Dabrafenib, an inhibitor of b-Raf serine-threonine kinase ( BRAF ) with V600E or V600K mutation, is an antineoplastic agent.1
Dabrafenib is used as combination therapy for the adjuvant treatment of melanoma in patients with b-Raf serine-threonine kinase ( BRAF ) V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.1 Dabrafenib is also used for the treatment of unresectable or metastatic melanoma in patients with a BRAF V600E mutation (as monotherapy) or BRAF V600E or V600K mutations (as combination therapy) as detected by an FDA-approved test.1
Dabrafenib is not indicated for treatment of patients with wild-type BRAF solid tumors.1
Dabrafenib is used in combination with trametinib as adjuvant therapy following complete resection of melanoma with a BRAF V600E or V600K mutation and nodal involvement.1 This indication for dabrafenib 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, 15 In this study, 870 patients were randomized (stratified by disease stage and BRAF mutation status) in a 1:1 ratio to receive dabrafenib 150 mg twice daily with trametinib 2 mg once daily or placebo for up to 12 months.1, 15 Enrolled patients were required to have undergone complete resection of melanoma with complete lymphadenectomy within 12 weeks of randomization.1 The primary measure of efficacy was relapse-free survival.1, 15 The median age of patients was 51 years; 99% of patients were Caucasian, 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 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 dabrafenib in combination with trametinib and was 16.6 months in those receiving placebo; however, dabrafenib in combination with trametinib reduced the risk of relapse by 53% compared with placebo.1, 15 In an updated analysis at a median follow-up of 44 or 42 months for patients receiving dabrafenib in combination with trametinib or those receiving placebo, respectively, relapse-free survival remained similar to the primary results.16 Dabrafenib in combination with trametinib was associated with a numerically, but not significantly, higher estimated 3-year overall survival rate as compared with placebo.15 Results of a subgroup analysis (based on disease stage, lymph node involvement, presence of tumor ulceration) suggested that the effect of dabrafenib in combination with trametinib was consistent across all subgroups.16
Unresectable or Metastatic Melanoma
Dabrafenib is used as monotherapy for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation.1, 2, 5, 7 Dabrafenib has been designated an orphan drug by FDA for this use.3 This indication is based principally on the results of an open-label, randomized, phase 3 study (BREAK-3) in patients with previously untreated stage IV or unresectable stage III melanoma positive for BRAF V600E mutation.1 Patients receiving dabrafenib experienced longer progression-free survival when compared with those receiving dacarbazine.1, 2 In the BREAK-3 study, 250 adults (median age of 52 years, 60% male, 99% white, 67% with ECOG performance status of 0, 66% with stage M1c disease, 62% with normal lactate dehydrogenase [LDH]) were randomized in a 3:1 ratio to receive oral dabrafenib 150 mg twice daily or IV dacarbazine 1 g/m2 every 3 weeks; treatment was continued until disease progression, death, or study withdrawal occurred.1, 2 Patients who experienced disease progression while receiving dacarbazine were allowed to cross over to dabrafenib treatment.1, 2 The median duration of follow-up was 5.1 months in patients receiving dabrafenib and 3.5 months in those receiving dacarbazine.1 The median progression-free survival assessed radiographically or photographically by the investigator was 5.1 or 2.7 months for those receiving dabrafenib or dacarbazine, respectively.1, 2 Progression-free survival as assessed by an independent review committee was 6.7 or 2.9 months for patients receiving dabrafenib or dacarbazine, respectively.2 The independent review committee reported a confirmed objective response in 50% of patients receiving dabrafenib compared with 6% of those receiving dacarbazine.2 The estimated median duration of response was 5.5 months for those receiving dabrafenib and was not yet reached for those receiving dacarbazine.1, 2
Dabrafenib treatment has been shown to be effective in patients with melanoma with brain metastasis.1, 7 Dabrafenib was evaluated in a single-arm, open-label, phase 2 study (BREAK-MB) of 139 adults with melanoma positive for BRAF mutation (V600E) and at least one asymptomatic brain metastasis.1, 7 Patients received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable toxicity occurred.1, 7 Up to 2 previous treatment regimens for extracranial metastatic melanoma were allowed, but patients could not have received prior treatment with a BRAF inhibitor or a mitogen-activated extracellular signal regulated kinase (MEK) inhibitor.1, 7 The BREAK-MB study consisted of 2 cohorts: patients with no prior treatment for brain metastasis (median 50 years of age, 72% male, 59% with ECOG performance status of 0, 57% with elevated LDH) and those with prior local treatment for brain metastasis (median 51 years of age, 63% male, 66% with ECOG performance status of 0, 54% with elevated LDH).1 Among 139 patients with melanoma positive for BRAF V600E mutation, 18% in each cohort achieved an overall intracranial response (i.e., best intracranial response was a complete or partial response) as assessed by an independent review committee.1 The median duration of overall intracranial response was 4.6 months in both cohorts.1
Dabrafenib is used in combination with trametinib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation.1 Dabrafenib has been designated an orphan drug by FDA for this use.3 This indication is based principally on the results of 2 randomized phase 3 studies (COMBI-d and COMBI-v) in patients with previously untreated stage IIIc or IV cutaneous melanoma with BRAF V600E or V600K mutation and a nonrandomized open-label phase 2 study in previously treated or untreated patients with metastatic disease (COMBI-MB).1, 17, 18, 41 In the COMBI-d and COMBI-v studies, the primary measures of efficacy were progression-free survival and overall survival, respectively.1, 17, 18 In the COMBI-MB study, the primary outcome measure was intracranial response rate in patients with BRAF V600E mutation and asymptomatic melanoma brain metastases who had not received prior local brain-directed therapy.41
In the COMBI-d study, 423 patients were randomized in a 1:1 ratio to receive either dabrafenib (150 mg twice daily) in combination with trametinib (2 mg once 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 The median age of patients was 56 years; almost all patients (>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 Most patients (85%) had BRAF V600E mutation and 15% had a V600K mutation.1, 18 At a median follow-up of 9 months, median progression-free survival or overall survival was 9.3 or 25.1 months, respectively, in patients receiving dabrafenib in combination with trametinib compared with 8.8 or 18.7 months, respectively, in those receiving dabrafenib and placebo.1, 18 An updated analysis confirmed prolonged median progression-free survival in patients receiving dabrafenib in combination with trametinib compared with those receiving placebo and dabrafenib (11 versus 8.8 months).29 A final analysis for overall survival estimated a prolonged median overall survival in the dabrafenib and trametinib group versus the dabrafenib only group (25.1 versus 18.7 months).29 In addition, patients receiving dabrafenib and trametinib had a higher overall response rate (66 versus 51%) compared with those receiving dabrafenib and placebo; complete responses were achieved in 10% of patients receiving dabrafenib in combination with trametinib and 8% of those receiving dabrafenib and placebo.1 The median duration of response in patients receiving dabrafenib and trametinib or those dabrafenib and placebo was 9.2 or 10.2 months, respectively.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 dabrafenib and trametinib on progression-free survival and overall survival were consistent across all subgroups.29
In the COMBI-v study, 704 patients were randomized in a 1:1 ratio to receive either dabrafenib (150 mg twice daily) in combination with trametinib (2 mg once daily) or vemurafenib (960 mg twice daily).1, 17 The median age of patients was 55 years; 96% were Caucasian, 70% had an ECOG performance status of 0, 67% had normal LDH concentrations, 61% had stage M1c disease, 6% had stage IIIc disease, and one patient had a history of brain metastases.1, 17 Most patients (89%) had BRAF V600E mutation and 10% had a V600K mutation.1, 17 The median follow-up period at the time of the interim analysis was 11 months for those receiving dabrafenib in combination with trametinib and 10 months for those receiving vemurafenib alone.17 Median overall survival had not been reached in patients receiving dabrafenib in combination with trametinib and was 17.2 months in those receiving vemurafenib alone; however, dabrafenib in combination with trametinib reduced the risk of death by 31% compared with vemurafenib alone.1, 17 Patients receiving dabrafenib in combination with trametinib also had longer median progression-free survival (11.4 versus 7.3 months) and higher overall response rates (64 versus 51%) compared with patients receiving vemurafenib alone.1, 17 Because of the survival benefit observed at the interim analysis, study investigators permitted patients previously randomized to receive vemurafenib alone to cross over to combination therapy with dabrafenib and trametinib.17 Results of a subgroup analysis (based on age, gender, BRAF mutation status, ECOG performance status, and baseline LDH concentration) suggested that the effect of dabrafenib in combination with trametinib was consistent across most subgroups; an overall survival benefit for combination therapy with dabrafenib and trametinib versus vemurafenib was not apparent in the subgroup of patients with an ECOG performance status of 1 (hazard ratio: 1.03).17
Dabrafenib in combination with trametinib also has been evaluated in adults with melanoma with brain metastases in an open-label, multicohort, phase 2 study (COMBI-MB).41 In this study, 121 patients with previously treated metastatic melanoma received dabrafenib 150 mg twice daily in combination with trametinib 2 mg daily.1 Treatment was continued until disease progression or unacceptable toxicity occurred.1 Most patients (85%) had BRAF V600E and 15% had a V600K mutation.1 Eligible patients were required to have at least one measurable intracranial lesion, but no leptomeningeal disease, parenchymal brain metastases greater than 4 cm in diameter, ocular melanoma, or primary mucosal melanoma.1 Prior to study entry, patients could have received up to two previous systemic treatments, except BRAF or MEK inhibitors, for the treatment of metastatic melanoma.41 The primary efficacy outcome was confirmed intracranial response rate as assessed by an independent review committee using 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 The median age of patients in this study was 54 years; 58% were male, 100% were white, 65% had a normal LDH level at baseline, and 97% had an ECOG performance status of 0 or 1.1 Intracranial metastases were asymptomatic in 87% of patients and were symptomatic in 13% of patients; 87% had extracranial metastases and 22% had received prior local therapy for brain metastases.1 Confirmed intracranial response rate was 50%; complete or partial response was achieved in 4.1 or 46% of patients, respectively.1 The median duration of response was 6.4 months (range 1-31 months).1 Stable or progressive disease was the best overall response in 9% of patients with an intracranial response.1
Trametinib in combination with dabrafenib has also been compared to immunotherapy in patients with unresectable stage III or IV melanoma in the 2-arm, 2-step, open-label, randomized phase 3, DREAMseq trial.42 The aim 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.42 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, cytotoxic T-cell lymphocyte-4, BRAF, or MEK inhibitor.42 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 in combination with ipilimumab (1 mg/kg and 3 mg/kg, respectively, 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, in which they crossed over to the alternate therapy.42 The primary endpoint of DREAMseq was 2-year overall survival among patients followed for at least 2 years.42
The median age of patients enrolled in DREAMseq was 61 years; 63% were male, 95% were white, and 60% had baseline LDH within normal limits.42 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%).42
Study accrual was halted by an independent data safety monitoring committee after an interim analysis; at the 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).42 The median follow-up was 27.7 months.42 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).42 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.42 Overall response rates to step 1 treatment were similar between groups; patients who received trametinib in combination with dabrafenib in step 1 appeared to have similar response rates to those who received this combination in step 2 (43% versus 48%, respectively), whereas response rates appeared to be higher in patients who received immunotherapy in step 1 compared to those who received immunotherapy in step 2 (46% versus 30%, respectively).42 Duration of response among responders to step 1 therapy was significantly prolonged with immunotherapy compared to trametinib in combination with dabrafenib (median not reached versus 12.7 months, respectively).42
The 2023 American Society of Clinical Oncology (ASCO) guideline on systemic therapy for melanoma recommends offering nivolumab or pembrolizumab for a duration of 52 weeks to patients with resected stage IIIA/B/C/D BRAF wild-type cutaneous melanoma and, in those with BRAF mutation-positive (V600E/K) cutaneous melanoma, nivolumab alone, pembrolizumab alone, or combination therapy with dabrafenib and trametinib for a duration of 52 weeks.200 ASCO makes no recommendation for or against dabrafenib in combination with trametinib in patients with completely resected stage III/IV melanoma with BRAF mutations other than V600E/K.200 Ipilimumab and high-dose interferon are not recommended for routine use in adjuvant therapy.200 Because patients with stage III disease (regardless of BRAF mutation status) with microscopic sentinel node metastasis <1 mm in diameter generally have a relatively better prognosis and lower risk of relapse, ASCO states that treatment should be individualized after discussing the potential risks and benefits of therapy in these patients.200
Unresectable or Metastatic Melanoma
The 2023 ASCO guideline on systemic therapy for melanoma recommends offering ipilimumab plus nivolumab followed by nivolumab, nivolumab plus relatlimab, nivolumab alone, or pembrolizumab alone in patients with unresectable or metastatic BRAF wild-type cutaneous melanoma and, in those with BRAF mutation-positive (V600) cutaneous melanoma, ipilimumab plus nivolumab followed by nivolumab, nivolumab plus relatlimab, nivolumab alone, pembrolizumab alone, or combination BRAF/MEK inhibitor therapy (i.e., dabrafenib and trametinib; encorafenib and binimetinib; vemurafenib and cobimetinib) may be offered.200 Combination therapy with nivolumab plus ipilimumab is preferred as first-line therapy 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 Similarly, 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 Patients with mucosal melanoma may be offered the same treatment regimens as those recommended for cutaneous melanoma; however, in the absence of additional data, the ASCO Expert Panel states that patients with unresectable/metastatic mucosal melanoma should be offered or referred for enrollment in clinical trials whenever possible.200
ASCO states that switching between BRAF/MEK inhibitor combination regimens may be reasonable if patients experience toxicity since toxicity profiles may differ for each combination; however, no data exist regarding the efficacy of switching to a different BRAF/MEK combination.200
Dabrafenib is used in combination with trametinib for the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.1 Dabrafenib has been designated an orphan drug by FDA when used in combination with trametinib for the treatment of this cancer.3
Dabrafenib is not indicated for treatment of patients with wild-type BRAF solid tumors.1
This indication for dabrafenib in combination with trametinib in 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, 30, 31, 32 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 consisted of 2 cohorts who received either single-agent dabrafenib (150 mg twice daily) or dabrafenib (150 mg twice daily) in combination with trametinib (2 mg once daily).1, 30, 31 The cohort of patients with previously untreated disease received dabrafenib (150 mg twice daily) in combination with trametinib (2 mg once daily).1, 32 Treatment was continued until disease progression or unacceptable toxicity occurred or the patient withdrew from the study.30, 31, 32 Patients with prior exposure to BRAF or MEK inhibitors were not eligible to enroll in the study;1, 30, 31, 32 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, 30, 31, 32 The primary measure of efficacy was objective response rate as assessed by an independent review committee according to RECIST and duration of response.1 The median age of patients was 66 years; 98% had squamous cell histology, 90% had an ECOG performance status of 0 or 1, 81% were Caucasian, 60% had a history of smoking, 48% were male, 32% were nonsmokers, 14% were Asian, 11% had received adjuvant chemotherapy, 8% were current smokers, 3% were black, and 2% were Hispanic.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 63% in patients receiving single-agent dabrafenib or combination therapy with dabrafenib and trametinib, respectively, and the median duration of response was 9.9 or 12.6 months, respectively.1 In the cohort of patients receiving dabrafenib in combination with trametinib for treatment-naive disease, the objective response rate was 61%.1 In the overall study population, 52 or 59-64% of the patients who responded to single-agent dabrafenib or dabrafenib and trametinib combination therapy, respectively, had durable responses of 6 months or more.1
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
For patients with stage IV NSCLC with a BRAF V600E mutation, the ASCO living guideline states that combination therapy with either dabrafenib and trametinib or encorafenib and binimetinib may be offered as first line treatment.203
In the second-line setting, 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.203 For patients with stage IV NSCLC with BRAF mutations other than V600E, clinicians should offer standard therapy following the ASCO nondriver alteration guideline.203, 205
Dabrafenib is used in combination with trametinib for the treatment of locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation, as detected by an FDA-approved test, when no satisfactory locoregional treatment options are available.1 Dabrafenib has been designated an orphan drug by FDA for this use.3
Dabrafenib is not indicated for treatment of patients with wild-type BRAF solid tumors.1
This indication for dabrafenib in combination with trametinib in the treatment of anaplastic thyroid cancer with BRAF V600E mutation is based principally on the results of an open-label, multicenter, nonrandomized, multi-cohort, phase 2, basket trial (BRF117019; ROAR) in patients with rare BRAF V600E mutation-positive malignancies.1, 33 In this trial, a cohort of 36 patients with locally advanced, unresectable, or metastatic anaplastic thyroid cancer received dabrafenib (150 mg twice daily) in combination with trametinib (2 mg once daily).1 Treatment was continued until disease progression or unacceptable toxicity occurred or the patient withdrew from the study.33 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 objective 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 Caucasian, 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 previously received systemic therapy.1 The objective 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
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
Dabrafenib is used in combination with trametinib for the treatment of adults and pediatric patients 1 year of age and older 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 This indication is approved under accelerated approval 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 a confirmatory trial(s).1 Dabrafenib is designated an orphan drug by FDA for the treatment of malignant glioma.3
Dabrafenib is not indicated for use in patients with BRAF -mutant colorectal cancer because of intrinsic resistance to BRAF inhibition.1 Dabrafenib is not indicated for the treatment of patients with wild-type BRAF solid tumors.1
The indication for dabrafenib in combination with trametinib for the treatment of unresectable or metastatic BRAF V600E-mutant solid tumors is based on the results of the phase 2 ROAR trial in adults (including patients with anaplastic thyroid cancer), additional phase 2 trials in adults (protocol EAY131-H of the NCI-MATCH study) and pediatric patients (CTMT212X2101), and previously-described data from the COMBI-d and COMBI-v trials in patients with melanoma and the BRF113928 study in patients with NSCLC.1, 33, 43, 44 In addition to adults with anaplastic thyroid cancer, the ROAR trial enrolled adults with high-grade glioma, low-grade glioma, GI stromal tumor, biliary tract cancer, and adenocarcinoma of the small intestine.1 EAY131-H was a multicenter, single-arm, open-label, phase 2, basket trial in patients with solid tumors, lymphoma, or multiple myeloma with BRAF V600 mutations who had received at least 1 prior line of standard therapy.43 Patients in the study received trametinib (2 mg once daily) and dabrafenib (150 mg twice daily) until disease progression or unacceptable toxicity occurred.43 Patients with melanoma, thyroid cancer, colorectal cancer, or NSCLC (following a protocol amendment), prior exposure to BRAF or MEK inhibitors, history of any RAS-mutant cancer, left ventricular ejection fraction below the lower limit of normal, or no measurable disease were excluded.43 The primary endpoint of both the ROAR and EAY131-H studies was objective response rate.33, 43
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, or peritoneal tumors.1 In this pooled cohort, the median age was 51 years; 56% were female, 85% were white, 9% were Asian, and 93% had an ECOG performance status of 0 or 1.1 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 with recurrent or refractory solid tumors.1, 44 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 Patients received trametinib and dabrafenib at recommended dosage levels according to weight and age.44
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 Among the patients with gliomas, the median age was 10 years (range: 1 to 17 years); 50% were male, 75% were white, 8% were Asian, 3% were Black, and 58% had a Karnofsky/Lansky performance status of 100.1 Most patients had undergone prior surgical (83%) and/or systemic treatment (92%).1 Objective response rate 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 or longer in 78% and 24 months or longer in 44% of patients.1
Dabrafenib is used in combination with trametinib for the treatment of pediatric patients 1 year of age and older with low-grade glioma with a BRAF V600E mutation who require systemic therapy.1
Dabrafenib is not indicated for treatment of patients with wild-type BRAF solid tumors.1
This indication for dabrafenib in combination with trametinib for the treatment of BRAF V600E mutation-positive low-grade glioma in pediatric patients ≥1 year of age is based on the results from a phase 2 study (Study CDRB436G2201; NCT 02684058) involving 110 patients.1, 46 In this study, patients with low-grade glioma who required systemic therapy were randomly assigned to dabrafenib plus trametinib or carboplatin plus vincristine (standard care) in a 2:1 ratio.1, 46 The dosing of dabrafenib plus trametinib was age- and weight-based, with administration until disease progression or unacceptable toxicity occurred.1, 46 The dosing of carboplatin and vincristine was body surface area-based at doses of 175 mg/m2 and 1.5 mg/m2 (0.05 mg/kg for patients <12 kg), respectively, with a single 10-week induction course followed by eight 6-week maintenance cycles.1
The median age of enrolled patients was 9.5 years (range: 1 to 17) and 60% were female.1 The primary outcome was overall response rate; additional efficacy outcomes were progression-free survival and overall survival.1, 46 The primary efficacy analysis was conducted after all patients had completed at least 32 weeks of therapy.1, 46 Results revealed a substantial improvement in overall response rate and progression-free survival with dabrafenib plus trametinib in comparison to carboplatin plus vincristine.1, 46 The overall response rate was 47% with dabrafenib plus trametinib and 11% with carboplatin plus vincristine; median progression-free survival was 20.1 months for the combination of dabrafenib plus trametinib versus 7.4 months with carboplatin plus vincristine.1, 46 At the time of the interim analysis of overall survival, there was one death in the carboplatin plus vincristine arm with no deaths reported in the dabrafenib plus trametinib arm.1, 46 The overall survival results at interim analysis did not reach statistical significance.1
Recurrent somatic alterations in BRAF , particularly V600E mutations and gene fusions, are encountered in certain CNS tumors in adults and children.204 These include select low- and high-grade gliomas in adults, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma (up to 70% with BRAF V600E), and ganglioglioma (20 to 60% with BRAF V600E), and pediatric low-grade gliomas.204 Surgery and/or radiation are the cornerstones of management of adult gliomas, with cytotoxic chemotherapy typically reserved for cases refractory to these interventions.204 In children, surgery is frequently utilized for diagnosis and symptomatic management, while cytotoxic chemotherapy is a typical mainstay of therapy for disease control due to long-term sequalae associated with radiotherapy.204
The 2022 European Association of Neuro-Oncology, European Network for Rare Cancers, and Society for Neuro-Oncology joint guidelines for management of circumscribed astrocytic gliomas, glioneuronal, and neuronal tumors make general recommendations for treatment of these conditions in adults and children.204 In patients with BRAF -altered pilocytic astrocytoma, pleomorphic xanthoastrocytoma, or ganglioglioma, these guidelines recommend that use of BRAF and/or MEK inhibitors be considered.204
Administer dabrafenib orally twice daily (as capsules or tablets for oral suspension), approximately every 12 hours.1
Dabrafenib capsules: Administer capsules on an empty stomach (at least 1 hour before or 2 hours after a meal).1 Do not open, crush, or break the capsules.1
Dabrafenib tablets for oral suspension: Do not chew or crush tablets and do not swallow whole.1 Prepare the suspension by dissolving the tablets with approximately 5 mL (1 to 4 tablets) or 10 mL (5 to 15 tablets) of water in the provided cup.1 Gently stir the mixture with the handle of a teaspoon; full dissolution may take at least 3 minutes.1 The resulting suspension should be cloudy white in appearance.1 Administer the suspension immediately after preparation from the cup, oral dosing syringe, or feeding tube (10 French gauge or larger for 1 to 3 tablets; 12 French gauge or larger for 4 to 15 tablets).1 Administer the suspension on an empty stomach (at least 1 hour before or 2 hours after a meal).1 If a pediatric patient is unable to tolerate the fasting conditions, breastfeeding and/or baby formula may be administered on demand.1 Discard the suspension if not administered within 30 minutes after preparation.1
If a dose of dabrafenib is missed, take the dose as soon as it is remembered, but only if it can be taken at least 6 hours prior to the next scheduled dose.1
If vomiting occurs after administration, do not take an additional dose.1 Take the next dose at its scheduled time.1
Store dabrafenib capsules and tablets for oral suspension in the original bottle with the dessicant at 20-25°C (excursions permitted between 15-30°C).1
Dosage of dabrafenib mesylate is expressed in terms of dabrafenib.1 Refer to the trametinib prescribing information for recommended trametinib dosage regimens.1
The recommended dosage of dabrafenib capsules in adults is 150 mg orally twice daily.1
The recommended dosage of the tablets for oral suspension in adults is based on body weight (see Table 1).1
Body Weight (kg) | Recommended Dosage |
|---|---|
8 to 9 | 20 mg twice daily |
10 to 13 | 30 mg twice daily |
14 to 17 | 40 mg twice daily |
18 to 21 | 50 mg twice daily |
22 to 25 | 60 mg twice daily |
26 to 29 | 70 mg twice daily |
30 to 33 | 80 mg twice daily |
34 to 37 | 90 mg twice daily |
38 to 41 | 100 mg twice daily |
42 to 45 | 110 mg twice daily |
46 to 50 | 130 mg twice daily |
≥51 | 150 mg twice daily |
Continue therapy for up to 1 year or until disease progression or unacceptable toxicity occurs in the adjuvant melanoma setting.1 Continue therapy until disease progression or unacceptable toxicity occurs in the unresectable or metastatic melanoma or solid tumor, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer settings.1
The recommended dosage of dabrafenib capsules in pediatric patients 1 year of age or older is 150 mg orally twice daily for patients who weigh ≥51 kg, 100 mg orally twice daily for those who weigh 38-50 kg, and 75 mg orally twice daily for those who weigh 26-37 kg.1 A recommended dosage of dabrafenib capsules has not been established for patients weighing <26 kg.1
The recommended dosage of the tablets for oral suspension in pediatric patients is based on body weight (see Table 1).1
Continue therapy until disease progression or unacceptable toxicity occurs in the unresectable or metastatic solid tumor or low-grade glioma settings.1
Dosage Modification for Toxicity
Dosage of dabrafenib may be reduced or therapy temporarily interrupted or discontinued in patients who develop adverse effects.1 Dosage reductions for dabrafenib capsules and dabrafenib tablets for oral suspension for adverse reactions are presented in Tables 2 and 3, respectively.1 Permanently discontinue dabrafenib capsules if a patient is unable to tolerate the 50 mg twice daily dosage regimen.1
Recommended Dosage | 75 mg orally twice daily | 100 mg orally twice daily | 150 mg orally twice daily |
|---|---|---|---|
First Dose Reduction | 50 mg orally twice daily | 75 mg orally twice daily | 100 mg orally twice daily |
Second Dose Reduction | Not applicable | 50 mg orally twice daily | 75 mg orally twice daily |
Third Dose Reduction | Not applicable | Not applicable | 50 mg orally twice daily |
Body Weight (Recommended Dosage) | First Dose Reduction | Second Dose Reduction | Third Dose Reduction |
|---|---|---|---|
8 to 9 kg (20 mg twice daily) | 10 mg twice daily | Not applicable | Not applicable |
10 to 13 kg (30 mg twice daily) | 20 mg twice daily | 10 mg twice daily | Not applicable |
14 to 17 kg (40 mg twice daily) | 30 mg twice daily | 20 mg twice daily | 10 mg twice daily |
18 to 21 kg (50 mg twice daily) | 30 mg twice daily | 20 mg twice daily | 10 mg twice daily |
22 to 25 kg (60 mg twice daily) | 40 mg twice daily | 30 mg twice daily | 20 mg twice daily |
26 to 29 kg (70 mg twice daily) | 50 mg twice daily | 40 mg twice daily | 20 mg twice daily |
30 to 33 kg (80 mg twice daily) | 50 mg twice daily | 40 mg twice daily | 30 mg twice daily |
34 to 37 kg (90 mg twice daily) | 60 mg twice daily | 50 mg twice daily | 30 mg twice daily |
38 to 41 kg (100 mg twice daily) | 70 mg twice daily | 50 mg twice daily | 30 mg twice daily |
42 to 45 kg (110 mg twice daily) | 70 mg twice daily | 60 mg twice daily | 40 mg twice daily |
46 to 50 kg (130 mg twice daily) | 90 mg twice daily | 70 mg twice daily | 40 mg twice daily |
≥51 kg (150 mg twice daily) | 100 mg twice daily | 80 mg twice daily | 50 mg twice daily |
New Primary Cutaneous Malignancies
If new primary cutaneous malignancies occur, no dosage modification of dabrafenib is recommended.1
New Primary Noncutaneous Malignancies
If new RAS mutation-positive, noncutaneous malignancies occur, permanently discontinue dabrafenib.1
If fever (temperature of 38-40°C) or any initial symptom of fever recurrence occurs, interrupt dabrafenib treatment until the adverse reaction resolves.1 Once fever resolves, resume dabrafenib at the same or a reduced dosage.1
If a higher fever (temperature >40°C) or fever complicated by rigors, hypotension, dehydration, or renal failure occurs, permanently discontinue dabrafenib treatment or interrupt dabrafenib treatment until such adverse reactions resolve for at least 24 hours.1 Once fever resolves, resume dabrafenib at a reduced dosage.1
If grade 2 skin toxicity develops and is intolerable, withhold dabrafenib for up to 3 weeks.1 If grade 2 toxicity improves within 3 weeks of withholding dabrafenib, resume the drug at a reduced dosage.1 If grade 2 skin toxicity does not improve within 3 weeks of withholding dabrafenib, permanently discontinue the drug.1
If grade 3 or 4 skin toxicity occurs, withhold dabrafenib for up to 3 weeks.1 If grade 3 or 4 skin toxicity improves within 3 weeks of withholding dabrafenib, resume the drug at a reduced dosage.1 If grade 3 or 4 skin toxicity does not improve within 3 weeks of withholding dabrafenib, permanently discontinue the drug.1
If severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS) occur, permanently discontinue dabrafenib.1
If symptomatic cardiomyopathy occurs or LVEF decreases by >20% from baseline and to a level below the institutional lower limit of normal (LLN), withhold dabrafenib therapy; resume therapy at the same dosage when LVEF improves to at least the institutional LLN and the absolute level is ≤10% lower than at baseline.1
If an intolerable grade 2 or any grade 3 hemorrhagic events occur, withhold dabrafenib therapy.1 If improvement to grade 0 or 1 is observed, resume dabrafenib at a reduced dosage.1 If no improvement, permanently discontinue dabrafenib.1
Permanently discontinue dabrafenib for all grade 4 hemorrhagic events.1
If uncomplicated venous thromboembolism (VTE) occurs in patients receiving dabrafenib in combination with trametinib, no dosage modification of dabrafenib is recommended.1
If retinal pigment epithelial detachment or retinal vein occlusion occurs in patients receiving combination therapy with trametinib, no dosage modification of dabrafenib is needed.1
If iritis occurs, continue dabrafenib therapy at the same dosage and initiate ocular therapy.1
If mild or moderate uveitis occurs and is unresponsive to ocular therapy, interrupt dabrafenib treatment for up to 6 weeks.1 If improvement to grade 0 or 1 is observed within 6 weeks, resume dabrafenib therapy at the same or a reduced dosage.1 If no improvement is observed within 6 weeks, permanently discontinue dabrafenib therapy.1
If severe uveitis occurs, interrupt dabrafenib treatment for up to 6 weeks and initiate ocular therapy as clinically indicated.1 If improvement to grade 0 or 1 is observed within 6 weeks, resume dabrafenib therapy at the same or a reduced dosage.1 If no improvement is observed within 6 weeks or for persistent uveitis of grade 2 or greater, permanently discontinue dabrafenib therapy.1
If interstitial lung disease or pneumonitis occurs during combination therapy with dabrafenib and trametinib, no dosage modification of dabrafenib is needed.1
If an intolerable grade 2 adverse reaction or any grade 3 adverse reaction occurs, interrupt dabrafenib treatment until the adverse reaction resolves to grade 1 or less.1 Once the adverse reaction has resolved, resume dabrafenib at a reduced dosage.1 If no improvement is observed, permanently discontinue dabrafenib.1
For a first occurrence of any grade 4 adverse reaction, permanently discontinue dabrafenib treatment or interrupt until the adverse reaction resolves to grade 1 or less.1 Once the adverse reaction has resolved, resume dabrafenib at a reduced dosage.1 If a grade 4 adverse reaction recurs, permanently discontinue dabrafenib therapy.1
In patients with mild hepatic impairment (bilirubin ≤ the upper limit of normal [ULN] and AST >ULN or bilirubin >1-1.5 times the ULN and any AST level), dosage adjustments are not necessary.1
Patients with moderate hepatic impairment (bilirubin >1.5-3 times the ULN and any AST) or severe hepatic impairment (bilirubin >3-10 times the ULN and any AST) may have increased exposure to dabrafenib; however, an appropriate dosage has not been established for these patients.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
When combination therapy with dabrafenib includes the use of trametinib, the manufacturer's prescribing information for trametinib should be consulted for detailed information on the usual cautions, precautions, and contraindications of this drug.
New primary cutaneous or noncutaneous malignancies have been reported in patients receiving b-Raf serine-threonine kinase (BRAF) inhibitors, including dabrafenib.1
In clinical trials, cutaneous squamous cell carcinomas and keratoacanthomas occurred in 11% and 4%, respectively, of adult patients receiving dabrafenib monotherapy.1 Basal cell carcinoma and new primary melanoma occurred in 4% and 1% of patients, respectively.1
Among adults receiving dabrafenib in combination with trametinib, cutaneous squamous cell carcinomas including keratoacanthomas occurred in 2% of patients in clinical studies.1 Basal cell carcinoma and new primary melanoma occurred in approximately 3% and <1% of patients, respectively.1
Among pediatric patients receiving dabrafenib in combination with trametinib, new primary melanoma occurred in <1% of patients.1
Although the mechanism for development of cutaneous squamous cell carcinoma has not been fully determined, it has been suggested that paradoxical activation of mitogen-activated protein kinase (MAPK) signaling may lead to accelerated growth of such skin lesions as well as development of other primary malignancies.1, 19, 20, 21, 22, 27, 28 MAPK-mediated events in wild-type BRAF cells have been observed in a study evaluating the pathology and immunohistochemistry of normal and proliferating skin lesions in patients receiving the weak b-Raf kinase inhibitor sorafenib.20, 21, 22 Another study performed a molecular analysis of DNA extracted from tumor specimens of patients receiving the BRAF inhibitor vemurafenib; results indicated that these patients have a secondary mutation (in addition to the BRAF V600E mutation) that appears to be activated by vemurafenib treatment.27 Some clinicians suggest that advanced age (i.e., 65 years of age or older), history of skin cancer, and chronic sun exposure may be risk factors for developing cutaneous squamous cell carcinoma.19, 27 Some data suggest that mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors (i.e., binimetinib, cobimetinib, trametinib) block the paradoxical activation of the MAPK pathway induced by BRAF inhibitors (i.e., dabrafenib, encorafenib, vemurafenib); therefore, combination therapy with a BRAF inhibitor and an MEK inhibitor may reduce the risk of developing cutaneous squamous cell carcinoma.23, 24, 25 Findings from a meta-analysis of randomized controlled studies that assessed the relative risk of development of cutaneous squamous cell carcinoma in cancer patients receiving a BRAF inhibitor indicate that the risk of cutaneous squamous cell carcinoma is higher in patients receiving a BRAF inhibitor than in patients receiving combination therapy with a BRAF inhibitor and an MEK inhibitor.26
Perform dermatologic evaluations prior to initiation of therapy, every 2 months during therapy, and for up to 6 months following discontinuance of dabrafenib monotherapy or combination therapy with trametinib.1 In patients who develop new primary cutaneous malignancies during combination therapy with dabrafenib and trametinib, the manufacturer states that no dosage adjustment of dabrafenib is necessary.1
In clinical trials, noncutaneous malignancies occurred in 1% of patients receiving dabrafenib monotherapy or dabrafenib in combination with trametinib.1
Monitor for signs and symptoms of new noncutaneous malignancies.1 If new primary RAS mutation-positive, noncutaneous malignancies occur, permanently discontinue dabrafenib therapy.1
Tumor Promotion in Wild-Type BRAF Tumors
In vitro evidence of increased MAPK signaling and cell proliferation in wild-type BRAF cells exposed to BRAF inhibitors has been observed.1
Confirm presence of BRAF V600E or V600K mutation prior to initiating dabrafenib monotherapy or combination therapy with trametinib.1 Use of dabrafenib is not recommended in patients with wild-type BRAF solid tumors.1
Hemorrhage, including major hemorrhagic events (i.e., symptomatic bleeding in a critical area or organ), has occurred when dabrafenib is used in combination with trametinib; some cases have been fatal.1 In clinical trials in adults, hemorrhagic events occurred in 17% of patients receiving dabrafenib in combination with trametinib.1 Gastrointestinal hemorrhage and intracranial hemorrhage occurred in 3% and 0.6%, respectively, of adult patients receiving dabrafenib in combination with trametinib.1 Fatal hemorrhagic events (e.g., cerebral hemorrhage, brainstem hemorrhage) occurred in 0.5% of adults receiving the combination therapy.1 In clinical trials in pediatric patients, hemorrhagic events occurred in 25% of patients, with epistaxis the most common type of bleeding.1 Serious bleeding events, including GI hemorrhage, cerebral hemorrhage, uterine hemorrhage, postprocedural hemorrhage, and epistaxis, were observed in 3.6% of pediatric patients.1
If hemorrhagic events occur, dosage modification and/or treatment discontinuance may be necessary.1
Cardiomyopathy has been reported in patients receiving dabrafenib in combination with trametinib.1
In clinical trials in adults, cardiomyopathy (defined as an absolute decrease in left ventricular ejection fraction [LVEF] from baseline of ≥10% and to a level below institution-specific lower limit of normal) occurred in 6% of adults receiving dabrafenib in combination with trametinib.1 Dosage interruption or discontinuance of dabrafenib was necessary in 3% or <1%, respectively, of patients receiving dabrafenib in combination with trametinib.1 Cardiomyopathy resolved in 45 of 50 patients receiving the combination therapy.1
In clinical trials in pediatric patients, cardiomyopathy occurred in 9% of patients receiving dabrafenib in combination with trametinib.1
Assess LVEF using echocardiogram or multigated radionuclide angiography (MUGA) prior to and 1 month after initiation of dabrafenib in combination with trametinib and then every 2-3 months during therapy.1 If left ventricular dysfunction occurs, temporary interruption of dabrafenib may be necessary.1
Uveitis has occurred in patients receiving dabrafenib monotherapy or combination therapy with trametinib; cases of biocular panuveitis or biocular iridocyclitis have been reported in the postmarketing setting.1 In clinical trials, uveitis has been reported in 1% of adults receiving dabrafenib and in 2% and 1.2% of adult and pediatric patients, respectively, receiving dabrafenib in combination with trametinib.1 Symptomatic treatment (e.g., ophthalmic corticosteroid or mydriatic preparations) was used during clinical trials for management of this condition.1
Monitor patients receiving dabrafenib for signs and symptoms of uveitis (e.g., vision change, photophobia, eye pain).1 Temporary interruption, dosage reduction, or discontinuance of dabrafenib and/or initiation of ocular therapy may be necessary if uveitis occurs during therapy with the drug.1
Serious febrile drug reactions (including fever accompanied by hypotension, rigors/chills, dehydration, or renal failure) have occurred in patients receiving dabrafenib as monotherapy or as combination therapy with trametinib.1 In clinical trials in adults, fever occurred in 30% of adults receiving dabrafenib monotherapy.1 Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills, dehydration or renal failure occurred in 6% of adult patients receiving dabrafenib monotherapy.1 Increased incidence and severity of pyrexia have been observed during combination therapy with dabrafenib and trametinib compared with dabrafenib alone.1 In clinical trials, fever occurred in 58% of adults receiving dabrafenib in combination with trametinib.1 Serious febrile reactions and fever of any severity complicated by hypotension, rigors, chills, dehydration, or renal failure occurred in 5% of adult patients.1 In pooled safety data in pediatric patients, pyrexia was reported in 66% of patients during combination therapy with dabrafenib and trametinib in clinical trials.1
Interrupt dabrafenib monotherapy and combination treatment with trametinib and evaluate the patient for manifestations of infection if the patient's temperature is ≥38ºC.1 If severe pyrexia occurs, monitor renal function (e.g., serum creatinine) during and following severe pyrexia.1 Administer prophylactic antipyretics in patients resuming dabrafenib 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 (DRESS), have been reported in postmarketing surveillance during therapy with dabrafenib in combination with trametinib.1 Across clinical trials, other serious dermatologic toxicity occurred in <1% of adults receiving dabrafenib in combination with trametinib; serious adverse events of skin and subcutaneous tissue disorders occurred in 1.8% of pediatric patients receiving dabrafenib in combination with trametinib.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 dabrafenib if SCARs occur.1 For other skin toxicities, withhold dabrafenib for intolerable or severe skin toxicity.1 Resume treatment at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks; permanently discontinue dabrafenib if skin toxicity has not improved within 3 weeks.1
Hyperglycemia requiring increased dosage of insulin or oral hypoglycemic agents or requiring initiation of these agents has occurred in patients receiving dabrafenib as monotherapy or as combination therapy with trametinib.1 Across clinical trials of dabrafenib monotherapy, 14% of adults with a history of diabetes mellitus required intensification of hypoglycemic therapy; grade 3 and 4 hyperglycemia occurred in 3% of patients.1 Across clinical trials of adults receiving dabrafenib in combination with trametinib, grade 3 or 4 hyperglycemia occurred in 2% of patients; grade 3 or 4 hyperglycemia occurred in <1% of pediatric patients receiving the combination therapy.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
Glucose-6-Phosphate Dehydrogenase Deficiency
Dabrafenib contains a sulfonamide moiety and has the potential to induce hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.1
Monitor patients with G-6-PD deficiency for manifestations of hemolytic anemia during dabrafenib therapy.1
Hemophagocytic Lymphohistiocytosis
Dabrafenib in combination with trametinib may result in hemophagocytic lymphohistiocytosis (HLH).1 Interrupt therapy if HLH is suspected.1 If a diagnosis is confirmed, discontinue therapy and initiate appropriate management of HLH.1
Fetal/Neonatal Morbidity and Mortality
Dabrafenib may cause fetal harm based on its mechanism of action and animal findings; the drug has been shown to be teratogenic and embryotoxic in rats administered dabrafenib dosages equivalent to 3 times the human exposure achieved with recommended dosages.1
Verify pregnancy status in females of reproductive potential prior to initiation of therapy.1 Advise females of reproductive potential to use effective nonhormonal contraception during treatment and for 2 weeks after the last dabrafenib dose.1
Advise females to contact their clinician if pregnancy is suspected or confirmed.1
Dabrafenib may cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.1 If dabrafenib is used during pregnancy, the patient should be informed of the potential hazard to the fetus.1
It is not known whether dabrafenib is distributed into human milk.1 Because of the potential for serious adverse reactions to dabrafenib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 2 weeks after the last dose.1 The effects of the drug on breast-fed infants or on the production of milk are unknown.1
Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiation of therapy.1
Since hormonal contraceptives may be ineffective when used concomitantly with dabrafenib, female patients of reproductive potential should use an effective nonhormonal method of contraception during dabrafenib therapy and for 2 weeks after the last dose.1
To avoid potential drug exposure to pregnant partners and female partners of reproductive potential, advise male patients (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with dabrafenib and for at least 2 weeks after the last dose.1
Results of animal studies suggest that dabrafenib may reduce male and female fertility.1 In fertility studies, impairment of fertility (reduced corpora lutea in females and impaired spermatogenesis in males) was observed in animals receiving dabrafenib at exposure levels approximately or up to 3 times the human exposure at the recommended dosage.1
The safety and efficacy of dabrafenib in combination with trametinib 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 satisfatory alternative treatment options, or with low-grade glioma with BRAF V600E mutation who require systemic therapy.1 Dabrafenib in combination with trametinib for these indications is supported by evidence from 2 studies that enrolled 171 patients (between the ages of 1 to <18 years) with BRAF V600 mutation-positive advanced solid tumors.1 Safety and efficacy of dabrafenib in combination with trametinib have not been established in pediatric patients younger than 1 year of age.1
Safety and efficacy of dabrafenib as monotherapy have not been established in pediatric patients.1
No substantial differences in safety and efficacy of dabrafenib monotherapy have been observed in patients ≥65 years of age relative to younger adults.1
In clinical trials evaluating dabrafenib in combination with trametinib in patients with melanoma, 21% of patients were ≥65 years of age and 5% were ≥75 years of age.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 dabrafenib and trametinib combination therapy in patients ≥65 years of age with non-small cell lung cancer (NSCLC) is insufficient to determine whether geriatric patients respond differently than younger adults.1
In clinical trials evaluating dabrafenib and trametinib combination therapy in patients with anaplastic thyroid cancer, 77% of patients were ≥65 years of age.1 An insufficient number of younger adults were included in the study to determine whether geriatric patients respond differently than younger adults.1
Patients with moderate hepatic impairment (bilirubin >1.5-3 times the ULN and any AST) or severe hepatic impairment (bilirubin >3-10 times the ULN and any AST) may have increased exposure to dabrafenib; however, an appropriate dosage has not been established for these patients.1
Clinically relevant pharmacokinetic differences have not been observed in patients with renal impairment (estimated glomerular filtration rate [eGFR] of 15-89 mL/minute per 1.73 m2).1
Adverse effects reported in ≥20% of adult patients receiving dabrafenib monotherapy include hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome).1
Adverse effects reported in ≥20% of adult patients receiving dabrafenib in combination with trametinib for the treatment of previously untreated unresectable or metastatic melanoma include pyrexia, rash, chills, headache, arthralgia, and cough.1
Adverse effects reported in ≥20% of adult patients receiving dabrafenib in combination with trametinib for the adjuvant treatment of melanoma include pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.1
Adverse effects reported in ≥20% of adult patients receiving dabrafenib in combination with trametinib for the treatment of metastatic NSCLC include pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.1
Adverse effects reported in ≥20% of adult patients receiving dabrafenib in combination with trametinib for the treatment of solid tumors include: pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema.1
Adverse effects reported in ≥20% of pediatric patients receiving dabrafenib in combination with trametinib for the treatment of solid tumors include: pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia.1
Adverse effects reported in ≥20% of pediatric patients receiving dabrafenib in combination with trametinib for the treatment of low-grade glioma incude pyrexia, rash, headache, vomiting, musculokeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform.1
Dabrafenib is metabolized primarily by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C8.1
Dabrafenib is an inducer of CYP isoenzymes 3A4, 1A2, and 2C9.1 In vitro studies show that dabrafenib induces CYP3A4 and CYP2B6 via activation of the pregnane X receptor and constitutive androstane receptor.1 Dabrafenib also may induce CYP2C isoenzymes via this same mechanism of action.1
Dabrafenib and its metabolites, hydroxyl-dabrafenib and desmethyldabrafenib, are substrates of human P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1 Dabrafenib and its hydroxy, carboxy, and desmethyl metabolites are inhibitors of organic anion-transporting polypeptide (OATP) 1B1 and 1B3 as well as organic anion transporters (OAT) 1 and 3 in vitro.1
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP3A4 and CYP2C8
Potential pharmacokinetic interactions may occur when dabrafenib is used concomitantly with potent inhibitors of CYP isoenzymes 3A4 or 2C8 (e.g., gemfibrozil, ketoconazole) resulting in increased dabrafenib concentrations.1 In a pharmacokinetic study, concomitant administration of dabrafenib 75 mg twice daily and ketoconazole 400 mg once daily (a potent CYP3A4 inhibitor) for 4 days resulted in a 71% increase in AUC of dabrafenib, an 82% increase in the AUC of hydroxy-dabrafenib, and a 68% increase in the AUC of desmethyl-dabrafenib.1 In another study, concomitant administration of dabrafenib 75 mg twice daily and gemfibrozil 600 mg twice daily (a potent CYP2C8 inhibitor) for 4 days resulted in a 47% increase in the AUC of dabrafenib with no change in the AUC of dabrafenib's metabolites.1 Alternative therapy to potent inhibitors of CYP3A4 or 2C8 is recommended during dabrafenib therapy.1 If concomitant use is unavoidable, monitor the patient closely for dabrafenib-associated adverse reactions.1
Potential pharmacokinetic interactions may occur when dabrafenib is used concomitantly with potent inducers of CYP3A4 or moderate inducers of CYP2C8 (e.g., rifampin) resulting in decreased dabrafenib concentrations.1 In a pharmacokinetic study, concomitant administration of dabrafenib 150 mg twice daily and rifampin 600 mg once daily (a potent CYP3A4 and moderate CYP2C8 inducer) for 10 days resulted in a 34% decrease in AUC of dabrafenib, a 30% decrease in the AUC of desmethyl-dabrafenib, and no change in the AUC of hydroxy-dabrafenib.1
Drugs Metabolized by Hepatic Microsomal Enzymes
In a pharmacokinetic study, concomitant use of dabrafenib 150 mg twice daily for 15 days and a single dose of midazolam 3 mg (a CYP3A4 substrate) resulted in a 65% decrease in midazolam AUC.1 In another study, concomitant administration of dabrafenib 150 mg twice daily for 15 days and a single dose of warfarin sodium 15 mg resulted in a 37% decrease in the AUC of S -warfarin (a CYP2C9 substrate) and a 33% reduction in the AUC of R -warfarin (a CYP3A4/CYP1A2 substrate).1 Monitor the international normalized ratio (INR) frequently in patients receiving warfarin during initiation or discontinuance of dabrafenib.1
Potential pharmacokinetic interactions may occur when dabrafenib is used concomitantly with substrates of CYP isoenzymes 3A4, 1A2, 2B6, 2C8, 2C9, or 2C19 (e.g., dexamethasone, hormonal contraceptives, midazolam, warfarin sodium) possibly resulting in decreased concentrations and reduced efficacy of the substrate drug.1 Alternative therapy to the substrate drug is recommended.1 If concomitant use is unavoidable, monitor the patient closely for reduced efficacy of the substrate drug.1
Drugs Affected by Transport Proteins
Potential pharmacokinetic interactions may occur when dabrafenib is used concomitantly with drugs transported by OATP1B1, OATP1B3, OAT1, or OAT3.1 Concomitant administration of a single dose of the sensitive OATP1B1 and OATP1B3 substrate rosuvastatin with dabrafenib (150 mg twice daily) resulted in a 2.6-fold increase in peak plasma concentrations of rosuvastatin and no change in AUC of rosuvastatin.1
Drugs Affecting Gastric Acidity
Concomitant use of dabrafenib (150 mg twice daily) with the proton-pump inhibitor rabeprazole (40 mg once daily for 4 days) resulted in no clinically important changes in peak plasma concentration or systemic exposure of dabrafenib or its metabolites.1
Concomitant use of dabrafenib with hormonal contraceptives that are metabolized by CYP3A4, 1A2, or 2C9 may result in decreased systemic exposure and reduced efficacy of the contraceptive.1 Alternative nonhormonal contraception is recommended.1 If concomitant use is unavoidable, monitor the patient closely for reduced efficacy of the hormonal contraceptive.1
Concomitant administration of dabrafenib 150 mg twice daily with trametinib 2 mg once daily resulted in a 23% increase in AUC of dabrafenib, a 33% increase in AUC of desmethyl-dabrafenib, and no change in AUC of hydroxy-dabrafenib compared with administration of dabrafenib alone.1
Dabrafenib is an inducer of CYP isoenzymes 3A4, 1A2, and 2C9.1 Concomitant use of dabrafenib with warfarin may result in decreased systemic exposure to S -warfarin (a CYP2C9 substrate) and R -warfarin (a CYP3A4/CYP1A2 substrate).1 Monitor INR frequently in patients receiving warfarin during initiation or discontinuance of dabrafenib.1
Dabrafenib, a potent inhibitor of b-Raf serine-threonine kinase (BRAF) with V600E or V600K mutation, is an antineoplastic agent.1, 7, 8 Approximately 50% of cutaneous melanomas carry a BRAF mutation.2, 9 The most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E);9, 35, 36, 37, 38, 39, 40 a less frequently occurring BRAF mutation is the substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K).37, 38, 39, 40 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 In vitro studies indicate that dabrafenib also inhibits BRAF with V600D mutation.1, 10 Paradoxical activation of MAPK and increased cell proliferation have been observed in BRAF wild-type cells exposed to BRAF inhibitors.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.12, 13, 14 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).12, 13, 14 Use of dabrafenib and trametinib in combination resulted in greater growth inhibition of melanoma cell lines testing positive for BRAF V600 mutations in vitro.1 In addition, combination therapy was associated with prolonged inhibition of tumor growth in melanoma xenografts testing positive for BRAF V600 mutations compared with either drug alone.1
Following administration, the absolute bioavailability of dabrafenib is 95% for the capsules and 76% for the tablets for oral suspension.1 The median time to peak plasma concentrations of dabrafenib is 2 hours after oral administration.1 Following administration of a single dabrafenib dose within the dosage range of 12-300 mg, the drug exhibits dose-proportional increases in peak plasma concentrations and AUC; however, these increases are less than dose proportional after repeated twice-daily dosing.1 Administration of dabrafenib capsules with a high-fat meal (approximately 1000 calories) decreased peak plasma concentrations and AUC of the drug by 51 and 31%, respectively, and delayed the rate of absorption (time to reach peak concentrations delayed by 3.6 hours).1 Dabrafenib is more than 99% bound to plasma proteins; in vitro studies suggest that dabrafenib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1 Dabrafenib is principally metabolized by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C8.1 Dabrafenib is an inducer of CYP3A4 and 2C19 and may induce other CYP isoenzymes.1 The metabolites hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib.1 The mean terminal half-life of dabrafenib is 8 hours.1 Following oral administration of a radiolabeled dose of dabrafenib, about 71% of the dose is recovered in feces and 23% is recovered in urine.1
The pharmacokinetics of dabrafenib in pediatric patients (1 to <18 years of age) with glioma and other solid tumors following single or multiple doses are with range of values observed in adults given the same dose based on weight.1 Weight (6 to 156 kg) had a statistically significant effect of dabrafenib oral clearance in this population.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. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions June 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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