"The U.S. Food and Drug Administration today approved two new drugs, Tafinlar (dabrafenib) and Mekinist (trametinib), for patients with advanced (metastatic) or unresectable (cannot be removed by surgery) melanoma, the most dangerous type of skin "...
Mechanism of Action
Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM, respectively, and other kinases such as SIK1, NEK11, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth [see INDICATIONS AND USAGE]. Dabrafenib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo.
After oral administration, median time to achieve peak plasma concentration (Tmax) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95%. Following a single dose, dabrafenib exposure (Cmax and AUC) increased in a dose-proportional manner across the dose range of 12 to 300 mg, but the increase was less than dose-proportional after repeat twice daily dosing. After repeat twice-daily dosing of 150 mg, the mean accumulation ratio was 0.73 and the inter-subject variability (CV%) of AUC at steady-state was 38%.
Administration of dabrafenib with a high-fat meal decreased Cmax by 51%, decreased AUC by 31%, and delayed median Tmax by 3.6 hours as compared to the fasted state [see DOSAGE AND ADMINISTRATION].
Dabrafenib is 99.7% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 70.3 L.
The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxydabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyldabrafenib is further metabolized by CYP3A4 to oxidative metabolites. Hydroxy-dabrafenib terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyldabrafenib metabolites exhibited longer half-lives (21 to 22 hours). Mean metabolite-to-parent AUC ratios following repeat-dose administration are 0.9, 11, and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on systemic exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib.
The mean terminal half-life of dabrafenib is 8 hours after oral administration. The apparent clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after 2 weeks of twice-daily dosing.
Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only.
Age, Body Weight and Gender: Based on the population pharmacokinetics analysis, age has no effect on dabrafenib pharmacokinetics. Pharmacokinetic differences based on gender and on weight are not clinically relevant.
Pediatric: Pharmacokinetics of dabrafenib have not been studied in pediatric patients.
Renal: No formal pharmacokinetic trial in patients with renal impairment has been conducted. The pharmacokinetics of dabrafenib were evaluated using a population analysis in 233 patients with mild renal impairment (GFR 60 to 89 mL/min/1.73 m²) and 30 patients with moderate renal impairment (GFR 30 to 59 mL/min/1.73 m²) enrolled in clinical trials. Mild or moderate renal impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with severe renal impairment.
Hepatic: No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. The pharmacokinetics of dabrafenib were evaluated using a population analysis in 65 patients with mild hepatic impairment enrolled in clinical trials. Mild hepatic impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with moderate to severe hepatic impairment.
Human liver microsome studies show that dabrafenib is a substrate of CYP3A4 and CYP2C8 while hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Dabrafenib is a substrate of human P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in vitro.
In human hepatocytes, dabrafenib produced dose-dependent increases in CYP2B6 and CYP3A4 mRNA levels up to 32 times the control levels and is a moderate inducer of CYP3A4 in vivo. In a clinical trial in 12 subjects following coadministration of repeat doses of dabrafenib and a single dose of midazolam (a CYP3A4 substrate), midazolam Cmax and AUC(0-∞) were decreased 61% and 74%, respectively. Dabrafenib is a moderate inducer of CYP3A4 and may induce other enzymes such as CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UDP glucuronosyltransferases (UGT) and may induce transporters.
Dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyldabrafenib, were inhibitors of human organic anion transporting polypeptide OATP1B1, OATP1B3, organic anion transporter OAT1 and OAT3 in vitro. Dabrafenib and desmethyldabrafenib are moderate inhibitors of BCRP in vitro.
Animal Toxicology and/or Pharmacology
Adverse cardiovascular effects were noted in dogs at dabrafenib doses of 50 mg/kg/day (approximately five times the human exposure at the recommended dose based on AUC) or greater, when administered for up to 4 weeks. Adverse effects consisted of coronary arterial degeneration/necrosis and hemorrhage, as well as cardiac atrioventricular valve hypertrophy/hemorrhage.
In Trial 1, the safety and efficacy of TAFINLAR were demonstrated in an international, multicenter, randomized (3:1), open-label, active-controlled trial conducted in 250 patients with previously untreated BRAF V600E mutation-positive, unresectable or metastatic melanoma. Patients with any prior use of BRAF inhibitors or MEK inhibitors were excluded. Patients were randomized to receive TAFINLAR 150 mg by mouth twice daily (n = 187) or dacarbazine 1,000 mg/m² intravenously every 3 weeks (n = 63). Randomization was stratified by disease stage at baseline [unresectable stage III (regional nodal or in-transit metastases), M1a (distant skin, subcutaneous, or nodal metastases), or M1b (lung metastases) vs. M1c melanoma (all other visceral metastases or elevated serum LDH)]. The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. In addition, an independent radiology review committee (IRRC) assessed the following efficacy outcome measures in prespecified supportive analyses: PFS, confirmed objective response rate (ORR), and duration of response.
The median age of patients in Trial 1 was 52 years. The majority of the trial population was male (60%), white (99%), had an ECOG performance status of 0 (67%), M1c disease (66%), and normal LDH (62%). All patients had tumor tissue with mutations in BRAF V600E as determined by a clinical trial assay at a centralized testing site. Tumor samples from 243 patients (97%) were tested retrospectively, using an FDA-approved companion diagnostic test, THxID™-BRAF assay.
The median duration of follow-up prior to initiation of alternative treatment in the TAFINLAR arm was 5.1 months and in the dacarbazine arm was 3.5 months. Twenty-eight (44%) patients crossed over from the dacarbazine arm at the time of disease progression to receive TAFINLAR.
Trial 1 demonstrated a statistically significant increase in progression-free survival in the patients treated with TAFINLAR. Table 5 and Figure 1 summarize the PFS results.
Table 5: Investigator-Assessed Progression-Free
Survival and Confirmed Objective Response Results
N = 187
N = 63
|Number of Events (%)||78 (42%)||41 (65%)|
|Median, months (95% CI)||5.1 (4.9, 6.9)||2.7 (1.5, 3.2)|
|HRa (95% CI)||0.33 (0.20, 0.54)|
|P-valueb||P < 0.0001|
|Confirmed Tumor Responses|
|Objective Response Rate||52%||17%|
|(95% CI)||(44, 59)||(9, 29)|
|CR, n (%)||6 (3%)||0|
|PR, n (%)||91 (48%)||11 (17%)|
|Duration of Response|
|Median, months (95% CI)||5.6 (5.4, NR)||NR (5.0, NR)|
|a Pike estimator, stratified by disease state.
b Stratified log-rank test.
CI = Confidence interval; CR = complete response; HR = hazard ratio; NR = not reached; PR =partial response
Figure 1: Kaplan-Meier Curves of Investigator-Assessed
In supportive analyses based on IRRC assessment and in an exploratory subgroup analysis of patients with retrospectively confirmed V600E mutation-positive melanoma with the THxID™- BRAF assay, the PFS results were consistent with those of the primary efficacy analysis.
The activity of TAFINLAR for the treatment of BRAF V600E mutation-positive melanoma, metastatic to the brain was evaluated in a single arm, open-label, two-cohort, multi-center trial (Trial 2). All patients received TAFINLAR 150 mg twice daily. Patients in Cohort A (n=74) had received no prior local therapy for brain metastases, while patients in Cohort B (n=65) had received at least one local therapy for brain metastases, including, but not limited to, surgical resection, whole brain radiotherapy, or stereotactic radiosurgery such as gamma knife, linearaccelerated- based radiosurgery, charged particles, or CyberKnife. In addition, patients in Cohort B were required to have evidence of disease progression in a previously treated lesion or an untreated lesion. Additional eligibility criteria were at least one measurable lesion of 0.5 cm or greater in largest diameter on contrast-enhanced MRI, stable or decreasing corticosteroid dose, and no more than two prior systemic regimens for treatment of metastatic disease. The primary outcome measure was estimation of the overall intracranial response rate (OIRR) in each cohort.
The median age of patients in Cohort A was 50 years, 72% were male, 100% were white, 59% had a pre-treatment ECOG performance status of 0, and 57% had an elevated LDH value at baseline. The median age of patients in Cohort B was 51 years, 63% were male, 98% were white, 66% had a pre-treatment ECOG performance status of 0, and 54% had an elevated LDH value at baseline. Efficacy results as determined by an independent radiology review committee, masked to investigator response assessments, are provided in Table 6.
Table 6: Efficacy Results in Patients with BRAF V600E
Melanoma Brain Metastases (Trial 2)
|Endpoint||IRRC Assessed Response|
N = 74
N = 65
|Overall Intracranial Response Rate (OIRR) % (95% CI)||18 (9.7, 28.2)||18 (9.9, 30.0)|
|Duration of OIRR||(N = 13)||(N = 12)|
|Median, months (95% CI)||4.6 (2.8, NR)||4.6 (1.9, 4.6)|
|IRRC = Independent radiology review committee; CI = Confidence interval; NR = not reached|
Last reviewed on RxList: 6/6/2013
This monograph has been modified to include the generic and brand name in many instances.
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