"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.
Dabrafenib and trametinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of dabrafenib and trametinib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone.
A dedicated study to evaluate the QT prolongation potential has not been conducted for TAFINLAR. In clinical trials, QTc (heart rate-corrected QT) prolongation to ≥ 500 ms occurred in 0.8% (2/264) of patients receiving TAFINLAR plus trametinib and in 1.5 % (4/264) of patients receiving TAFINLAR as a single agent. The QTc was increased > 60 ms from baseline in 3.8% (10/264) of patients receiving TAFINLAR plus trametinib and 3% (8/264) of patients treated with TAFINLAR as a single agent.
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 with 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 carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites. 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. Hydroxy-dabrafenib terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl-dabrafenib metabolites exhibit longer half-lives (21 to 22 hours). 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 has not been studied in pediatric patients.
Renal Impairment: 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 Impairment: No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. The pharmacokinetics of dabrafenib was 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.
Effect of Strong Inhibitors of CYP3A4 or CYP2C8 on Dabrafenib: In vitro studies show that dabrafenib is a substrate of CYP3A4 and CYP2C8 while hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Coadministration of dabrafenib 75 mg twice daily and ketoconazole 400 mg once daily (a strong CYP3A4 inhibitor) for 4 days increased dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%. Coadministration of dabrafenib 75 mg twice daily and gemfibrozil 600 mg twice daily (a strong CYP2C8 inhibitor) for 4 days increased dabrafenib AUC by 47%, with no change in the AUC of dabrafenib metabolites.
Effect of Dabrafenib on CYP Substrates: In vitro data demonstrate that dabrafenib is an inducer of CYP3A4 and CYP2B6 via activation of the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) nuclear receptors. Dabrafenib may also induce CYP2C enzymes via the same mechanism. Coadministration of dabrafenib 150 mg twice daily for 15 days and a single dose of midazolam 3 mg (a CYP3A4 substrate) decreased midazolam AUC by 74%. Coadministration of dabrafenib 150 mg twice daily for 15 days and a single dose of warfarin 15 mg decreased the AUC of S-warfarin (a CYP2C9 substrate) by 37% and the AUC of R-warfarin (a CYP3A4/CYP1A2 substrate) by 33% [see DRUG INTERACTIONS].
Effect of Transporters on Dabrafenib: Dabrafenib is a substrate of human P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate of organic cation transporter (OCT1) or organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1) in vitro. Hydroxy-dabrafenib and desmethyl-dabrafenib are not substrates of OATP1B1 or OATP1B3 in vitro.
Effect of Dabrafenib on Transporters: Dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl-dabrafenib, are inhibitors of OATP1B1, OATP1B3 and organic anion transporter (OAT1 and OAT3) in vitro. Dabrafenib and desmethyl-dabrafenib are inhibitors of BCRP in vitro.
Effect of Trametinib on Dabrafenib: Coadministration of trametinib 2 mg daily with dabrafenib 150 mg twice 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 as compared with administration of dabrafenib.
Effect of Acid Reducing Agents on Dabrafenib: Drugs that alter the pH of the upper GI tract (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of dabrafenib. When TAFINLAR is coadministered with a proton pump inhibitor, H2-receptor antagonist, or antacid, systemic exposure of dabrafenib may be decreased and the effect on efficacy of TAFINLAR is unknown.
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.
BRAF V600E Mutation-Positive Unresectable Or Metastatic Melanoma – TAFINLAR Administered As A Single Agent
In Trial 1, the safety and efficacy of TAFINLAR as a single agent 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 orally 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) versus 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 pre-specified 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 durations of follow-up prior to initiation of alternative treatment in patients randomized to receive TAFINLAR 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 7 and Figure 1 summarize the PFS results.
Table 7: Investigator-Assessed Progression-Free
Survival and Confirmed Objective Response Results in Trial 1
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)|
|† CI = Confidence interval; HR = Hazard ratio; CR =
Complete response; PR = Partial response; NR = Not reached.
a Pike estimator, stratified by disease state.
b Stratified log-rank test.
Figure 1: Kaplan-Meier Curves of Investigator-Assessed
Progression-Free Survival in Trial 1
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 multicenter trial. 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, linear-accelerated-based radiosurgery, or charged particles. 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 8.
Table 8: Efficacy Results in Patients with BRAF V600E
Melanoma Brain Metastases
|IRRC-assessed Endpoints||Cohort A
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.|
BRAF V600E Or V600K Unresectable Or Metastatic Melanoma – TAFINLAR Administered With Trametinib
The safety and efficacy of TAFINLAR administered with trametinib were evaluated in two international, randomized, active-controlled trials: one double-blind trial (Trial 2) and one open-label trial (Trial 3).
Trial 2 compared TAFINLAR and trametinib to TAFINLAR and placebo as first-line therapy for patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive TAFINLAR 150 mg twice daily and trametinib 2 mg once daily or TAFINLAR 150 mg twice daily plus matching placebo. Randomization was stratified by lactate dehydrogenase (LDH) level ( > the upper limit of normal (ULN) vs. ≤ ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR).
Trial 3 compared TAFINLAR and trametinib to vemurafenib as first-line treatment therapy for patients with unresectable (Stage IIIc) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive TAFINLAR 150 mg twice daily and trametinib 2 mg once daily or vemurafenib 960 mg twice daily. Randomization was stratified by lactate dehydrogenase (LDH) level ( > the upper limit of normal (ULN) vs. ≤ ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome measure was overall survival. Additional efficacy outcome measures were PFS and ORR as assessed by investigator per RECIST v1.1.
In Trial 2, 423 patients were randomized to TAFINLAR plus trametinib (n = 211) or TAFINLAR plus placebo (n = 212). The median age was 56 years (range: 22 to 89 years), 53% were male, > 99% were White, 72% had ECOG performance status of 0, 4% had Stage IIIc, 66% had M1c disease, 65% had a normal LDH, and 2 patients had a history of brain metastases. All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing, 85% with BRAF V600E mutations and 15% with BRAF V600K mutations.
In Trial 3, 704 patients were randomized to TAFINLAR plus trametinib (n = 352) or single-agent vemurafenib (n = 352). The median age was 55 years (range: 18 to 91 years), 96% were White, and 55% were male, 6% percent of patients had Stage IIIC, 61% had M1c disease, 67% had a normal LDH, 70% had ECOG performance status of 0, 89% had BRAF V600E mutation-positive melanoma, and one patient had a history of brain metastases.
Trial 2 and Trial 3 demonstrated statistically significant improvements in OS and PFS (see Table 9 and Figures 2 and 3).
Table 9: Efficacy Results in Patients with BRAF V600E
or V600K Melanomaa
|Endpoint†||Trial 2||Trial 3|
|TAFINLAR plus Trametinib
|TAFINLAR plus Placebo
|TAFINLAR plus Trametinib
|Number of deaths (%)||99 (47%)||123 (58%)||100 (28%)||122 (35%)|
|Median, months (95% CI)||25.1 (19.2, NR)||18.7 (15.2, 23.1)||NR (18.3, NR)||17.2 (16.4, NR)|
|HR (95% CI)||0.71 (0.55, 0.92)||0.69 (0.53, 0.89)|
|P value (log-rank test)||0.01||0.005a|
|Progression-Free Survival (PFS)b|
|Number of events (%)||102 (48%)||109 (51%)||166 (47%)||217 (62%)|
|Median, months (95% CI)||9.3 (7.7, 11.1)||8.8 (5.9, 10.9)||11.4 (9.9, 14.9)||7.3 (5.8, 7.8)|
|HR (95% CI)||0.75 (0.57, 0.99)||0.56 (0.46, 0.69)|
|P value (log-rank test)||0.035||< 0.001|
|Overall Response Rate (ORR)b|
|ORR, % (95% CI)||66 (60, 73)||51 (44, 58)||64 (59, 69)||51 (46, 56)|
|P value||< 0.001||< 0.001|
|Median duration of response, months (95% CI)||9.2 (7.4, NR)||10.2 (7.5, NR)||13.8 (11.0, NR)||7.5 (7.3, 9.3)|
|† CI = Confidence interval; HR = Hazard ratio; CR =
Complete response; PR = Partial response; NR = Not reached.
a P-value is comparing with the allocated alpha of 0.021 for the interim analysis based on 77% information.
b PFS and ORR were assessed by investigator.
Figure 2: Kaplan-Meier Curves for Overall Survival in
Figure 3: Kaplan-Meier Curves for Overall Survival in
Last reviewed on RxList: 3/22/2016
This monograph has been modified to include the generic and brand name in many instances.
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