This site is intended for U.S. healthcare professionals.

Visit Pfizer Medical

Menu

Close

Sign InLog Out
ProductsOrderMaterialsCo-pay Cards & Patient Savings OffersRequest SamplesHospital ProductsVaccinesPatient AssistancePfizer Oncology TogetherPfizer RxPathwaysExplore ContentEventsMaterialsVideosContact
Search

Menu

Close

Log Out
HomeMOAEfficacyEfficacyCOLUMBUS trialSelect patient characteristicsProgression-free survivalOverall survivalOverall response rateDuration of responseSafetySafetyAdverse reactionsLaboratory abnormalitiesPyrexiaDosingDosingDosing and administrationDose adjustmentsDrug interactionsResourcesResourcesAccess and patient supportMaterialsVideos 
BRAFTOVI:Prescribing InformationMedication GuideMEKTOVI:Prescribing InformationPatient InformationIndicationPatient Site
Overall survival (OS)An oral treatment combination for adults with unresectable or metastatic melanoma with a BRAF V600E/K mutation1,233.6 months median OS vs 16.9 months for vemurafenib (control)1,233.6 months median OS vs 16.9 months for vemurafenib (control)1,2

The hierarchical testing procedure prevented formal assessment of the statistical significance of OS; therefore, the OS results are descriptive in nature only.

 Primary analysis: OS1-3

The median represents a single point on the Kaplan-Meier curve. It is important to consider the entire curve when evaluating OS.

The median represents a single point on the Kaplan-Meier curve. It is important to consider the entire curve when evaluating OS.

  • In the primary analysis of OS (data cutoff of November 7, 2017), the number of events observed in each arm was 105/192 (55%) with BRAFTOVI® (encorafenib) + MEKTOVI® (binimetinib) and 127/191 (67%) with vemurafenib1-3​​​
Post hoc OS analysis at 5 yearsPost hoc OS analysis at 5 years

The 5-year OS analysis is a descriptive post hoc analysis and should be interpreted in the context of this limitation. No conclusions regarding efficacy may be drawn.

HR was analyzed using a stratified Cox regression model.

 Post hoc OS analysis4,5 Post hoc analysis: Median OS3,6

The median should be considered in the context of the entire Kaplan-Meier curve when evaluating OS.

The median should be considered in the context of the entire Kaplan-Meier curve when evaluating OS.

  • In this post hoc analysis of OS (minimum follow-up of 65.3 months; data cutoff: September 15, 2020), the number of events observed in each arm was 131/192 (68%) with BRAFTOVI + MEKTOVI and 145/191 (76%) with vemurafenib4,5
Post hoc OS analysis of nonprespecified subgroups4Post hoc OS analysis of nonprespecified subgroups4

The graph below depicts a post hoc OS analysis of nonprespecified subgroups of the overall COLUMBUS trial population. These analyses are considered exploratory. No adjustments were made for multiple comparisons in the subgroup analyses. Small patient numbers can be a limitation of subgroup analyses. These analyses are not intended to demonstrate efficacy in particular subgroups.

HR was analyzed using an unstratified Cox regression model.

 AJCC, American Joint Committee on Cancer; BRAF, v-raf murine sarcoma oncogene homolog B; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LDH, lactate dehydrogenase.
References:BRAFTOVI® (encorafenib) Prescribing Information. Array BioPharma, Inc.; February 2022.MEKTOVI® (binimetinib) Prescribing Information. Array BioPharma, Inc.; October 2020.Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open label, randomised, phase 3 trial. Lancet Oncol. 2018;19(10):1315-1327.Dummer R, Flaherty KT, Robert C, et al. COLUMBUS 5-year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600–mutant melanoma [published online ahead of print, July 21, 2022]. J Clin Oncol. doi:10.1200/JCO.21.02659Data on file. Pfizer Inc.
Safety data for BRAFTOVI + MEKTOVI ViewLoading
COLUMBUS 5-year Update Publication Read the JCO publication Loading

The link above is provided for your convenience. The website is neither controlled nor owned by Pfizer. Pfizer does not endorse and is not responsible for its content or services.

 Expert videos

Hear noted oncologist perspectives on the treatment of metastatic or unresectable melanoma in adults with a BRAF V600E/K mutation

 Watch videos Loading

To report an adverse event, please call 1-800-438-1985

To report an adverse event, please call 1-800-438-1985

Pfizer for Professionals 1-800-505-4426

This site is intended only for U.S. healthcare professionals. The products discussed in this site may have different product labeling in different countries. The information provided is for educational purposes only.

© 2023 Pfizer Inc. All rights reserved.

PP-BMK-USA-0684
You are now leaving PfizerYou are now leaving a Pfizer operated website. Links to all outside sites are provided as a resource to our visitors. Pfizer accepts no responsibility for the content of sites that are not owned and operated by Pfizer. 

PP-MCL-USA-0367
INDICATIONS AND USAGEBRAFTOVI® (encorafenib) and MEKTOVI® (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test. Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma
IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

New Primary Malignancies, cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Median time to first occurrence of cuSCC/KA was 5.8 months. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation using an FDA-approved test prior to initiating BRAFTOVI.

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the COLUMBUS trial, evidence of cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) was 3.6 months. Cardiomyopathy resolved in 87% of patients. Assess left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition (MUGA) scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. 

Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Hemorrhage: Hemorrhage can occur when BRAFTOVI is administered in combination with MEKTOVI. In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥ Grade 3 hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months. Retinal vein occlusion (RVO) is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with BRAFTOVI (n=690), 1 patient experienced RVO (0.1%). The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis was reported in 4% of patients treated with MEKTOVI in combination with BRAFTOVI. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% (2 of 690 patients) with BRAF mutation-positive melanoma receiving MEKTOVI with BRAFTOVI. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. 

Hepatotoxicity: Hepatotoxicity can occur when MEKTOVI is administered in combination with BRAFTOVI. In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation. Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. 

Rhabdomyolysis: Rhabdomyolysis can occur when MEKTOVI is administered in combination with BRAFTOVI. In the COLUMBUS trial, elevation of laboratory values of serum CPK occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% (1 of 690 patients) with BRAF mutation-positive melanoma receiving MEKTOVI with BRAFTOVI. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

QT Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the COLUMBUS trial, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI in combination with MEKTOVI. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms. Embryo-Fetal Toxicity: BRAFTOVI and MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI. Risks Associated with BRAFTOVI as a Single Agent: There is an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with MEKTOVI. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI single agent compared to 2% in patients treated with BRAFTOVI in combination with MEKTOVI. If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended. 

ADVERSE REACTIONS

The most common adverse reactions (≥ 20%, all grades, in the COLUMBUS trial) for BRAFTOVI and MEKTOVI compared to vemurafenib were: fatigue (43% vs. 46%), nausea (41% vs. 34%), diarrhea (36% vs. 34%), vomiting (30% vs. 16%), abdominal pain (28% vs. 16%), arthralgia (26% vs. 46%), myopathy (23% vs. 22%), hyperkeratosis (23% vs. 49%), rash (22% vs. 53%), headache (22% vs. 20%), constipation (22% vs. 6%), visual impairment (20% vs. 4%), serous retinopathy/RPED (20% vs. 2%). Other clinically important adverse reactions occurring in <10% of patients in the COLUMBUS trial were facial paresis, pancreatitis, panniculitis, drug hypersensitivity, and colitis.  In the COLUMBUS trial, the most common laboratory abnormalities (all grades) (≥ 20%) for BRAFTOVI and MEKTOVI compared to vemurafenib included increased creatinine (93% vs. 92%), increased creatine phosphokinase (58% vs. 3.8%), increased gamma glutamyl transferase (GGT) (45% vs. 34%), anemia (36% vs. 34%), increased ALT (29% vs. 27%), hyperglycemia (28% vs. 20%), increased AST (27% vs. 24%), and increased alkaline phosphatase (21% vs. 35%).

DRUG INTERACTIONS

Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors (including grapefruit juice) or CYP3A4 inducers and use caution with sensitive CYP3A4 substrates. Avoid coadministration of BRAFTOVI with hormonal contraceptives.

Modify BRAFTOVI dose if coadministration with a strong or moderate CYP3A4 inhibitor cannot be avoided.

Avoid coadministration of BRAFTOVI with drugs known to prolong QT/QTc interval.

Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI.

The information above applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information.

INDICATIONS AND USAGE BRAFTOVI® (encorafenib) and MEKTOVI® (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test.Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma.