentration, visceral involvement, number of disease sites, and BRAF V600 mutation status) suggested that the effects of combination therapy with trametinib and dabrafenib on progression-free survival and overall survival were consistent across all subgroups.30
Trametinib in combination with dabrafenib also has been evaluated in 121 adults with melanoma and brain metastases in an open-label, multicohort phase 2 study (COMBI-MB).41 In this study, patients received dabrafenib 150 mg twice daily in combination with trametinib 2 mg daily until disease progression or unacceptable toxicity occurred.1 Eligible patients were required to have at least one measurable intracranial lesion.1 Patients with leptomeningeal disease, parenchymal brain metastases greater than 4 cm in diameter, ocular melanoma, or primary mucosal melanoma were excluded.1, 41 Previous therapy with up to two systemic therapies (except BRAF or MEK inhibitors) for metastatic melanoma was permitted prior to study entry.41 The primary efficacy outcome measure was intracranial response rate as assessed by independent review.1 Intracranial response rate was defined as the percentage of patients with confirmed intracranial complete or partial response (according to a modified Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 to allow up to 5 intracranial target lesions ≥5 mm in diameter).1, 41 Enrolled patients (N=121) were a median of 54 years of a 58% were male, 100% were white, 65% had baseline LDH concentrations within normal limits, and 97% had an ECOG performance status of 0 or 1.1 Most (87%) patients with intracranial metastases were asymptomatic and 13% were symptomatic; 87% of patients had extracranial metastases and 22% of patients had received prior therapy for brain metastases.1 The intracranial response rate was 50%; complete response was 4.1% and partial response rate was 46%.1 The median duration of intracranial response was 6.4 months (range 1-31 months).1 Stable or progressive disease was the best overall intracranial response for 9% of the responders.1
Trametinib in combination with dabrafenib has also been compared to immunotherapy (nivolumab and ipilimumab) in patients with unresectable stage III or IV melanoma in a 2-arm, 2-step, open-label, randomized phase 3 trial (DREAMseq).37 The goal of DREAMseq was to determine whether immunotherapy or the combination of BRAF and MEK inhibition should be preferred as initial therapy in patients with BRAF -mutant melanoma.37 Patients were required to have an ECOG performance status of 0 or 1 and be untreated in the metastatic setting, but were eligible if they had received adjuvant therapy that did not include a programmed death 1 (PD-1), programmed death-ligand 1 (PDL-1), cytotoxic T-cell lymphocyte-4, BRAF, or MEK inhibitor.37 In step 1 of this study, 265 patients were randomized in a 1:1 ratio to receive either trametinib (2 mg once daily) in combination with dabrafenib (150 mg twice daily) until disease progression or unacceptable toxicity occurred or nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) once every 3 weeks for 4 doses, followed by nivolumab alone (240 mg once every 2 weeks for up to 72 weeks); patients who experienced disease progression by RECIST criteria proceeded to step 2 where they crossed over to the alternate therapy.37 The primary endpoint of DREAMseq was 2-year overall survival among patients followed for at least 2 years.37
Enrolled patients were a median of 61 years of a 63% were male, 95% were white, and 60% had baseline LDH within normal limits.37 Most patients had BRAF V600E mutations; a higher proportion of patients randomized in step 1 to receive trametinib in combination with dabrafenib had BRAF V600K mutations (25%) compared to those randomized to immunotherapy (12%).37 Study accrual was halted by an independent data safety monitoring committee after an interim analysis, at which time 265 patients were randomized in step 1 and 73 patients had crossed over in step 2 (63% of whom were initially randomized to trametinib in combination with dabrafenib).37 The median follow-up was 27.7 months.37
The 2-year overall survival rate was substantially lower in patients initially randomized to trametinib in combination with dabrafenib compared to those initially randomized to immunotherapy (51.5% versus 71.8%, respectively).37 The data safety monitoring committee determined that this difference was clinically meaningful and recommended closing the study to accrual, with patients initially randomized to trametinib in combination with dabrafenib given the option to cross over to immunotherapy without prerequisite disease progression.37 The overall response rate for patients who received trametinib in combination with dabrafenib in step 1 was 43%, similar to this combination in step 2 (48%).37 Response rates appeared to be higher in patients who received immunotherapy in step 1 (46%) compared to those who received immunotherapy in step 2 (30%).37 The median duration of response among responders to step 1 therapy was not reached with immunotherapy and was 12.7 months with the combination of trametinib and dabrafenib.37
The 2023 American Society of Clinical Oncology (ASCO) guidelines on systemic therapy for melanoma provide recommendations for adjuvant treatment of patients with resected stage IIIA-D melanoma with BRAF mutation (V600E/K).200 For such patients, adjuvant therapy options include nivolumab, pembrolizumab, or dabrafenib plus trametinib, with no preference for one therapy over another, all given for 52 weeks.200 For patients with resected stage IV melanoma with BRAF mutation (V600E/K), dabrafenib plus trametinib can be offered.200
Patients with unresectable and/or metastatic mucosal melanoma may be offered the same treatment regimens as those recommended for cutaneous melanoma.200 However, due to limited data, the ASCO Expert Panel states that these patients should be offered or referred for enrollment in clinical trials whenever possible.200
Unresectable or Metastatic Melanoma
The 2023 ASCO guideline on systemic therapy for melanoma recommends one of the following as first-line therapy in patients with unresectable and/or metastatic cutaneous melanoma with BRAF mutations (V600): programmed cell death protein (PD-1) inhibitors (nivolumab alone; pembrolizumab alone; nivolumab plus ipilimumab followed by nivolumab; or nivolumab plus relatlimab); or combination BRAF/MEK inhibitor therapy (dabrafenib plus trametinib; encorafenib plus binimetinib; or vemurafenib plus cobimetinib).200 Per the ASCO guidelines, nivolumab plus ipilimumab is preferred as first-line therapy for patients with unresectable and/or metastatic BRAF - mutant (V600) disease over BRAF/MEK inhibitor combination therapy.200
For patients with BRAF mutation-positive (V600) unresectable/metastatic cutaneous melanoma who progress on first-line PD-1 inhibitor therapy, combination BRAF/MEK inhibitor therapy may be offered.200 Patients with BRAF mutation-positive (V600) unresectable/metastatic cutaneous melanoma who had disease progression following combination BRAF/MEK inhibitor therapy may be offered PD-1 inhibitor therapy.200
Trametinib is used in combination with dabrafenib for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients with BRAF V600E mutations.1 Trametinib has been designated an orphan drug by the FDA when used in combination with dabrafenib for the treatment of this cancer.3 An FDA-approved diagnostic test (e.g., THxID® BRAF kit) is required to confirm the presence of the BRAF V600E mutation prior to initiation of therapy.1, 6
Efficacy of trametinib in combination with dabrafenib for the treatment of metastatic NSCLC with BRAF V600E mutation is based principally on the results of an open-label, multicenter, nonrandomized, 3-cohort, phase 2 study (BRF113928).1, 31, 32, 33 Patients in the BRF113928 study were enrolled into 2 cohorts: those previously treated with 1-3 systemic therapies with disease progression following at least one platinum-containing regimen and those with treatment-naive metastatic NSCLC.1 The cohort of patients with previously treated disease received either single-agent dabrafenib (150 mg twice daily) or trametinib (2 mg once daily) in combination with dabrafenib (150 mg twice daily).1, 31, 33 The cohort of patients with previously untreated disease received trametinib (2 mg once daily) in combination with dabrafenib (150 mg twice daily).1, 32 Treatment was continued until disease progression or unacceptable toxicity occurred or the patient withdrew from the study.31, 32, 33 Patients with prior exposure to BRAF or MEK inhibitors were not eligible to enroll in the study;1, 31, 32, 33 however, prior exposure to epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitors was permitted in patients with EGFR- or ALK-positive tumors.1, 31, 32, 33 The primary measure of efficacy was objective response rate as assessed by an independent review committee according to RECIST and duration of response.1
Enrolled patients (N=171) were a median of 66 years of a 98% had squamous cell histology, 90% had an ECOG performance status of 0 or 1, 48% were male, 81% were white, 60% had a history of smoking, 48% were male, 32% were nonsmokers, 14% were Asian, 11% had received adjuvant chemotherapy, and 8% were current smokers.1 The majority (99%) of patients had metastatic disease; brain or liver metastases were present in 6 or 14% of these patients, respectively.1 Among the cohort of patients with previously treated disease, 58% had received only one prior systemic therapy for metastatic disease.1
In the cohort of patients with previously treated disease, the objective response rate was 27 or 61% in patients receiving single-agent dabrafenib or combination therapy with trametinib and dabrafenib, respectively, and the median duration of response was 18 or 9 months, respectively.1 In the cohort of patients receiving trametinib in combination with dabrafenib for treatment-naive disease, the overall response rate was 61%, with a median duration of response of 15.2 months.1 In an updated 5-year survival analysis of previously treated and treatment-naive patients, the overall response rates with dabrafenib in combination with trametinib were 68.4 or 63.9%, respectively.42 Median progression-free survival was 10.2 or 10.8 months for previously-treated and treatment-naive patients, respectively.42 Median overall survival was 18.2 or 17.3 months, respectively.42
Approximately 60% of patients with lung cancer have driver alterations (e.g., mutations in EGFR , ALK , or BRAF ; ROS-1 fusions, RET fusions, MET exon 14 skipping mutations, and NTRK fusions).201 The ASCO and Ontario Health (OH; previously known as Cancer Care Ontario) living guideline specifically addresses treatment of stage IV NSCLC with driver alterations, including BRAF gene alterations.201
For patients with stage IV NSCLC with a BRAF V600E mutation, dabrafenib and trametinib or encorafenib and binimetinib should be offered as first line treatment; however, standard first-line therapy based on the ASCO/OH nondriver mutation guideline may also be offered if these therapies are unavailable.201
In the second line setting, standard first-line treatment based on the ASCO/OH nondriver mutation guideline should be offered in patients with stage IV NSCLC harboring BRAF V600E driver alterations who were previously treated with BRAF/MEK inhibitor combination therapy.201 In patients who did not receive BRAF-targeted therapy in the first-line setting, dabrafenib in combination with trametinib or encorafenib in combination with binimetinib may be offered.201 For patients with stage IV NSCLC with BRAF mutations other than V600E, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.201
Trametinib is used in combination with dabrafenib for the treatment of locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation when no satisfactory locoregional treatment options are available.1 Trametinib has been designated an orphan drug by the FDA when used in combination with dabrafenib for the treatment of this cancer.3 Confirmation of the presence of the BRAF V600E mutation is necessary prior to initiation of therapy; no FDA-approved diagnostic test for the detection of the BRAF V600E mutation in anaplastic thyroid cancer is currently available.1
Efficacy of trametinib in combination with dabrafenib for the treatment of anaplastic thyroid cancer with BRAF V600E mutation is based principally on the results of an open-label, multicenter, nonrandomized, multicohort, phase 2 basket trial (BRF117019, ROAR) in patients with rare BRAF V600E mutation-positive malignancies.1, 34 In this trial, a cohort of 36 patients with locally advanced, unresectable, or metastatic anaplastic thyroid cancer received trametinib (2 mg once daily) in combination with dabrafenib (150 mg twice daily).1 Treatment was continued until disease progression or unacceptable toxicity occurred or the patient withdrew from the study.34 Patients with prior exposure to BRAF or MEK inhibitors, symptomatic or untreated CNS metastases, airway obstruction, or inability to swallow or retain oral drugs were not eligible to enroll in the study.1 The primary measure of efficacy was overall response rate as assessed by an independent review committee according to RECIST and duration of response.1
The median age of patients enrolled in the anaplastic thyroid cancer cohort was 71 years; 44% were male, 50% were white, 44% were Asian, and 94% had an ECOG performance status of 0 or 1.1 The majority of patients had received prior surgery and external beam radiation therapy (83% each) and 67% had received systemic therapy.1 The overall response rate in 36 evaluable patients in the anaplastic thyroid cancer cohort was 53%; complete response was achieved in 6% of the evaluable patients.1 The median duration of response was 13.6 months.1 Duration of response was ≥6 or ≥12 months in 68 or 53% of patients, respectively.1 A final analysis of data from the ROAR trial reported a median duration of response of 14.4 months, with a median progression-free survival of 6.7 months.43 The overall response rate was 56% based on investigator assessment.43
Approximately 40-70% of patients with anaplastic thyroid cancer have BRAF V600E driver alterations.202 Mainstays of therapy in addition to surgery involve locoregional approaches (commonly radiotherapy with or without concurrent chemotherapy) or systemic therapy (cytotoxic therapy or targeted therapy).202
The 2021 American Thyroid Association (ATA) guidelines for the management of anaplastic thyroid cancer recommend BRAF/MEK inhibitor combination therapy (dabrafenib in combination with trametinib) over other systemic therapies in patients with stage 4C or unresectable stage 4B anaplastic thyroid cancer harboring BRAF V600E mutation who decline radiation therapy.202 If radiotherapy is feasible in patients with BRAF V600E mutation-positive unresectable stage 4B anaplastic thyroid cancer, ATA recommends chemoradiotherapy or neoadjuvant dabrafenib-trametinib combination therapy as alternatives to initial treatment.202
BRAF V600E-mutant Solid Tumors
Trametinib is used in combination with dabrafenib for the treatment of adult and pediatric patients ≥1 year of age with unresectable or metastatic solid tumors (excluding colorectal cancer) harboring the BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment.1 The accelerated approval of the use of trametinib with dabrafenib for this indication is based on overall response rate and duration of response.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory studies.1 Trametinib has been designated an orphan drug by the FDA for the treatment of malignant glioma with BRAF V600 mutation.3 Confirmation of the presence of the BRAF V600E mutation is necessary prior to initiation of therapy; no FDA-approved diagnostic test for the detection of the BRAF V600E mutation in solid tumors other than melanoma and NSCLC is currently available.1
Trametinib is not indicated for use in patients with BRAF -mutant colorectal cancer because of intrinsic resistance to BRAF inhibition.1
Efficacy of trametinib in combination with dabrafenib for the treatment of unresectable or metastatic BRAF V600E-mutant solid tumors was shown in trials BRF117019 (ROAR), NCI-MATCH, CTMT212X2101, and CDRB436G2201, and supported by results of the COMBI-d, COMBI-v, and BRF113928 trials.1, 34, 35, 36, 43
In addition to adults with anaplastic thyroid cancer, the ROAR trial enrolled adults with high-grade glioma (N=45), low-grade glioma (N=13), gastrointestinal stromal tumor (N=1), biliary tract cancer (N=43), and adenocarcinoma of the small intestine (N=3).1
NCI-MATCH is a precision medicine clinical trial platform with multiple subprotocol cohorts; subprotocol H (EAY131-H) was a multicenter, single-arm, open-label phase 2 basket trial in adult patients with solid tumors, lymphoma, or multiple myeloma with BRAF V600 mutations who had received at least 1 prior line of standard therapy.35 Patients in NCI-MATCH received trametinib (2 mg once daily) and dabrafenib (150 mg twice daily) until disease progression or unacceptable toxicity occurred or the patient withdrew from the study.35 Patients were excluded from NCI-MATCH if they had melanoma, thyroid cancer, colorectal cancer, or NSCLC (following a protocol amendment), prior exposure to BRAF or MEK inhibitors, history of any RAS-mutant cancer, or left ventricular ejection fraction below the lower limit of normal, or if they did not have measurable disease.35 The primary endpoint of ROAR and EAY131-H was objective response rate.34, 35
A pooled analysis of ROAR and EAY131-H included a total of 131 patients with BRAF V600E-mutant solid tumors (excluding patients with NSCLC and anaplastic thyroid cancer).1 Among patients in the pooled analysis, 37% had biliary tract cancers, 37% had high-grade gliomas, 11% had low-grade gliomas, and 15% had other GI, lung, gynecologic, peritoneal, or various other tumors.1 In this pooled cohort, patients were a median of 51 years of a 56% were female, 85% were white, and 93% had an ECOG performance status of 0 (37%) or 1 (56%).1 Most patients (90%) had received prior systemic therapy.1
Among disease groups composed of more than 5 patients, RECIST objective response rate was 33% in those with high-grade gliomas, 46% in those with biliary tract cancers, and 50% in those with low-grade gliomas.1 Median duration of response was 13.6 months and 9.8 months in patients with high-grade gliomas and biliary tract cancers, respectively.1
CTMT212X2101 was a multicenter, multi-cohort, open-label phase 2 trial investigating trametinib monotherapy and trametinib in combination with dabrafenib in pediatric patients 1 to 17 years of age with recurrent or refractory cancers.1, 36 Part C of this study was a dose escalation of trametinib and dabrafenib in pediatric patients with BRAF V600-mutant tumors; part D was an expansion cohort in pediatric patients with BRAF V600-mutant low-grade glioma or Langerhans cell histiocytosis.44, 45 Patients received trametinib and dabrafenib at recommended dosage levels according to weight and age.36
A pooled analysis of parts C and D of the CTMT212X2101 trial included a total of 48 pediatric patients with BRAF V600E-mutant tumors, including 34 patients with low-grade gliomas and 2 patients with high-grade gliomas.1 Enrolled patients with gliomas were a median of 10 years of a 50% were male, 75% were white, and 58% had a Karnofsky/Lansky performance status of 100.1 Most patients had undergone prior surgical (83%) and/or systemic treatment (92%).1
Overall response rate among the pediatric patients with gliomas as assessed by independent review according to Response Assessment in Neuro-Oncology (RANO) criteria for gliomas, the major efficacy outcome in the pooled glioma analysis, was 25%.1 Among responders, duration of response was ≥6 months in 78% and ≥24 months in 44% of patients.1
Study CDRB436G2201 was a multicenter, randomized, open-label, phase 2 trial in chemotherapy-naïve pediatric patients with BRAF V600E-mutant low-grade gliomas and pediatric patients with relapsed or progressive BRAF V600E-mutant high-grade gliomas.1, 46 Forty-one patients with high-grade gliomas were enrolled and received trametinib plus dabrafenib.1 Enrolled patients in the cohort with high-grade gliomas were a median of 13 years of a 56% were female, 61% white, 27% Asian, and 37% had a Karnofsky/Lanksy performance status of 100.1 The primary endpoint was overall response rate, with secondary endpoints of duration of response and progression-free survival.46 At a median follow-up of 25.1 months, the overall response rate was 56% (29.3% assessed as complete response and 26.8% as partial response), with a median duration of response of 22.2 months.46 The rate of progression-free survival was 58.5%.46
Trametinib in combination with dabrafinib is used for treatment of low-grade glioma with BRAF V600E mutation in pediatric patients ≥1 year of age who require systemic therapy.1 Trametinib has been designated an orphan drug by the FDA when used in combination with dabrafenib for the treatment of this cancer.3 Confirmation of the presence of the BRAF V600E mutation is necessary prior to initiation of therapy; no FDA-approved diagnostic test for the detection of the BRAF V600E mutation in low-grade glioma is currently available.1
Efficacy of trametinib in combination with dabrafenib for treatment of low-grade glioma in pediatric patients was shown in a phase 2, multicenter, open-label trial (CDRB436G2201).1, 47 Patients 1 to <18 years of age with BRAF V600E-mutant low-grade glioma requiring systemic therapy were randomized to treatment at a 2:1 ratio to either trametinib plus dabrafenib or carboplatin plus vincristine.1, 47 Trametinib and dabrafenib were administered at age- and weight-based dosages until loss of clinical benefit or unacceptable toxicity occurred; carboplatin and vincristine were given as a single 10-week induction course followed by eight 6-week cycles.1 The primary outcome assessed was overall response rate, with secondary outcomes of progression-free survival and overall survival.1
Enrolled patients (N=110) were a median of 9.5 years of age and 60% were female.1 The overall response rate with trametinib plus dabrafenib was 46.6% (2.7% complete response and 44% partial response) versus 10.8% (2.7% complete response and 8% partial response) with chemotherapy.1 The median duration of response was 23.7 months with trametinib plus dabrafenib; the median duration of response was not estimable with chemotherapy.1 The median progression-free survival was 20.1 months with trametinib plus dabrafenib versus 7.4 months with chemotherapy.1
Trametinib is administered orally once daily (approximately every 24 hours), at least 1 hour before or 2 hours after a meal.1
If a dose of trametinib is missed by ≤12 hours, the missed dose should be taken as soon as it is remembered.1
If a dose of trametinib is vomited, do not take an additional dose; take the next dose at the regularly scheduled time.1
Do not crush or break trametinib tablets.1
Store trametinib tablets in the refrigerator at 2-8ºC; dispense the drug in its original bottle, protected from moisture and light, and instruct patients not to remove the desiccant or to repackage the drug in a pill box.1
Trametinib powder for oral solution must be reconstituted prior to use and is intended for administration by a caregiver.1
To reconstitute, tap the bottle to loosen the powder.1 Then, add 90 mL of distilled or purified water to the bottle and invert or shake for up to 5 minutes until powder is dissolved, yielding a clear solution.1
Once reconstituted, the solution yields a trametinib concentration of 0.05 mg/mL.1
The oral solution may be administered from an oral dosing syringe or feeding tube.1
Store unreconstituted powder in the refrigerator at 2-8ºC in the original carton to protect from moisture and light.1 After reconstitution, store oral solution at <25°C and do not freeze.1 Discard any remaining reconstituted solution after 35 days.1
Dosage of trametinib dimethyl sulfoxide is expressed in terms of trametinib.1
BRAF V600E-mutant Solid Tumors
When used in combination with dabrafenib for the treatment of pediatric patients ≥1 year of age with unresectable or metastatic solid tumors (excluding colorectal cancer) harboring the BRAF V600E mutation who have progressed following prior treatment and who have no satisfactory alternative treatment, the recommended dosage of trametinib oral solution and tablets is based on body weight (see Table 1 and Table 2).1 A recommended tablet dosage has not been established for patients weighing <26 kg.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
BRAF V600E-mutant Low-Grade Glioma
When used in combination with dabrafenib for the treatment of pediatric patients ≥1 year of age with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy, the recommended dosage of trametinib oral solution and tablets is based on body weight (see Table 1 and Table 2).1 A recommended tablet dosage has not been established for patients weighing <26 kg.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Body Weight | Recommended Oral Dosage |
|---|---|
8 kg | 0.3 mg (6 mL) once daily |
9 kg | 0.35 mg (7 mL) once daily |
10 kg | 0.35 mg (7 mL) once daily |
11 kg | 0.4 mg (8 mL) once daily |
12—13 kg | 0.45 mg (9 mL) once daily |
14—17 kg | 0.55 mg (11 mL) once daily |
18—21 kg | 0.7 mg (14 mL) once daily |
22—25 kg | 0.85 mg (17 mL) once daily |
26—29 kg | 0.9 mg (18 mL) once daily |
30—33 kg | 1 mg (20 mL) once daily |
34—37 kg | 1.15 mg (23 mL) once daily |
38—41 kg | 1.25 mg (25 mL) once daily |
42—45 kg | 1.4 mg (28 mL) once daily |
46—50 kg | 1.6 mg (32 mL) once daily |
≥51 kg | 2 mg (40 mL) once daily |
aConcentration of trametinib oral solution: 0.05 mg/mL.1
Body Weight | Recommended Oral Dosage |
|---|---|
26—37 kg | 1 mg (two 0.5-mg tablets) once daily |
38—50 kg | 1.5 mg (three 0.5-mg tablets) once daily |
≥51 kg | 2 mg once daily |
When used in combination with dabrafenib as adjuvant treatment following complete resection of melanoma with BRAF V600E or V600K mutation and nodal involvement, the recommended adult dosage of trametinib is 2 mg once daily.1 Therapy should be continued for up to 1 year or until disease progression or unacceptable toxicity occurs.1
When used for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation, the recommended adult dosage of trametinib (as a single agent or in combination with dabrafenib) is 2 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
When used in combination with dabrafenib for the treatment of metastatic NSCLC with BRAF V600E mutation, the recommended adult dosage of trametinib is 2 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
When used in combination with dabrafenib for the treatment of locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation when no satisfactory locoregional treatment options are available, the recommended adult dosage of trametinib is 2 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
BRAF V600E-mutant Solid Tumors
When used in combination with dabrafenib for the treatment of unresectable or metastatic solid tumors (excluding colorectal cancer) harboring the BRAF V600E mutation when no satisfactory alternative treatment is available, the recommended adult dosage of trametinib is 2 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
Dosage of trametinib may be reduced or therapy temporarily interrupted in patients who develop adverse effects.1 Up to 2 dosage reductions for toxicity may be made.1 Recommended dosage modifications for trametinib tablets and oral solutions are presented in Tables 3 and 4, respectively.1 Permanently discontinue trametinib if the patient is unable to tolerate a maximum of 2 dosage reductions.1
Recommended Dosage | 1 mg orally once daily | 1.5 mg orally once daily | 2 mg orally once daily |
|---|---|---|---|
First dose reduction | 0.5 mg (one 0.5-mg tablet) orally once daily | 1 mg (two 0.5-mg tablets) orally once daily | 1.5 mg (three 0.5-mg tablets) orally once daily |
Second dose reduction a | N/A | 0.5 mg (one 0.5-mg tablet) orally once daily | 1 mg (two 0.5-mg tablets) orally once daily |
aPermanently discontinue trametinib if unable to tolerate a maximum of 2 dosage reductions.1
Body Weight and Recommended Dosage | First Dose Reduction | Second Dose Reductionb |
|---|---|---|
8 kg 0.3 mg (6 mL) once daily | 5 mL once daily | 3 mL once daily |
9 kg 0.35 mg (7 mL) once daily | 5 mL once daily | 4 mL once daily |
10 kg 0.35 mg (7 mL) once daily | 5 mL once daily | 4 mL once daily |
11 kg 0.4 mg (8 mL) once daily | 6 mL once daily | 4 mL once daily |
12—13 kg 0.45 mg (9 mL) once daily | 7 mL once daily | 5 mL once daily |
14—17 kg 0.55 mg (11 mL) once daily | 8 mL once daily | 6 mL once daily |
18—21 kg 0.7 mg (14 mL) once daily | 11 mL once daily | 7 mL once daily |
22—25 kg 0.85 mg (17 mL) once daily | 13 mL once daily | 9 mL once daily |
26—29 kg 0.9 mg (18 mL) once daily | 14 mL once daily | 9 mL once daily |
30—33 kg 1 mg (20 mL) once daily | 15 mL once daily | 10 mL once daily |
34—37 kg 1.15 mg (23 mL) once daily | 17 mL once daily | 12 mL once daily |
38—41 kg 1.25 mg (25 mL) once daily | 19 mL once daily | 13 mL once daily |
42—45 kg 1.4 mg (28 mL) once daily | 21 mL once daily | 14 mL once daily |
46—50 kg 1.6 mg (32 mL) once daily | 24 mL once daily | 16 mL once daily |
≥51 kg 2 mg (40 mL) once daily | 30 mL once daily | 20 mL once daily |
aConcentration of trametinib oral solution: 0.05 mg/mL.1
bPermanently discontinue trametinib if unable to tolerate a maximum of 2 dosage reductions.1
Dosage Modification for New Primary Cutaneous Malignancies
If new primary cutaneous malignancies occur, no dosage modification of trametinib is recommended.1
Dosage Modification for New Primary Noncutaneous Malignancies
If new noncutaneous malignancies occur during combination therapy with trametinib and dabrafenib, no dosage modification of trametinib is required.1
Dosage Modification for Febrile Drug Reactions
If fever (temperature of 38-40°C) or any initial symptom of fever recurrence occurs, interrupt trametinib therapy until the adverse reaction resolves.1 Once fever resolves, trametinib may be resumed at the same or a reduced dosage.1
If fever (temperature exceeding 40°C) or fever complicated by rigors, hypotension, dehydration, or renal failure occurs, interrupt trametinib treatment until the adverse reaction resolves for at least 24 hours.1 Once fever has resolved, resume trametinib at the same or reduced dosage or permanently discontinue trametinib.1
Dosage Modification for Dermatologic Effects
If grade 2 skin toxicity develops and is intolerable, interrupt trametinib for up to 3 weeks.1 If grade 2 toxicity improves within 3 weeks of withholding trametinib, resume at a reduced dosage.1 If grade 2 skin toxicity does not improve within 3 weeks of withholding trametinib, permanently discontinue trametinib.1
If grade 3 or 4 skin toxicity occurs, interrupt trametinib for up to 3 weeks.1 If grade 3 or 4 skin toxicity does not improve within 3 weeks of withholding trametinib, permanently discontinue trametinib.1 If grade 3 or 4 skin toxicity improves within 3 weeks of withholding trametinib, resume at a reduced dosage.1
If severe cutaneous adverse reactions (SCARs) occur, permanently discontinue trametinib.1
Dosage Modification for Cardiac Effects
If an asymptomatic decrease in left ventricular ejection fraction (LVEF) from baseline of 10% or more and to a level below institution-specific lower limit of normal occurs, interrupt trametinib for up to 4 weeks.1 If LVEF improves to normal values within 4 weeks of withholding trametinib, resume at a reduced dosage.1 If LVEF does not improve to normal values within 4 weeks of withholding trametinib, permanently discontinue trametinib.1
If symptomatic cardiomyopathy or an absolute decrease in LVEF from baseline exceeding 20% and to a level below institution-specific lower limit of normal occurs, permanently discontinue.1
Dosage Modification for Hemorrhage
If grade 3 hemorrhagic events occur, interrupt trametinib treatment.1 If improvement is observed, resume trametinib at a lower dosage.1 If grade 3 hemorrhagic events do not improve, permanently discontinue trametinib.1
If any grade 4 hemorrhagic events occur, permanently discontinue trametinib.1
Dosage Modification for Venous Thromboembolism
If uncomplicated deep-vein thrombosis (DVT) or pulmonary embolism (PE) occurs, interrupt trametinib for up to 3 weeks.1 If improvement to grade 0 or 1 is observed within 3 weeks, resume trametinib at a lower dosage.1 If no improvement is observed within 3 weeks, permanently discontinue trametinib.1
If life-threatening PE occurs, permanently discontinue trametinib.1
Dosage Modification for Ocular Effects
If retinal pigment epithelial detachment occurs, interrupt trametinib for up to 3 weeks.1 If retinal pigment epithelial detachment improves within 3 weeks of withholding trametinib, resume at the same or a reduced dosage.1 If retinal pigment epithelial detachment does not improve within 3 weeks of withholding trametinib, resume at a reduced dosage or permanently discontinue trametinib.1
If retinal vein occlusion occurs, permanently discontinue trametinib.1
If uveitis occurs during combination therapy with trametinib and dabrafenib, no dosage modification of trametinib is necessary.1
Dosage Modification for Pulmonary Effects
If treatment-related interstitial lung disease or pneumonitis occurs, permanently discontinue trametinib.1
Dosage Modification for Other Toxicity
If an intolerable grade 2 or any grade 3 adverse reaction occurs, interrupt trametinib treatment.1 If the adverse reaction improves to grade 0 or 1, resume trametinib at a reduced dosage.1 If the adverse reaction does not improve to grade 0 or 1, permanently discontinue trametinib.1
At the first occurrence of any grade 4 adverse reaction, interrupt trametinib until the adverse reaction improves to grade 0 or 1 and then resume at a reduced dosage.1 If the grade 4 adverse reaction does not improve to grade 0 or 1, permanently discontinue trametinib.1 If there is a recurrent grade 4 adverse reaction, permanently discontinue trametinib.1
In patients with mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN, with any AST concentration), dosage adjustment is not necessary.1
An appropriate dosage has not been established in patients with moderate (bilirubin concentration >1.5-3 times the ULN and any AST concentration) to severe (bilirubin concentration 3-10 times the ULN and any AST concentration) hepatic impairment.1 No increase in exposure of trametinib occurred in patients with moderate or severe hepatic impairment compared with patients with normal hepatic function.1 Consider the potential risks and benefits of the drug when initiating trametinib therapy and when determining the appropriate dosage in patients with moderate or severe hepatic impairment.1
In patients with renal impairment (estimated glomerular filtration rate [GFR] 15-89 mL/minute per 1.73 m2), dosage adjustments are not necessary; no clinically important effects on the exposure of trametinib are anticipated.1
The manufacturer does not make any specific dosage recommendations for geriatric patients.1
When combination therapy with trametinib includes the use of dabrafenib, consult the manufacturer's prescribing information for dabrafenib for detailed information on the usual cautions, precautions, and contraindications of this drug.
New primary cutaneous and noncutaneous malignancies are a known class effect of b-Raf serine-threonine kinase (BRAF) inhibitors (i.e., dabrafenib, encorafenib, vemurafenib).29 Among adult patients receiving trametinib in combination with dabrafenib, cutaneous squamous cell carcinomas and keratoacanthomas occurred in 2% of patients in the pooled safety population.1 Basal cell carcinoma and new primary melanoma occurred in approximately 3% and <1% of patients, respectively.1 Among pediatric patients receiving trametinib in combination with dabrafenib, new primary melanoma was reported in <1% of patients.1
Dabrafenib may promote the growth and development of RAS mutation-positive noncutaneous malignancies.1 Among adult patients receiving trametinib in combination with dabrafenib, noncutaneous malignancies occurred in 1% of patients in the pooled safety population.1
Perform dermatologic evaluations for new cutaneous malignancies prior to initiation of combination therapy with trametinib and dabrafenib, every 2 months during therapy, and for up to 6 months following discontinuance of combination therapy.1 Close monitoring for signs and symptoms of new noncutaneous malignancies also is necessary.1 In patients developing new primary cutaneous malignancies or noncutaneous malignancies during combination therapy, dosage modification of trametinib is not necessary.1
Hemorrhage, including major hemorrhagic events (i.e., symptomatic bleeding in a critical area or organ), sometimes fatal, has occurred when trametinib is used in combination with dabrafenib.1 In the pooled safety population of adult patients receiving trametinib in combination with dabrafenib, hemorrhagic events occurred in 17% of patients.1 GI hemorrhage and intracranial hemorrhage occurred in 3% and 0.6% of patients receiving trametinib in combination with dabrafenib, respectively.1 Fatal hemorrhagic events (e.g., cerebral or brainstem hemorrhage) occurred in 0.5% of patients receiving trametinib in combination with dabrafenib.1
In the pooled safety population of pediatric patients receiving trametinib in combination with dabrafenib, hemorrhagic events occurred in 25% of patients.1 The most common type of bleeding was epistaxis, which occurrred in 16% of patients.1 Serious bleeding events developed in 3.6% of pediatric patients, which included GI hemorrhage (1.2%), cerebral hemorrhage (0.6%), uterine hemorrhage (0.6%), post-procedural hemorrhage (0.6%), and epistaxis (0.6%).1
If hemorrhagic events occur, dosage modification and/or treatment discontinuance may be necessary.1 For grade 3 hemorrhagic events, interrupt use of trametinib.1 If improvement occurs, resume trametinib at a lower dosage level.1 If improvement does not occur, permanently discontinue trametinib.1 For grade 4 hemorrhagic events, permanently discontinue trametinib.1
Colitis and GI perforation, sometimes fatal, have occurred in patients receiving trametinib as monotherapy or in combination with dabrafenib.1 In the pooled safety population of adults taking trametinib as monotherapy or in combination with dabrafenib, colitis and GI perforation each occurred in <1% of patients.1 In the pooled safety population of pediatric patients receiving trametinib in combination with dabrafenib, colitis occurred in <1% of patients.1
Patients should be monitored closely for manifestations of colitis and GI perforation.1
Venous thromboembolism (VTE) has occurred when trametinib is used in combination with dabrafenib.1 In the pooled safety population, deep-vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of adult patients receiving trametinib in combination with dabrafenib.1 In the pooled safety population of pediatric patients receiving trametinib in combination with dabrafenib, rates of embolism were <1%.1
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.1 Dosage modification or treatment discontinuance may be necessary if DVT or PE occurs.1
Cardiomyopathy, including cardiac failure, has occurred in patients receiving trametinib.1
Across the pooled safety population of adult patients receiving trametinib in combination with dabrafenib, cardiomyopathy (defined as an absolute decrease in left ventricular ejection fraction [LVEF] from baseline of ≥10% and to a level below the institution-specific lower limit of normal [LLN]) occurred in 6% of patients.1 Dosage interruption or discontinuance of trametinib was necessary in 3% or <1 %, respectively.1 Cardiomyopathy resolved in 45 of 50 patients receiving combination therapy with trametinib and dabrafenib.1 In the pooled safety population of pediatric patients receiving trametinib in combination with dabrafenib, cardiomyopathy occurred in 9% of patients.1
Before initiation of trametinib, as monotherapy or in combination with dabrafenib, assess LVEF using echocardiogram or multigated radionuclide angiography (MUGA).1 Reassess LVEF 1 month after initiation of trametinib and then every 2-3 months during treatment.1 Interrupt trametinib treatment for up to 4 weeks in patients experiencing an asymptomatic absolute decrease in LVEF from baseline of 10% or more and to a level below institution-specific lower limit of normal; if LVEF improves to normal values, may resume trametinib at a lower dose, but discontinue permanently if this improvement does not occur.1 Permanently discontinue trametinib in patients experiencing symptomatic cardiomyopathy or an absolute decrease in LVEF from baseline exceeding 20% and to a level below institution-specific lower limit of normal.1
Retinal pigment epithelial detachment and retinal vein occlusion can occur with trametinib.1
Retinal pigment epithelial detachment may be bilateral and multifocal, occurring in the macular region of the retina or other sites in the retina.1 Routine ophthalmologic examinations were not performed to detect asymptomatic retinal pigment epithelial detachment in clinical trials evaluating trametinib in patients with melanoma or non-small cell lung cancer (NSCLC); therefore, the true incidence of this adverse effect is unknown.1 In the pooled safety population of pediatric patients receiving trametinib in combination with dabrafenib, retinal pigment epithelial detachment occurred in <1% of patients.1
Retinal vein occlusion may lead to macular edema, decreased visual function, neovascularization, and glaucoma.1 Retinal vein occlusion occurred in 0.6% of adult patients receiving trametinib monotherapy in the pooled safety population; no cases of retinal vein occlusion were reported across the pooled safety population of patients who received trametinib with dabrafenib.1
Perform ophthalmologic examinations periodically and as clinically indicated during trametinib therapy.1 If visual disturbances are reported, urgent ophthalmologic evaluation (within 24 hours) is needed.1
If retinal pigment epithelial detachment is diagnosed, interrupt trametinib treatment.1 If repeat ophthalmologic evaluation confirms resolution of retinal pigment epithelial detachment within 3 weeks, resume trametinib at the same or a reduced dosage.1 If no improvement is observed within 3 weeks, resume trametinib at a reduced dosage or permanently discontinue trametinib. 1
If retinal vein occlusion is diagnosed, permanently discontinue trametinib.1
If uveitis occurs in patients receiving combination therapy with trametinib and dabrafenib, no dosage modification of trametinib is required.1
Interstitial Lung Disease/Pneumonitis
Interstitial lung disease or pneumonitis has been reported in patients receiving trametinib monotherapy or combination therapy with dabrafenib.1 In the pooled safety population, interstitial lung disease or pneumonitis occurred in 2% of adult patients receiving trametinib monotherapy.1 Across the pooled safety population, interstitial lung disease or pneumonitis occurred in 1% of adult patients receiving trametinib in combination with dabrafenib.1
In patients presenting with new or progressive pulmonary symptoms (including cough, dyspnea, hypoxia, pleural effusion, infiltrates), interrupt trametinib pending results of clinical investigation.1 Permanently discontinue trametinib in patients diagnosed with treatment-related interstitial lung disease or pneumonitis.1
Serious febrile drug reactions (including fever accompanied by hypotension, rigors/chills, dehydration, or renal failure) have occurred in patients receiving combination therapy with trametinib and dabrafenib.1
Across the pooled safety population evaluating combination therapy with trametinib and dabrafenib in adult patients, the incidence of pyrexia was 58%.1 In these studies, serious febrile reactions or fever of any severity complicated by hypotension, severe rigors/chills, dehydration, renal failure, or syncope occurred in 5% of patients receiving combination therapy with trametinib and dabrafenib.1 Fever was complicated by severe chills/rigors, renal failure, syncope, dehydration, or hypotension in <1, 1, 2, 3, or 4%, respectively, of patients receiving combination therapy with trametinib and dabrafenib.1 In the pooled safety population of pediatric patients receiving trametinib in combination with dabrafenib, pyrexia occurred in 66% of patients.1
Interrupt trametinib, and dabrafenib if used in combination, if the patient's temperature is ≥ 100.4°F (38.0°C).1 Evaluate for signs and symptoms of infection and monitor renal function (e.g., serum creatinine) during and following severe pyrexia.1 If the patient has recovered from the febrile reaction for at least 24 hours, restart trametinib, and dabrafenib if used in combination, at the same or reduced dosage.1 Administer prophylactic antipyretics in patients resuming trametinib following a serious febrile reaction or fever associated with complications.1 For second or subsequent occurrences of prolonged fever (lasting longer than 3 days) or fever associated with complications (e.g., dehydration, hypotension, renal failure, severe chills/rigors) without evidence of an active infection, administer corticosteroids (e.g., prednisone 10 mg daily) for at least 5 days.1
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms, have been reported in postmarketing surveillance during therapy with trametinib in combination with dabrafenib.1 Across the pooled safety population, other serious dermatologic toxicity occurred in <1% of adult patients receiving trametinib in combination with dabrafenib.1 Across the pooled safety population of pediatric patients receiving trametinib in combination with dabrafenib, serious skin and subcutaneous tissue disorders were reported in 1.8% of patients.1
Monitor for new or worsening serious skin toxicities.1 If dermatologic toxicity occurs, dosage modification or treatment discontinuance may be necessary.1 Permanently discontinue trametinib if SCARs occur.1
Hyperglycemia has occurred in patients receiving combination therapy with trametinib and dabrafenib.1 Across the pooled safety population, grade 3 or 4 hyperglycemia occurred in 2% of adult patients receiving trametinib in combination with dabrafenib.1 Among patients with a history of diabetes mellitus, 15% required intensification of antihyperglycemic therapy.1 In the pooled safety population of pediatric patients receiving trametinib in combination with dabrafenib, grade 3 or 4 hyperglycemia was reported in <1% of patients.1
Monitor serum glucose concentrations prior to initiation of therapy and as clinically appropriate in patients with preexisting diabetes mellitus or hyperglycemia.1 Initiate or optimize antihyperglycemic therapy as clinically indicated.1
Hemophagocytic Lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) has been reported in postmarketing reports from patients receiving trametinib in combination with dabrafenib.1 If HLH is suspected, treatment interruption is recommended.1 After confirmation of HLH, discontinue treatment and initiate appropriate management of HLH.1
Fetal/Neonatal Morbidity and Mortality
Trametinib may cause fetal harm in humans based on its mechanism of action and animal findings; the drug has been shown to be abortifacient and embryotoxic in rabbits at dosages resulting in exposures as low as 0.3 times the human exposure at recommended adult dosages.1
Verify pregnancy status in females of reproductive potential prior to initiating trametinib.1 Women with reproductive potential should use effective contraceptive methods while receiving trametinib and for 4 months following discontinuance of the drug.1 If pregnancy is confirmed or suspected during therapy, the patient should contact her clinician.1 If a woman is or becomes pregnant while taking trametinib, she should be informed of the risk to the fetus.1
Trametinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 Verify pregnancy status in females of reproductive potential prior to initiating trametinib.1
There are no data on the presence of trametinib in human milk, the effects on the breast-fed infant, or the effects on milk production.1 Because of the potential for serious adverse reactions to trametinib in breast-fed infants, advise women not to breast-feed while receiving the drug and for 4 months after the last dose.1
Females and Males of Reproductive Potential
Results of animal studies suggest that trametinib may reduce female fertility.1 In fertility studies, impairment of fertility (increased follicular cysts and reduced corpora lutea) was observed in female animals receiving trametinib at exposure levels equivalent to 0.3 times the human exposure at the recommended adult dosage.1
Verify pregnancy status in females of reproductive potential prior to initiating trametinib.1 Females of reproductive potential should use effective contraceptive methods during trametinib therapy and for 4 months following discontinuance of the drug.1
To avoid potential drug exposure to female partners who are pregnant or of reproductive potential, males should use condoms during trametinib therapy and for at least 4 months after the last dose.1
Safety and efficacy of trametinib monotherapy have not been established in pediatric patients.1
Safety and efficacy of trametinib in combination with dabrafenib have been established in pediatric patients ≥1 year of age with BRAF V600E mutation-positive unresectable or metastatic solid tumors who progressed on prior therapy (with no satisfactory treatment options) and BRAF V600E mutation-positive low-grade glioma requiring systemic therapy.1 The use of trametinib for these indications is supported by evidence from a study in pediatric patients with refractory or recurrent solid tumors (CTMT212X2101), and a study in pediatric patients with low-grade glioma (CDRB436G2201).1
Safety and efficacy of trametinib in combination with dabrafenib have not been established for these indications in pediatric patients <1 year of age.1
Clinical experience with trametinib monotherapy in patients 65 years of age or older with melanoma is insufficient to determine whether geriatric patients respond differently than younger adults.1
In clinical studies evaluating trametinib in combination with dabrafenib in patients with melanoma, 21% of patients were 65 years of age or older and 5% were 75 years of age or older.1 No overall differences in efficacy were observed between geriatric patients and younger adults, but some adverse effects (i.e., peripheral edema, anorexia) occurred more frequently in geriatric patients with metastatic melanoma.1
Clinical experience with trametinib in patients 65 years of age or older with NSCLC is insufficient to determine whether geriatric patients respond differently than younger adults.1
In clinical studies evaluating trametinib in combination with dabrafenib in anaplastic thyroid cancer, 77% of patients were 65 years of age and older and 31% were 75 years of age or older.1 An insufficient number of younger adults were included in the study to determine if there are differences in response to trametinib.1
In population pharmacokinetic analyses, systemic exposure of trametinib was not affected in patients with mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN, with any AST concentration).1
An appropriate dosage has not been established in patients with moderate (bilirubin concentration greater than 1.5-3 times the ULN and any AST concentration) to severe (bilirubin concentration 3-10 times the ULN and any AST concentration) hepatic impairment.1 No increase in exposure of trametinib occurred in patients with moderate or severe hepatic impairment compared with patients with normal hepatic function.1 Consider the potential risks and benefits of the drug when initiating trametinib therapy or determining the appropriate dosage in patients with moderate or severe hepatic impairment.1
During clinical trials, dose-limiting toxicities were not observed during the first cycle of therapy in 5 patients with moderate hepatic impairment (3 patients received an initial trametinib dosage of 1.5 mg once daily and 2 patients received an initial dosage of 2 mg once daily) and in 3 patients with severe hepatic impairment receiving trametinib (initial trametinib dosage of 1 mg once daily).1 One patient with severe hepatic impairment who received an initial trametinib dosage of 1.5 mg once daily experienced grade 3 acneiform rash.1
Systemic exposure of trametinib was not affected by renal impairment in patients with estimated glomerular filtration rate (eGFR) 15-89 mL/minute per 1.73 m2.1
The most common adverse reactions (≥20%) in adults with unresectable or metastatic melanoma receiving trametinib monotherapy are rash, diarrhea, and lymphedema.1
The most common adverse reactions (≥ 20%) in adults receiving trametinib in combination with dabrafenib for adjuvant treatment of melanoma include pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.1
The most common adverse reactions (≥ 20%) in adults receiving trametinib in combination with dabrafenib for unresectable or metastatic melanoma include pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema.1
The most common adverse reactions (≥ 20%) in adults receiving trametinib in combination with dabrafenib for metastatic NSCLC include pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.1
The most common adverse reactions (≥ 20%) in adults receiving trametinib in combination with dabrafenib for other solid tumors include pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema.1
The most common adverse reactions (≥ 20%) in pediatric patients receiving trametinib in combination with dabrafenib for solid tumors include pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia.1
The most common adverse reactions (≥ 20%) in pediatric patients receiving trametinib in combination with dabrafenib for low-grade glioma (LGG) include pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform.1
In vitro studies have indicated that trametinib is an inhibitor of cytochrome P-450 (CYP) isoenzyme 2C8.1
Trametinib is a substrate of P-glycoprotein (P-gp) and bile salt export pump (BSEP).1 Pharmacokinetic interactions are unlikely with drugs that inhibit the P-gp transport system since trametinib exhibits high passive permeability and bioavailability.1
Trametinib is not a substrate for CYP isoenzymes, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 1, multidrug resistance-associated protein (MRP) 2, or multidrug and toxic compound extrusion 1 (MATE1).1 Trametinib is not an inhibitor of CYP 1A2, 2A6, 2B6, 2C9, 2C19, or 2D6, and also is not an inhibitor of OATP1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, OCT2, P-gp, BCRP, BSEP, MRP2, or MATE1.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant use of trametinib 2 mg once daily with a sensitive CYP3A4 substrate had no clinically relevant effects on the area under the concentration-time curve (AUC) or peak plasma concentration of the sensitive CYP3A4 substrate.1
Concomitant administration of trametinib 2 mg once daily with dabrafenib resulted in no change in AUC of trametinib.1
Trametinib, a selective, reversible inhibitor of mitogen-activated extracellular signal regulated kinase (MEK) 1 and MEK2 activation and kinase activity in cells with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutations, is an antineoplastic agent.1, 2, 7 MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.1 Approximately 50% of cutaneous melanomas carry a BRAF mutation.2, 8, 9, 11 The most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 (BRAF V600E); a less frequently occurring BRAF mutation is the substitution of lysine for valine at codon 600 (BRAF V600K).7, 9 BRAF V600 mutations result in activation of the BRAF pathway that includes MEK 1 and 2.1 The mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).1, 9 Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo by decreasing cell proliferation, causing cell cycle arrest, and inducing apoptosis.1, 7 Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.1
Clinical resistance to monotherapy with a BRAF inhibitor, generally occurring 6-7 months following initiation of therapy, has been attributed to several possible resistance mechanisms mostly relying on reactivation of the MAPK/ERK pathway.13, 14, 15 Complete inhibition of the MAPK/ERK pathway resulting in durable responses may be achieved with the use of combination therapy with a BRAF inhibitor (i.e., dabrafenib, encorafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib).13, 14, 15 Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of tumor cell lines testing positive for BRAF V600 mutations in vitro.1 In addition, combination therapy was associated with prolonged inhibition of tumor growth in tumor xenografts testing positive for BRAF V600 mutations compared with either drug alone.1
Following oral administration, the absolute bioavailability of trametinib tablets and oral solution is 72 and 81%, respectively.1 Peak plasma concentrations of trametinib occur within 1.5 hours after oral administration.1 Following single and repeated once-daily doses of 0.125-4 mg as tablets, increases in peak plasma concentrations and AUC are dose proportional.1 Trametinib is 97.4% bound to plasma proteins.1 Administration of a single dose of trametinib tablets with a high-fat, high-calorie meal (approximately 1000 calories) decreased peak plasma concentrations and AUC of the drug by 70 and 24%, respectively, and delayed the rate of absorption (time to reach peak concentrations delayed by 4 hours).1 Trametinib is principally metabolized by deacetylation with or without mono-oxygenation or in combination with glucuronidation in vitro.1 The estimated terminal half-life of trametinib is 3.9-4.8 days.1 Following oral administration of a radiolabeled dose of trametinib, more than 80% of the dose is recovered in feces and less than 20% is recovered in urine.1 Age (18—93 years), sex, body weight (36—170 kg), and renal impairment (estimated glomerular filtration rate 15—89 mL/minute/1.73 m2) do not have a clinically significant impact on trametinib exposure.1 Insufficient data are available to assess whether race or ethnicity affect trametinib exposure.1 In pediatric patients 1—17 years of age, the pharmacokinetic exposures of trametinib at the recommended weight-adjusted dosage were within the range of those observed in adults.1 In this population, weight (6—156 kg) was shown to have a substantial impact on oral clearance of trametinib.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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