Encorafenib, an inhibitor of b-Raf serine-threonine kinase (BRAF) V600E or V600K mutation, is an antineoplastic agent.1, 2
Encorafenib is used in combination with binimetinib for the treatment of unresectable or metastatic melanoma with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutation.1, 2, 3 Encorafenib has been designated an orphan drug by FDA for the treatment of this cancer.4 An FDA-approved diagnostic test is required to confirm the presence of the BRAF V600E or V600K mutation in tumor specimens prior to initiation of therapy.1, 2 In patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, combined therapy with encorafenib and binimetinib has been shown to prolong progression-free and overall survival, and increase response rate compared with vemurafenib alone.1, 2, 3
The safety and efficacy of encorafenib in patients with wild-type BRAF melanoma have not been established; encorafenib is not indicated for use in these patients.1
The melanoma indication for encorafenib is based principally on the results of a randomized, open-label, phase 3 study (COLUMBUS) in patients with unresectable locally advanced or metastatic melanoma positive for BRAF V600E or V600K mutation as detected by the bioMerieux THxID® BRAF V600 mutation test.1, 2, 3 In this study, 577 patients were randomized (stratified by disease stage, Eastern Cooperative Oncology Group [ECOG] performance status, and prior immunotherapy use) in a 1:1:1 ratio to receive encorafenib 450 mg once daily with binimetinib 45 mg twice daily (encorafenib-binimetinib), encorafenib 300 mg once daily alone, or vemurafenib 960 mg twice daily.1, 2, 3 Treatment was continued until disease progression or unacceptable toxicity occurred or the patient withdrew from the study.1, 2, 3 The primary measure of efficacy was progression-free survival (as evaluated by a blinded independent central review committee).1, 2, 3 The median age of patients randomized to the encorafenib-binimetinib or vemurafenib treatment groups was 56 years; 91% of patients were white, 59% were male, 95% had metastatic disease, 65% had stage M1c disease, 72% had a baseline ECOG performance status of 0, 28% had elevated LDH concentrations, 45% had tumor involvement in at least 3 organs, and 3% of patients had brain metastases.1 Approximately 4% of patients enrolled in the encorafenib-binimetinib or vemurafenib treatment groups received prior therapy with an anti-programmed-death 1 (anti-PD-1), anti-programmed-death ligand-1 (anti-PD-L1), or anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) antibody.1, 2 Most patients (88%) randomized to receive encorafenib-binimetinib or vemurafenib had BRAF V600E mutation; 11% had V600K mutation and <1% had both BRAF V600E and V600K mutations.1 Patients who had received immunotherapy in the adjuvant setting or one prior immunotherapy regimen for unresectable locally advanced or metastatic melanoma were eligible for this study; however, patients with prior exposure to BRAF or mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors were not eligible to enroll in the study.1
At a median follow-up of 16.7 or 14.4 months in patients receiving encorafenib-binimetinib or vemurafenib alone, respectively, median progression-free survival was 14.9 months in patients receiving encorafenib-binimetinib compared with 7.3 months in those receiving vemurafenib.1, 2 The overall response rate was 63% for patients receiving encorafenib-binimetinib and 40% for those receiving vemurafenib; complete response was achieved in 8% of patients receiving encorafenib-binimetinib and 6% of those receiving vemurafenib.1, 2 The median duration of response in patients receiving encorafenib-binimetinib or vemurafenib alone was 16.6 or 12.3 months, respectively.1, 2 After a median follow-up of 48.8 months for the overall study population, the median overall survival was 33.6 or 16.9 months in patients receiving encorafenib-binimetinib or vemurafenib alone, respectively.3, 1 The risk for death was reduced by 39% with encorafenib-binimetinib as compared to vemurafenib alone.1, 3 In general, the overall survival benefit for combination therapy with binimetinib and encorafenib versus vemurafenib was consistent in most subgroup analyses (e.g., age, gender, race, ECOG performance status, geographic region, baseline serum LDH concentration, BRAF mutation status, disease stage, organ involvement, presence of brain metastases, prior use of first-line immunotherapy or adjuvant therapy).3, 2
Guidance from the American Society of Clinical Oncology (ASCO) in 2023 on systemic therapy for melanoma recommends that in the setting of unresectable and/or metastatic cutaneous melanoma, patients with confirmed BRAF-mutant (V600) disease should be offered one of the following treatment options as first-line therapy: nivolumab plus ipilimumab followed by nivolumab, nivolumab plus relatlimab, or nivolumab or pembrolizumab or dabrafenib plus trametinib, or encorafenib plus binimetinib, or vemurafenib plus cobimetinib.200 For patients who progress after first-line therapy with programmed-death receptor-1 (PD-1) inhibitors, combination BRAF/MEK inhibitors may be offered; PD-1 inhibitors may be offered after progression on first-line combination BRAF/MEK inhibitors.200
Encorafenib is used in combination with cetuximab for the treatment of metastatic colorectal cancer in adults with a BRAF V600E mutation after prior therapy.1 In patients with metastatic colorectal cancer with BRAF V600E mutation and disease progression after 1 or 2 prior therapies, combined therapy with encorafenib and cetuximab has been shown to improve overall survival, overall response rate, and progression-free survival compared with combination chemotherapy with cetuximab.1, 29, 30
Encorafenib is also used in combination with cetuximab and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for the treatment of patients with metastatic colorectal cancer with a BRAF V600E mutation.1, 203 This indication is approved under accelerated approval based on response rate and durability of response.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1
An FDA-approved diagnostic test is required to confirm the presence of the BRAF V600E mutation in plasma or tumor tissue prior to initiation of therapy.1 If no mutation is detected in a plasma specimen, test tumor tissue.1 The safety and efficacy of encorafenib in patients with wild-type BRAF colorectal cancer have not been established; encorafenib is not indicated for use in these patients.1
The use of encorafenib in combination with cetuximab is based principally on the results of a randomized, open-label, phase 3 study (BEACON CRC) in patients with metastatic colorectal cancer positive for BRAF V600E mutation with disease progression after 1 or 2 prior therapies.1 In this study, 665 patients were randomized (stratified by ECOG performance status, history of previous irinotecan use, and cetuximab formulation used [US-licensed versus EU-approved]) in a 1:1:1 ratio to receive encorafenib 300 mg once daily with cetuximab, encorafenib 300 mg once daily with binimetinib 45 mg twice daily and cetuximab, or irinotecan with cetuximab or FOLFIRI (leucovorin, fluorouracil, and irinotecan) with cetuximab (control).1, 29 In all groups, the cetuximab dosage was 400 mg/m2 followed by 250 mg/m2 weekly, administered IV.1, 29 Treatment was administered in 28-day cycles until disease progression or unacceptable toxicity occurred.1, 29 The primary measure of efficacy for encorafenib-cetuximab doublet therapy was overall survival.1, 29 In the encorafenib-cetuximab and control groups, the median age of patients randomized was 61 years; 80% of patients were white, 15% were Asian, 53% were female, and 50% had a baseline ECOG performance status of 0.1 Two-thirds of patients had received 1 prior therapy and the remaining patients previously received 2 therapies; 93% of patients previously had received oxaliplatin.1 Patients with prior exposure to RAF, MEK, or epidermal growth factor receptor (EGFR) inhibitors were not eligible to enroll in the study.1, 30
At a median follow-up of 7.8 months, median overall survival was improved in patients receiving encorafenib-cetuximab (8.4 months) as compared with those in the control group (5.4 months), corresponding to a 40% reduction in the risk for death with encorafenib-cetuximab.1, 29 Median progression-free survival was 4.2 months and 1.5 months in the encorafenib-cetuximab and control groups, respectively.1, 29 The overall response rate was 20% for patients receiving encorafenib-cetuximab and 2% for those in the control group; complete response was achieved in 5% of patients receiving encorafenib-cetuximab and in 0 patients in the control group.1, 29 In an updated survival analysis after a median follow-up of 12.8 months, median overall survival was 9.3 months and 5.9 months in the encorafenib-cetuximab and control groups, respectively; overall survival results were similar between encorafenib-cetuximab and the triplet therapy (encorafenib-binimetinib-cetuximab) groups.30
Combination with Cetuximab and mFOLFOX6
The use of encorafenib in combination with cetuximab and mFOLFOX6 is based principally on the results of a randomized, active-controlled, open-label, multicenter, phase 3 study (BREAKWATER) in patients with metastatic colorectal cancer positive for BRAF V600E mutation.1, 203 In this study, patients were initially randomized in a 1:1:1 ratio to encorafenib 300 mg orally once daily plus cetuximab 500 mg/m2 IV infusion every 2 weeks; encorafenib 300 mg orally once daily plus cetuximab 500 mg/m2 IV infusion every 2 weeks and all components of mFOLFOX6 (fluorouracil, leucovorin, oxaliplatin) every 2 weeks; or standard care (i.e., investigator's choice of mFOLFOX6 [every 2 weeks], FOLFIRI [every 2 weeks], or CAPOX [every 3 weeks], each with or without bevacizumab).1, 203 Enrollment in the encorafenib plus cetuximab arm (n=158) was eventually discontinued and subsequently enrolled patients were randomly assigned in a 1:1 ratio to the encorafenib, cetuximab, and mFOLFOX6 arm (n=236) or the standard care arm (n=243).1, 203 Treatment was administered until disease progression, unacceptable toxicity, withdrawal of consent, death, or loss to follow-up.1, 203 The 2 primary end points were objective response rate and progression-free survival compared between the encorafenib, cetuximab, and mFOLFOX6 group and the standard care group.203 Among the patients randomized to these 2 arms, the median age was 61 years; 50% were female, 60% were white, 37% Asian, 12% Hispanic or Latino, and 0.2% Black or African American.1 A baseline ECOG performance status of 0 was seen in 54% of patients.1
Results revealed an improvement in the percentage of patients with a confirmed objective response with the administration of encorafenib plus cetuximab and mFOLFOX6 as compared to standard care (65.7 versus 37.4%), with a median time to response of 7 weeks in the encorafenib plus cetuximab and mFOLFOX6 group and 7.3 weeks in the standard care group.203 The median duration of response was 13.9 and 10.8 months, respectively.203 The median progression-free survival was also improved in the encorafenib plus cetuximab and mFOLFOX6 group as compared to standard care (12.8 months versus 7.1 months), with a median follow-up for progression-free survival of 16.8 and 9.8 months, respectively.203 In an interim analysis, encorafenib plus cetuximab and mFOLFOX6 was associated with significantly longer median overall survival as compared to standard care (30.3 versus 15.1 months).203
According to the National Cancer Institute, surgery is generally a recommended treatment for patients with any stage of colon or rectal cancer.1017, 1018 The use of chemotherapy or other systemic therapy before and/or after surgery may be an option dependent upon cancer stage, prior treatments, and patient overall health.1017, 1018
The American Society of Clinical Oncology (ASCO) guideline on late-stage colorectal cancer states that most patients receive treatment with chemotherapy, where chemotherapy is available.201 Approximately 12% of patients with metastatic colorectal cancer express mutations in the BRAF gene.202 Some experts recommend the combination of encorafenib and an EGFR inhibitor (cetuximab) as second- or third-line treatment options for BRAF V600E-mutated metastatic colorectal cancer.202
Encorafenib is used in combination with binimetinib for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation.1 Encorafenib has been designated an orphan drug by FDA for the treatment of this cancer.4 An FDA-approved diagnostic test is required to confirm the presence of the BRAF V600E mutation in tumor or plasma specimens prior to initiation of therapy.1 If no mutation is detected in a plasma specimen, test tumor tissue.1
The safety and efficacy of encorafenib in patients with wild-type BRAF NSCLC have not been established; encorafenib is not indicated for use in these patients.1
This indication for encorafenib use is based principally on the results of an open-label, single-arm, multicenter, phase 2 study (PHAROS) in patients with metastatic NSCLC positive for a BRAF V600E mutation.1, 31 In this study, 98 patients received binimetinib 45 mg orally twice daily in combination with encorafenib 450 mg orally once daily in 28-day cycles; 59 patients were treatment-naïve and 39 were previously treated.1, 31 Treatment was continued until disease progression or unacceptable toxicity occurred.1 The primary end point was confirmed objective response rate per RECIST version 1.1 criteria.31
The median age of enrolled patients was 70 years (range: 47 to 86 years); 88% of patients were white, 7% Asian, 3% Black or African American, and 1% American Indian or Alaska Native; 53% were female; 57% were former smokers; 73% had an ECOG performance status of 1; and 97% had adenocarcinoma.1, 31 Results revealed an objective response rate of 75% in treatment-naïve patients and 46% in previously treated patients.1, 31 A complete response was observed in 9 (15%) and 4 (10%) patients in the treatment-naïve and previously treated groups, respectively, with a partial response documented in 35 (59%) and 14 (36%) patients, respectively.1, 31 At the time of this analysis, the median duration of response was not estimable in the treatment naïve group and was 16.7 months in the previously treated group.1, 31 Durable responses lasting ≥12 months were seen in 59% of treatment naïve and 33% of previously treated patients.1, 31 The disease control rate after 24 weeks was 64% among treatment naïve patients and 41% in previously treated patients.31 Median progression-free survival was not estimable in the treatment naïve group and was 9.3 months in the previously treated group.31
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).1019 The ASCO and Ontario Health (OH; previously known as Cancer Care Ontario) 2021 guideline specifically addresses treatment of stage IV NSCLC with driver alterations, including BRAF gene alterations.1019 The 2024 update to this guideline recommends that, for patients with stage IV NSCLC with a BRAF V600E mutation, clinicians may offer dabrafenib and trametinib or encorafenib and binimetinib as first-line treatment.1020 If these treatment options are unavailable, clinicians may offer standard first-line therapy following the nondriver alteration guideline.1020
In the second-line setting, standard initial treatment based on the ASCO nondriver mutation guideline should be offered in patients with stage IV NSCLC harboring BRAF V600E driver alterations who were previously treated with BRAF or MEK targeted therapy.1020 In patients who did not receive BRAF-targeted therapy in the first-line setting, dabrafenib and trametinib or encorafenib and binimetinib may be offered.1020 For patients with stage IV NSCLC with BRAF mutations other than V600E, standard treatment based on the ASCO nondriver mutation guideline should be offered.1020
Encorafenib is administered orally once daily without regard to meals.1
If a dose of encorafenib is missed by more than 12 hours, the missed dose should be skipped and the next dose should be taken at the regularly scheduled time.1 Patients should not take extra capsules of the drug to make up for the missed dose.1
If vomiting occurs following administration of encorafenib, a replacement dose should not be administered, and the next dose should be taken at the regularly scheduled time.1
Store encorafenib capsules at 20-25°C (excursions permitted between 15-30°C).1 Store in the original container, tightly closed, with desiccant.1
For use in combination with binimetinib in the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation, the recommended adult dosage of encorafenib is 450 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
For use in combination with cetuximab in the treatment of metastatic colorectal cancer with BRAF V600E mutation, the recommended adult dosage of encorafenib is 300 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Combination with Cetuximab and mFOLFOX6
For use in combination with biweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) in the treatment of metastatic colorectal cancer with BRAF V600E mutation, the recommended dosage of encorafenib is 300 mg once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Non-small Cell Lung Cancer (NSCLC)
For use in combination with binimetinib in the treatment of adults with metastatic NSCLC with a BRAF V600E mutation, the recommended dosage of encorafenib is 450 mg (six 75 mg capsules) once daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse reactions occur, interruption of therapy, dosage reduction, and/or permanent discontinuance of encorafenib may be required based on severity of the reaction.1
No dosage adjustment of encorafenib when given in combination with binimetinib or cetuximab is necessary in patients who experience interstitial lung disease, pneumonitis, cardiac dysfunction, increased creatine phosphokinase concentrations, rhabdomyolysis, or venous thromboembolism.1
Melanoma or NSCLC Dose Modifications
If dosage modification of encorafenib is necessary, an initial dosage reduction to 300 mg once daily is recommended.1 If further dosage reduction is necessary, the dosage should be reduced to 225 mg once daily.1 Dosages less than 225 mg once daily are not recommended; the drug should be permanently discontinued if the 225 mg once daily dosage is not tolerated.1
If binimetinib is withheld, reduce encorafenib to a maximum dose of 300 mg once daily until binimetinib is resumed.1
Colorectal Cancer Dose Modifications
If dosage modification of encorafenib is necessary, an initial dosage reduction to 225 mg once daily is recommended.1 If further dosage reduction is necessary, the dosage should be reduced to 150 mg once daily.1 Dosages less than 150 mg once daily are not recommended; the drug should be permanently discontinued if the 150 mg once daily dosage is not tolerated.1
If concomitant therapy with cetuximab is discontinued, discontinue encorafenib.1
Development of New Primary Malignancies
If new primary RAS mutation-positive, noncutaneous malignancies occur, encorafenib therapy should be permanently discontinued.1
No dosage adjustment of encorafenib is necessary in patients who develop new primary cutaneous malignancies during combination therapy with encorafenib and binimetinib.1
If symptomatic congestive heart failure or an absolute decrease in left ventricular ejection fraction (LVEF) >20% from baseline that is also below the institutional lower limit of normal (LLN) occurs, reduce encorafenib by one dose level.1 If LVEF improves to at least the institutional LLN and absolute decrease to ≤10% compared to baseline, continue encorafenib at the reduced dose.1 If no improvement, withhold encorafenib until improvement to at least the institutional LLN and absolute decrease to ≤10% compared to baseline and then resume therapy at the reduced dosage or reduce the encorafenib dosage an additional dosage level.1
If grade 1 or 2 uveitis unresponsive to ocular therapy occurs, encorafenib therapy should be withheld for up to 6 weeks.1 If the toxicity improves within 6 weeks of withholding therapy, therapy may be resumed at the same or reduced dosage.1 If the toxicity does not improve within 6 weeks of withholding therapy, encorafenib therapy should be permanently discontinued.1
If grade 3 uveitis occurs, encorafenib therapy should be withheld for up to 6 weeks.1 If grade 3 uveitis improves within 6 weeks of withholding therapy, therapy may be resumed at the same or reduced dosage.1 If the toxicity does not improve within 6 weeks of withholding therapy, encorafenib therapy should be permanently discontinued.1
If grade 4 uveitis occurs, encorafenib therapy should be permanently discontinued.1
If adverse ocular reactions other than uveitis, iritis, or iridocyclitis occur during combination therapy with encorafenib and binimetinib, no dosage modification of encorafenib is necessary.1
If the QT interval (corrected for heart rate using Fridericia's formula [QTcF]) exceeds 500 msec and increases by no more than 60 msec from baseline, encorafenib therapy should be withheld; therapy may be resumed at a reduced dosage when QTcF decreases to 500 msec or less.1 If there is more than one recurrence, encorafenib therapy should be permanently discontinued.1
If QTcF exceeds 500 msec and increases more than 60 msec from baseline, encorafenib therapy should be permanently discontinued.1
In patients who develop grade 2 elevations of serum aminotransferases (ALT or AST), encorafenib therapy may be continued at the same dosage for up to 4 weeks.1 If the toxicity persists, encorafenib therapy should be withheld; therapy may be resumed at the same dosage when the toxicity improves to grade 1 or less or to baseline.1
For the first occurrence of grade 3 elevations of serum ALT or AST, encorafenib therapy should be withheld for up to 4 weeks; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less or to baseline.1 If the toxicity does not improve to grade 1 or less or to baseline within 4 weeks of withholding therapy, the drug should be permanently discontinued.1 If recurrent grade 3 hepatic toxicity occurs, permanent discontinuance of encorafenib should be considered.1
For the first occurrence of grade 4 elevations of serum ALT or AST, encorafenib therapy may be permanently discontinued or temporarily interrupted.1 If encorafenib therapy is temporarily interrupted, the drug should be withheld for up to 4 weeks; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less or to baseline.1 If the toxicity does not improve to grade 1 or less or to baseline within 4 weeks of withholding therapy, the drug should be permanently discontinued.1 If recurrent grade 4 hepatic toxicity occurs, the drug should be permanently discontinued.1
If grade 2 dermatologic reactions occur (other than hand-foot skin reactions), encorafenib therapy may be continued at the same dosage for up to 2 weeks.1 If the toxicity persists, encorafenib therapy should be withheld; therapy may be resumed at the same dosage when the toxicity improves to grade 1 or less1
For the first occurrence of grade 3 dermatologic reactions (other than hand-foot skin reactions), encorafenib therapy should be withheld; therapy may be resumed at the same dosage when the toxicity improves to grade 1 or less.1 If grade 3 dermatologic reactions recur, encorafenib therapy should be withheld; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less.1
If grade 4 dermatologic reactions occur (other than hand-foot skin reactions), encorafenib therapy should be permanently discontinued.1
Other Toxicities Including Hemorrhage and Hand-Foot Skin Reaction
For recurrent grade 2 adverse reactions, encorafenib therapy should be withheld for up to 4 weeks; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less or to baseline.1 If the toxicity does not improve to grade 1 or less or to baseline within 4 weeks of withholding therapy, the drug should be permanently discontinued.1
For the first occurrence of any grade 3 adverse reaction, encorafenib therapy should be withheld for up to 4 weeks; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less or to baseline.1 If the toxicity does not improve to grade 1 or less or to baseline within 4 weeks of withholding therapy, the drug should be permanently discontinued.1 If a grade 3 adverse reaction recurs, permanent discontinuance of encorafenib should be considered.1
For the first occurrence of any grade 4 adverse reaction, encorafenib therapy may be permanently discontinued or temporarily interrupted.1 If encorafenib therapy is temporarily interrupted, the drug should be withheld for up to 4 weeks; therapy may be resumed at a reduced dosage when the toxicity improves to grade 1 or less or to baseline.1 If the grade 4 adverse reaction does not improve to grade 1 or less or to baseline within 4 weeks of withholding therapy, the drug should be permanently discontinued.1 For recurrent grade 4 adverse reactions, encorafenib therapy should be permanently discontinued.1
Concomitant Use with Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of encorafenib with moderate or strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 should be avoided; however, if such concomitant use cannot be avoided, the manufacturer recommends reducing the dosage of encorafenib based on the recommendations in Table 1.1 If concomitant use of the strong or moderate CYP3A4 inhibitor is discontinued, the encorafenib dosage should be returned (after 3-5 terminal half-lives of the CYP3A4 inhibitor) to the dosage used prior to initiation of the strong or moderate CYP3A4 inhibitor.1
Current Encorafenib Dosage | Recommended Dosage with Moderate CYP3A4 Inhibitor | Recommended Dosage with Strong CYP3A4 Inhibitor |
|---|---|---|
450 mg | 225 mg | 150 mg |
300 mg | 150 mg | 75 mg |
225 mg | 75 mg | 75 mg |
150 mg | 75 mg | 75 mga |
aWhen coadministered with a strong CYP3A4 inhibitor, exposure to encorafenib at the 75-mg dosage is expected to be higher than the 150-mg dosage without concomitant CYP3A4 inhibitor and similar to the 225-mg dosage without concomitant CYP3A4 inhibitor. Closely monitor for adverse reactions and use clinical judgement when encorafenib 150 mg is used in combination with a strong CYP3A4 inhibitor.
Dosage adjustment is not necessary in patients with mild hepatic impairment (Child-Pugh class A).1 Use of encorafenib in patients with moderate or severe (Child-Pugh class B or C) hepatic impairment has not been studied, and the manufacturer provides no specific dosage recommendations for such patients.1
Dosage adjustment is not necessary in patients with mild or moderate renal impairment (creatinine clearance of 30 to <90 mL/minute).1 Use of encorafenib in patients with severe renal impairment (creatinine clearance <30 mL/minute) has not been studied, and the manufacturer provides no specific dosage recommendations for such patients.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
When encorafenib is used in combination with binimetinib, cetuximab, or mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin), the usual cautions, precautions, and contraindications associated with these agents must be considered in addition to those associated with encorafenib.1
Development of New Primary Malignancies
New primary cutaneous or noncutaneous malignancies have been reported in patients receiving b-Raf serine-threonine kinase (BRAF) inhibitors, including encorafenib.1
In the COLUMBUS study, cutaneous squamous cell carcinoma (including keratoacanthoma) or basal cell carcinoma occurred in 8 or 1%, respectively, of patients receiving single-agent encorafenib compared with 2.6 or 1.6%, respectively, of those receiving encorafenib in combination with binimetinib.1 New primary melanoma also was reported in 5% of patients receiving single-agent encorafenib.1 The median time to first onset of cutaneous squamous cell carcinoma or keratoacanthoma in patients receiving encorafenib in combination with binimetinib was 5.8 months (range: 1-9 months).1
In the BEACON CRC study, cutaneous squamous cell carcinoma (including keratoacanthoma) or new primary melanoma occurred in 1.4 or 1.4%, respectively, of patients receiving encorafenib in combination with cetuximab.1
In the PHAROS study, cutaneous squamous cell carcinoma and skin papilloma each occurred in 2% of patients receiving encorafenib in combination with binimetinib.1
In the BREAKWATER study, skin papilloma, basal cell carcinoma, squamous cell carcinoma of the skin, keratoacanthoma, and malignant melanoma in situ occurred in 2.6, 1.3, 0.9, 0.4, and 0.4%, respectively, of patients receiving encorafenib in combination with cetuximab and mFOLFOX6.1
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, 7, 15, 16, 17, 18 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.21, 22, 23 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.25 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.24, 25 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; therefore, combination therapy with a BRAF inhibitor and a MEK inhibitor may reduce the risk of developing cutaneous squamous cell carcinoma.14, 17, 19 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 a MEK inhibitor.20
A dermatologic evaluation should be performed at baseline, every 2 months during therapy, and for up to 6 months following discontinuance of therapy.1 Suspicious cutaneous lesions should be treated as appropriate and excised for pathologic evaluation.1 Patients should be monitored for signs and symptoms of new noncutaneous malignancies.1 If new primary RAS mutation-positive, noncutaneous malignancies occur, encorafenib therapy should be permanently discontinued.1 In patients who develop new primary cutaneous malignancies, the manufacturer states that no dosage adjustment of encorafenib is necessary.1
Tumor Promotion in Wild-type BRAF Tumors
In vitro, paradoxical activation of MAPK signaling and increased cell proliferation have been observed in wild-type BRAF cells exposed to BRAF inhibitors.1 Presence of BRAF V600E or V600K mutation must be confirmed prior to initiation of therapy.1
Cardiomyopathy, which may manifest as a symptomatic or asymptomatic decrease in left ventricular ejection fraction (LVEF), has been reported in patients receiving encorafenib in combination with binimetinib.1 In the COLUMBUS study, cardiomyopathy (defined as an absolute decrease in LVEF from baseline of ≥10% and to a level below the lower limit of normal [LLN]) occurred in 7% of patients receiving encorafenib in combination with binimetinib; grade 3 left ventricular dysfunction occurred in 1.6% of patients receiving combination therapy.1 The median time to first onset of left ventricular dysfunction was 3.6 months (range: 0-21 months).1 Cardiomyopathy resolved in 87% of patients receiving combination therapy with encorafenib and binimetinib.1
Evidence of cardiomyopathy was observed in 11% of patients administered encorafenib in combination with binimetinb in the PHAROS study, with grade 3 left ventricular dysfunction occurring in 1% of patients.1 Cardiomyopathy resolved in 82% of patients.1
Safety of combination therapy with encorafenib and binimetinib has not been established in patients with a baseline LVEF below the LLN or <50%.1
LVEF should be assessed using echocardiogram or multigated radionuclide angiography (MUGA) prior to and 1 month after initiation of encorafenib and then every 2-3 months during therapy.1 Close monitoring during therapy is indicated in patients with preexisting cardiovascular risk factors.1 If left ventricular dysfunction occurs, temporary interruption followed by dosage reduction or discontinuance of encorafenib may be necessary.1
Liver function test abnormalities have been reported in patients receiving combination therapy with encorafenib and binimetinib.1 In the COLUMBUS study, grade 3 or 4 elevations in ALT, AST, and alkaline phosphatase concentrations occurred in 6, 2.6, and 0.5%, respectively, of patients receiving combination therapy with encorafenib and binimetinib.1 In the PHAROS study, grade 3 or 4 elevations in ALT, AST, and alkaline phosphatase concentrations occurred in 9%, 10%, and 3.2%, respectively, of patients receiving encorafenib in combination with binimetinib.1 In the BREAKWATER study, grade 3 or 4 elevations in ALT, AST, and alkaline phosphatase concentrations occurred in 1.3, 0.9, and 2.2%, respectively, of patients receiving encorafenib in combination with cetuximab and mFOLFOX6.1
Liver function tests should be performed prior to initiation of encorafenib therapy and then monthly, or more frequently as clinically indicated, during therapy with the drug.1 Temporary interruption, dosage reduction, or discontinuance of encorafenib may be necessary if liver function test abnormalities occur during therapy with the drug.1
Hemorrhage has been reported in patients receiving encorafenib.1 In the COLUMBUS study, hemorrhage occurred in 19% of patients and was grade 3 or greater in 3.2% of patients receiving encorafenib in combination with binimetinib.1 The most common hemorrhagic events in patients receiving encorafenib in combination with binimetinib were GI hemorrhage, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).1 Intracranial hemorrhage was fatal in 1.6% of patients with new or progressive brain metastases receiving combination therapy with encorafenib and binimetinib.1
In the BEACON CRC study, hemorrhage occurred in 19% of patients and was grade 3 or greater in 1.9% of patients receiving encorafenib in combination with cetuximab.1 The most common hemorrhagic events in patients receiving encorafenib in combination with cetuximab were epistaxis (6.9%), hematochezia (2.3%), and rectal hemorrhage (2.3%); fatal GI hemorrhage was reported in 0.5% of patients.1
In the PHAROS study, hemorrhage occurred in 12% of patients receiving encorafenib in combination with binimetinib, including fatal intracranial hemorrhage in 1% of patients.1 Grade 3 or 4 hemorrhage was reported in 4.1% of patients.1 The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each).1
In the BREAKWATER study, hemorrhage occurred in 30% of patients receiving encorafenib in combination with cetuximab and mFOLFOX6; 3% of patients experienced grade 3 or 4 hemorrhage.1
If hemorrhagic events occur, therapy interruption followed by dosage reduction or discontinuance of encorafenib may be necessary.1
Uveitis, including iritis and iridocyclitis, have occurred in patients receiving encorafenib in combination with binimetinib.1 In the COLUMBUS study, uveitis occurred in 4% of patients receiving encorafenib in combination with binimetinib.1 In PHAROS, uveitis occurred in 1% of patients administered encorafenib in combination with binimetinib.1
Ophthalmologic examinations should be performed regularly and as clinically indicated (i.e., if new or worsening visual disturbances occur; to follow new or persistent ophthalmologic findings) during encorafenib therapy.1 Patients should be monitored for visual symptoms at each visit.1 Temporary interruption, dosage reduction, or discontinuance of encorafenib may be necessary if ocular toxicities occur during therapy with the drug.1
Encorafenib is associated with dose-dependent prolongation of the QT interval.1 In the COLUMBUS study, a QT interval (corrected for heart rate using Fridericia's formula [QTcF]) exceeding 500 msec was observed in 1 of 192 patients (0.5%) receiving encorafenib in combination with binimetinib.1 In PHAROS, an increase in QTcF exceeding 500 msec was measured in 2 of 95 patients (2.1%) receiving encorafenib in combination with binimetinib.1 In BREAKWATER, an increase in QTcF exceeding 500 msec was measured in 8 of 222 patients (3.6%) receiving encorafenib in combination with cetuximab and mFOLFOX6.1
Patients at an increased risk for QTc-interval prolongation, including those with a history of long QT syndromes, clinically important bradyarrhythmias, or severe or uncontrolled heart failure, and those concurrently receiving other drugs known to prolong the QT interval should be monitored.1 Hypokalemia and hypomagnesemia should be corrected prior to administration of encorafenib and as clinically indicated during therapy.1 If prolongation of the QT interval occurs, therapy interruption followed by dosage reduction or discontinuance of encorafenib may be necessary.1
Fetal/Neonatal Morbidity and Mortality
Encorafenib may cause fetal harm in humans based on its mechanism of action and animal findings; the drug has been shown to be embryotoxic, fetotoxic, and teratogenic in animals.1 There are no available data regarding the risk of encorafenib use in pregnant women to date.1 In animal reproduction studies, embryofetal toxicity (i.e., decreases in fetal body weight) and teratogenic effects (i.e., skeletal anomalies) have been demonstrated in pregnant rats receiving encorafenib at exposure levels equivalent to approximately 26 times the human exposure at the recommended human dosage.1 Postimplantation loss and abortion also were observed in rabbits receiving encorafenib at exposure levels of approximately 178 times the human exposure at the recommended human dosage.1 Although formal placental transfer studies have not been conducted, encorafenib has been detected in fetal plasma of rats and rabbits at concentrations up to 1.7 and 0.8%, respectively, of maternal plasma concentrations.1
Pregnancy should be avoided during encorafenib therapy.1 The manufacturer states that pregnancy status should be verified prior to initiation of encorafenib therapy in women of childbearing potential and that such women should be advised to use an effective nonhormonal method of contraception while receiving encorafenib and for 2 weeks after the last dose.1 Patients should be apprised of the potential hazard to the fetus if the drug is used during pregnancy.1
Some adverse effects may occur less frequently during combination therapy with encorafenib and binimetinib compared to single-agent encorafenib.1 Grade 3 or 4 dermatologic reactions occurred in 21 or 2% of patients receiving single-agent encorafenib or combination therapy with encorafenib and binimetinib, respectively.1
Encorafenib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
Pregnancy status should be verified in women of childbearing potential prior to initiation of encorafenib therapy.1
It is not known whether encorafenib or its metabolites are distributed into human milk.1 Because of the potential for serious adverse reactions to encorafenib in breast-fed infants, women 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
Results of animal studies suggest that encorafenib may reduce male fertility.1 The effect of the drug on fertility in humans is not known.1
For women of childbearing potential, an effective nonhormonal method of contraception should be used while receiving encorafenib and for 2 weeks after the last dose.1 Advise patients to use a nonhormonal method as encorafenib can interact with hormonal contraceptives and render them ineffective.1
Safety and efficacy of encorafenib have not been established in pediatric patients.1
In the clinical trials evaluating encorafenib (300-600 mg once daily) in combination with binimetinib (45 mg twice daily) in patients with BRAF mutation-positive melanoma, 20% of patients were 65-74 years of age and 8% were 75 years of age or older.1
Among 216 patients with metastatic BRAF mutation-positive colorectal cancer who received encorafenib 300 mg once daily in combination with cetuximab in a clinical trial, 29% of patients were 65-74 years of age and 9% were ≥75 years of age.1
Among 231 patients with metastatic BRAF V600E mutation-positive colorectal cancer who received encorafenib 300 mg once daily in combination with cetuximab and mFOLFOX6 in a clinical trial, 36% of patients were ≥65 years of age and 7% were ≥75 years of age.1
In a clinical trial of patients with BRAF V600E mutation-positive metastatic NSCLC administered encorafenib in combination with binimetinib, 63% of patients were ≥65 years of age and 20% were ≥75 years of age.1
No overall differences in safety or efficacy of encorafenib in combination with binimetinib, encorafenib in combination with cetuximab, or encorafenib in combination with cetuximab and mFOLFOX6 were observed between geriatric patients and younger adults.1
In population pharmacokinetic analyses, systemic exposure of encorafenib was similar in patients with mild hepatic impairment (Child-Pugh class A) and those with normal hepatic function.1, 5
The pharmacokinetic profile of encorafenib has not been established in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1
In population pharmacokinetic analyses, systemic exposure of encorafenib was similar in patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute) and those with normal renal function.1, 5
The pharmacokinetic profile of encorafenib has not been established in patients with severe renal impairment (creatinine clearance <30 mL/minute).1
The most common adverse effects (≥25%) in patients with melanoma receiving encorafenib in combination with binimetinib include fatigue, nausea, vomiting, abdominal pain, and arthralgia.1
The most common adverse effects (≥25%) in patients with colorectal cancer receiving encorafenib in combination with cetuximab include fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.1
The most common adverse effects (≥25%) in patients with colorectal cancer receiving encorafenib in combination with cetuximab and mFOLFOX6 include peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia.1
The most common adverse effects (≥25%) in patients with NSCLC receiving encorafenib in combination with binimetinib include fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.1
Encorafenib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP isoenzymes 2C19 and 2D6.1, 5 In vitro studies also indicate that encorafenib is a reversible inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2D6, and 3A.1, 5 The drug has demonstrated time-dependent inhibition of CYP3A4 at clinically relevant concentrations.1 In vitro, encorafenib induces CYP isoenzymes 2B6, 2C9, and 3A4 at clinically relevant concentrations.1
Encorafenib is an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic cation transporter (OCT) 2, organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, and OATP1B3, but does not inhibit OCT1 or multidrug resistance-associated protein (MRP) 2 at clinically relevant concentrations.1
In vitro studies indicate that encorafenib is a substrate of P-gp, but is not a substrate for BCRP, MRP2, OATP1B1, OATP1B3, or OCT1 at clinically relevant concentrations.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of encorafenib with strong or moderate inhibitors of CYP3A4 may result in increased peak plasma concentrations and systemic exposure (AUC) of encorafenib and an increased incidence of adverse effects.1 When the strong CYP3A4 inhibitor posaconazole was administered concomitantly with encorafenib (single 50-mg dose), the peak plasma concentration and AUC of encorafenib were increased by 68% and 3-fold, respectively.1, 5 When the moderate CYP3A4 inhibitor diltiazem hydrochloride was administered concomitantly with encorafenib (single 50-mg dose), the peak plasma concentration and AUC of encorafenib were increased by 45% and 2-fold, respectively.1, 5
Concomitant use of encorafenib with strong (e.g., posaconazole)1 or moderate (e.g., diltiazem) inhibitors of CYP3A4 should be avoided.1 If such concomitant use cannot be avoided, the manufacturer recommends reducing the dosage of encorafenib based on the recommendations in Table 1.1 If concomitant use of the strong or moderate CYP3A4 inhibitor is discontinued, the encorafenib dosage should be returned (after 3-5 terminal half-lives of the CYP3A4 inhibitor) to the dosage used prior to initiation of the potent or moderate CYP3A4 inhibitor.1
Concomitant use of encorafenib with strong or moderate inducers of CYP3A4 may result in decreased systemic exposure and reduced efficacy of encorafenib.1 When the moderate CYP3A4 inducer (modafinil) was administered concomitantly with encorafenib 450 mg once daily and binimetinib 45 mg twice daily, the peak plasma concentration and AUC of encorafenib were decreased by 20% and 24%, respectively, compared to encorafenib alone.1
Because formal drug interaction studies with strong CYP3A4 inducers have not been performed, the manufacturer states that concomitant use of encorafenib with strong inducers of CYP3A4 should be avoided.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Concomitant administration of encorafenib with sensitive CYP3A4 substrates may decrease plasma concentrations of the CYP3A4 substrate (e.g., midazolam) and result in reduced efficacy of the substrate drug.1 Avoid concomitant use of encorafenib with CYP3A4 substrates for which a decrease in plasma concentration may lead to reduced substrate efficacy.1 If concurrent use cannot be avoided, refer to the CYP3A4 substrate prescribing information for recommendations.1
Drugs that Prolong the QT Interval
Because encorafenib has been associated with QT-interval prolongation, concomitant use of encorafenib with drugs known to prolong the QT interval should be avoided.1
Drugs Affecting Gastric Acidity
Concomitant administration of encorafenib (single 100-mg dose) with the proton-pump inhibitor rabeprazole (20 mg once daily for 5 days) resulted in no clinically important changes in peak plasma concentration or systemic exposure of encorafenib.1, 5
Drugs Affecting Efflux Transport Systems
Repeated, concomitant administration of encorafenib (450 mg once daily) and binimetinib (45 mg twice daily) with a single dose of rosuvastatin, a sensitive substrate for OATP1B1, OATP1B3, and BCRP, resulted in an increase in peak plasma concentration and AUC of rosuvastatin by 2.7- and 1.6-fold, respectively.1
Concomitant use of encorafenib with grapefruit products (CYP3A4 inhibitor) may result in increased peak plasma concentrations and systemic exposure of encorafenib.1 Patients receiving encorafenib should be advised to avoid consuming grapefruit products.1
Concomitant use of encorafenib with hormonal contraceptives that are metabolized by CYP3A4 may result in decreased systemic exposure to the substrate drug and reduced contraceptive efficacy.1 Concomitant use of encorafenib with hormonal contraceptives should be avoided.1
Concomitant administration of encorafenib with binimetinib, a UGT1A1 substrate, did not substantially alter systemic exposure of binimetinib.1
Concomitant administration of encorafenib with cetuximab did not substantially alter systemic exposure of either drug.1
Encorafenib, an inhibitor of b-Raf serine-threonine kinase (BRAF) with V600E or V600K mutation, is an antineoplastic agent.1, 2 Approximately 40-60% of cutaneous melanomas carry a BRAF mutation.2, 3, 8, 11 The most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E);8, 9, 11 a less frequently occurring BRAF mutation is the substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K).8, 9, 11 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).7, 8, 9 Encorafenib induced tumor regression associated with inhibition of the MAPK/ERK signal transduction pathway in xenograft models of tumor cells with BRAF V600E mutation in mice.1 In vitro studies have demonstrated that encorafenib inhibited tumor growth of cell lines testing positive for BRAF with V600E, V600D, or V600K mutation.1 Encorafenib also inhibits wild-type b-Raf and other kinases such as c-Raf, c-Jun NH(2)-terminal protein kinase (JNK)1, JNK2, JNK3, LIM domain kinase (LIMK)1, LIMK2, mitogen-activated extracellular signal-regulated kinase (MEK)4, and serine/threonine kinase (STK)36 and substantially reduces ligand binding to these kinases at clinically relevant concentrations.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.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 (e.g., dabrafenib, encorafenib, vemurafenib) and a MEK inhibitor (e.g., binimetinib, cobimetinib, trametinib).3, 11, 14 In vitro, use of encorafenib in combination with binimetinib resulted in increased antiproliferative activity compared with either drug alone in BRAF mutation-positive cell lines.1 The combination of encorafenib and binimetinib also has demonstrated increased inhibition of tumor growth and delayed emergence of resistance compared with either drug alone in xenograft models of melanoma harboring BRAF V600E mutations in mice.1 Single agent BRAF or MEK inhibitor treatment is no longer recommended by experts as combination BRAF/MEK inhibition has demonstrated superior outcomes with a similar safety profile.200
In metastatic colorectal cancer, approximately 12% of patients express mutations in the BRAF gene; the BRAF V600E mutation is a poor prognostic factor, associated with a reduced median survival.202 Single agent BRAF inhibition has demonstrated only modest activity in BRAF mutation-positive colorectal cancer, which may be attributed to resistance mechanisms that reactivate epidermal growth factor receptor (EGFR).202 Synergistic inhibition of tumor growth and improved activity have been demonstrated with BRAF and EGFR inhibitor combinations in xenograft models and clinical studies.202
Following oral administration of encorafenib, at least 86% of the dose is rapidly absorbed with peak plasma concentrations occurring in 2 hours.1 Systemic exposure of encorafenib is proportional to dose following single administration of the drug over the dosage range of 50-700 mg, but less than proportional to dose following repeated administration of the drug over the dosage range of 50-800 mg once daily.1 Steady-state concentrations are achieved within 15 days.1 In a physiologically based pharmacokinetic model, systemic exposure of encorafenib at steady state was 50% lower compared to the systemic exposure following the initial dose, suggesting that encorafenib causes autoinduction of its own metabolism; however, intersubject variability ranged from 12-69%.1, 5 Administration of a single 100-mg dose of encorafenib with a high-fat, high-calorie meal (approximately 150 calories from protein, 350 calories from carbohydrates, 500 calories from fat) decreased mean peak plasma concentrations of the drug by 36%, but did not affect the extent of absorption (AUC).1 Encorafenib is 86% bound to plasma proteins.1 Encorafenib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2C19 and CYP2D6.1 The mean terminal half-life of encorafenib is 3.5 hours.1 Following oral administration of a radiolabeled dose of encorafenib, 47% of the dose is recovered in feces (5% of the dose as unchanged drug) and 47% is recovered in urine (2% of the dose as unchanged drug).1
The pharmacokinetics of encorafenib do not appear to be affected substantially by age (19-89 years), gender, or body weight.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.
Encorafenib can only be obtained through select specialty pharmacies.27 Contact the manufacturer or consult the Braftovi® and Mektovi® website for specific availability information ([Web]).27
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 75 mg | Braftovi® |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions September 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Array BioPharma, Inc. Braftovi® (encorafenib) capsules prescribing information. Boulder, CO; 2025 Mar.
2. Dummer R, Ascierto PA, Gogas HJ et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol . 2018; 19:603-15.
3. Ascierto PA, Dummer R, Gogas HJ, et al. Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Eur J Cancer . 2020:126:33-44;
4. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 Apr 23. [Web]
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15. Arnault JP, Mateus C, Escudier B et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res . 2012; 18:263-72. [PubMed 22096025]
16. Poulikakos PI, Zhang C, Bollag G et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature . 2010; 464:427-30. [PubMed 20179705]
17. Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med . 2012; 366:207-15. [PubMed 22256804]
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20. Peng L, Wang Y, Hong Y et al. Incidence and relative risk of cutaneous squamous cell carcinoma with single-agent BRAF inhibitor and dual BRAF/MEK inhibitors in cancer patients: a meta-analysis. Oncotarget . 2017; 8:83280-83291. [PubMed 29137342]
21. Ernstoff MS. Been there, not done that--melanoma in the age of molecular therapy. N Engl J Med . 2011; 364:2547-8. [PubMed 21639809]
22. Arnault JP, Mateus C, Escudier B et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res . 2012; 18:263-72. [PubMed 22096025]
23. Poulikakos PI, Zhang C, Bollag G et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature . 2010; 464:427-30. [PubMed 20179705]
24. Sosman JA, Kim KB, Schuchter L et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med . 2012; 366:707-14. [PubMed 22356324]
25. Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med . 2012; 366:207-15. [PubMed 22256804]
27. Pfizer. Braftovi® (encorafenib) capsules and Mektovi®(binimetinib) tablets: access and patient support. From Braftovi® Mektovi® for Healthcare Professionals website. [Web]
28. Food and Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). From FDA website. Accessed 2024 Apr 23. [Web]
29. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med . 2019;381(17):1632-1643.
30. Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol . 2021;39(4):273-284.
31. Riely GJ, Smit EF, Ahn MJ, et al. Phase II, open-label study of encorafenib plus binimetinib in patients with BRAFV600-mutant metastatic non-small-cell lung cancer. J Clin Oncol . 2023;41(21):3700-10.
200. Seth R, Agarwala SS, Messersmith H. et al. Systemic Therapy for Melanoma: ASCO guideline update. J Clin Oncol . 2023;41(30):4794-4820.
201. Chiorean EG, Nandakumar G, Fadelu T, et al. Treatment of patients with late-stage colorectal cancer: ASCO resource-stratified guideline. JCO Glob Oncol . 2020;6:414-438.
202. Grothey A, Fakih M, Tabernero J. Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines. Ann Oncol . 2021;32(8):959-967.
203. Elez E, Yoshino T, Shen L, et al. for the BREAKWATER trial investigators. Encorafenib, cetuximab, and mFOLFOX6 in BRAF-mutated colorectal cancer. N Engl J Med . 2025;392(24):2425
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