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Mechanism Of Action
Vemurafenib is a low molecular weight, orally available inhibitor of some mutated forms of BRAF serinethreonine kinase, including BRAF V600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAF V600E.
In a multi-center, open-label, single-arm study in 132 patients with BRAF V600E mutation-positive metastatic melanoma, patients administered vemurafenib 960 mg orally twice daily did not experience large changes in mean QTc interval (i.e., > 20 ms) from baseline. Vemurafenib is associated with concentrationdependent QTc interval prolongation. The largest mean change from baseline in the first month of treatment occurred at 2 hours post-dose on Day 15—an increase of 12.8 ms (upper boundary of the two-sided 90% confidence interval of 14.9 ms). In the first 6 months of treatment, the largest observed mean change from baseline occurred at a pre-dose time point—an increase of 15.1 ms (upper boundary of the two-sided 90% confidence interval of 17.7 ms).
The pharmacokinetics of vemurafenib were determined in patients with BRAF mutation-positive metastatic melanoma following 15 days of 960 mg twice daily with dosing approximately 12 hours apart. The population pharmacokinetic analysis pooled data from 458 patients. At steady-state, vemurafenib exhibits linear pharmacokinetics within the 240 mg to 960 mg dose range.
The bioavailability of vemurafenib has not been determined. The median Tmax was approximately 3 hours following multiple doses.
The mean (± SD) Cmax and AUC0-12 were 62 ± 17 µg/mL and 601 ± 170 µg*h/mL, respectively. The median accumulation ratio estimate from the population pharmacokinetic analysis for the twice daily regimen is 7.4, with steady-state achieved at approximately 15 to 22 days.
In clinical trials, vemurafenib was administered without regard to food. A food effect study has demonstrated that a single dose of vemurafenib administered with a high-fat meal increased AUC by approximately 5-fold, increased Cmax by 2.5-fold, and delayed Tmax by approximately 4 hours as compared to the fasted state.
QTc prolongation may occur with increased exposures as vemurafenib is associated with concentration-dependent QTc interval prolongation [see Pharmacodynamics, Cardiac Electrophysiology].
Vemurafenib is highly bound ( > 99%) to human albumin and alpha-1 acid glycoprotein plasma proteins. The population apparent volume of distribution is estimated to be 106 L (with 66% inter-patient variability).
Following oral administration of 960 mg of 14C-vemurafenib, mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma over 48 hours, respectively.
Following oral administration of 960 mg of 14C-vemurafenib, approximately 94% of the radioactive dose was recovered in feces and approximately 1% was recovered in the urine. The population apparent clearance is estimated to be 31 L/day (with 32% inter-patient variability). The median elimination half-life estimate for vemurafenib is 57 hours (the 5th and 95th percentile range is 30 to 120 hours).
Hepatic Impairment: The pharmacokinetics of vemurafenib were examined in patients with metastatic melanoma enrolled in the clinical trials with normal hepatic function (n=158, total bilirubin ≤ ULN) and mild (n=58, total bilirubin 1.0-1.5 x ULN), moderate (n=27, total bilirubin 1.5-3 x ULN), or severe (n=3, total bilirubin > 3 x ULN) hepatic impairment. Patients received vemurafenib 960 mg orally twice daily. The apparent clearance of vemurafenib in patients with mild and moderate hepatic impairment was similar to that in patients with normal hepatic function. The appropriate dose for patients with severe hepatic impairment cannot be determined as clinical and pharmacokinetic data were available for only three patients [see Use in Specific Populations].
Renal Impairment: The pharmacokinetics of vemurafenib were examined in patients with metastatic melanoma enrolled in the clinical trials with normal renal function (CLcr ≥ 90 mL/min) and mild (n=94, CLcr > 60 to 89 mL/min), moderate (n=11, CLcr 30 to 59 mL/min) or severe (n=1, CLcr < 29 mL/min) renal impairment. Patients received vemurafenib 960 mg orally twice daily. The apparent clearance of vemurafenib in patients with mild and moderate renal impairment was similar to that in patients with normal renal function. The appropriate dose for patients with severe renal impairment cannot be determined as clinical and pharmacokinetic data were available for only one patient [see Use in Specific Populations].
Age, Body Weight, Sex, and Race: Based on the population pharmacokinetic analysis, age, body weight, and sex do not have a clinically important effect on the exposure of vemurafenib. There are insufficient data to evaluate potential differences in the pharmacokinetics of vemurafenib by race.
Pediatrics: No studies have been conducted to investigate the pharmacokinetics of vemurafenib in pediatric patients.
Drug Interaction Studies
Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib: In vitro studies have demonstrated that vemurafenib is a CYP3A4 substrate. The effect of strong CYP3A4 inhibitors or strong CYP3A4 inducers on the systemic exposure of vemurafenib has not been evaluated in vivo [see DRUG INTERACTIONS].
Effect of Vemurafenib on CYP Substrates: In vitro studies suggest that vemurafenib is an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5.
Coadministration of tizanidine 2 mg (a sensitive CYP1A2 substrate) on day 21 with vemurafenib which was administered 960 mg twice daily for 21 days increased tizanidine AUCinf by 4.7-fold (90% CI: 3.6, 6.3) and Cmax by 2.2-fold (90% CI: 1.7, 2.7) in 16 cancer patients [see DRUG INTERACTIONS]. In an in vivo phenotypic cocktail drug-drug interaction study in patients with cancer, a single dose of the CYP probe substrate cocktail (for CYP1A2, 2D6, 3A4, 2C19 and 2C9) was administered before and concomitantly with vemurafenib (following 15 days of dosing at 960 mg twice daily). Coadministration of vemurafenib increased the mean AUC of caffeine (CYP1A2 substrate) by 2.6-fold [see DRUG INTERACTIONS]. Coadministration of vemurafenib increased the mean AUC of dextromethorphan (CYP2D6 substrate) by 47% and the AUC of S-warfarin (CYP2C9 substrate) by 18%, while it decreased the mean AUC of midazolam (CYP3A4 substrate) by 39%. Coadministration of vemurafenib did not change the mean systemic exposure to omeprazole (CYP2C19 substrate).
Effect of Vemurafenib on Transporters: In vitro studies suggest that vemurafenib is both a substrate and an inhibitor of the efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Administration of vemurafenib 960 mg twice daily for 22 days increased digoxin AUC by 1.8-fold (90% CI:1.6, 2.0) and Cmax by 1.5-fold (90% CI:1.3, 1.7) in 26 cancer patients who were coadministered a single dose of digoxin 0.25 mg (sensitive P-gp substrate) [see DRUG INTERACTIONS].
Animal Toxicology And/Or Pharmacology
Consistent with the increased incidence of cutaneous squamous cell carcinomas in patients treated with vemurafenib, the treatment of mice implanted with human cuSCC cells with vemurafenib caused a dosedependent acceleration of the growth of the implanted tumors.
Trial 1, an international, open-label, randomized controlled trial, equally allocated 675 patients with treatment-naive, BRAF V600E mutation-positive unresectable or metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, to receive ZELBORAF 960 mg by mouth twice daily (n=337) or dacarbazine 1000 mg/m² intravenously on Day 1 every 3 weeks (n=338). Randomization stratification factors were disease stage, lactate dehydrogenase (LDH), ECOG performance status, and geographic region. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. The major efficacy outcome measures of the trial were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate.
Baseline characteristics were balanced between treatment groups. Most patients were male (56%) and caucasian (99%), the median age was 54 years (24% were ≥ 65 years), all patients had ECOG performance status of 0 or 1, and the majority of patients had metastatic disease (95%).
Trial 1 demonstrated statistically significant increases in overall survival and progression-free survival in the ZELBORAF arm compared to the dacarbazine control arm. Table 3 and Figure 1 summarize the efficacy results.
Table 3 : Efficacy of ZELBORAF in Treatment-Naive
Patients with BRAF V600E Mutation-Positive Melanomaa
|Number of Deathsb||78 (23%)||122 (36%)|
|Hazard Ratio(95% CI)c||0.47 (0.35, 0.62)||< 0.0001|
|Updated Median Survival (months)(95 % CI) d, e||13.6(12.0, 15.3)||10.3(9.1, 12.8)||-|
|Hazard Ratio(95% CI)c||0.26 (0.20, 0.33)||< 0.0001|
|Median PFS (months)(95% CI)d||5.3(4.9, 6.6)||1.6(1.6, 1.7)||-|
|a As detected by the cobas® 4800 BR AF V600
b Total o f 200 deaths (Zelboraf median follow-up 6.2 months)
c Hazard ratio estimated using Cox model; a hazard ratio o f < 1 favors ZE LBO R A F
d K aplan-Meier estimate
e Updated based on 478 deaths (Zelboraf median follow-up 13.4 months)
f Unstratified log-rank test
Figure 1 : Kaplan-Meier Curves of Overall Survival -
The confirmed, investigator-assessed best overall response rate was 48.4% (95% CI: 41.6%, 55.2%) in the ZELBORAF arm compared to 5.5% (95% CI: 2.8%, 9.3%) in the dacarbazine arm. There were 2 complete responses (0.9%) and 104 partial responses (47.4%) in the ZELBORAF arm and all 12 responses were partial responses (5.5%) in the dacarbazine arm.
Patients Who Received Prior Systemic Therapy
In a single-arm, multicenter, multinational trial (Trial 2), 132 patients with BRAF V600E mutation-positive metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, who had received at least one prior systemic therapy, received ZELBORAF 960 mg by mouth twice daily. The median age was 52 years with 19% of patients being older than 65 years. The majority of patients were male (61%) and Caucasian (99%). Forty-nine percent of patients received ≥ 2 prior therapies. The median duration of follow-up was 6.87 months (range, 0.6 to 11.3).
The confirmed best overall response rate as assessed by an independent review committee (IRC) was 52% (95% CI: 43%, 61%). There were 3 complete responses (2.3%) and 66 partial responses (50.0%). The median time to response was 1.4 months with 75% of responses occurring by month 1.6 of treatment. The median duration of response by IRC was 6.5 months (95% CI: 5.6, not reached).
Patients With Wild-Type BRAF Melanoma
ZELBORAF has not been studied in patients with wild-type BRAF melanoma [see WARNINGS AND PRECAUTIONS].
Last reviewed on RxList: 5/23/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Zelboraf Information
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