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New primary malignant tumors (cutaneous and non-cutaneous) have been observed in patients receiving BRAF inhibitor treatment, and may also occur with encorafenib.
In the COLUMBUS trial, among patients receiving encorafenib in combination with binimetinib:
The incidence of cutaneous squamous cell carcinoma (including keratoacanthoma) was 2.6%.
The incidence of basal cell carcinoma was 1.6%.
The median time to first occurrence of cutaneous squamous cell carcinoma/keratoacanthoma was 5.8 months.
Among patients receiving encorafenib monotherapy:
The reported rate of cutaneous squamous cell carcinoma/keratoacanthoma was 8%.
The rate of basal cell carcinoma was 1%.
The rate of new melanoma was 5%.
In the BEACON CRC trial, among colorectal cancer patients receiving encorafenib in combination with cetuximab:
The incidence of cutaneous squamous cell carcinoma/keratoacanthoma was 1.4%.
The incidence of new melanoma was 1.4%.
In the PHAROS trial, among patients receiving encorafenib in combination with binimetinib:
The incidence of cutaneous squamous cell carcinoma and cutaneous papilloma was 2% each.
In the BREAKWATER trial, among patients receiving encorafenib in combination with cetuximab and the mFOLFOX6 regimen:
The reported rate of cutaneous papilloma was 2.6%.
The rate of basal cell carcinoma was 1.3%.
The rate of cutaneous squamous cell carcinoma was 0.9%.
The rate of keratoacanthoma was 0.4%.
The rate of in situ malignant melanoma was 0.4%.
Dermatological evaluations should be performed before the start of treatment, every 2 months during treatment, and for up to 6 months after treatment discontinuation. Suspected cutaneous lesions should be managed with excision and cutaneous pathological assessment. No dosage adjustment is recommended for new primary cutaneous malignant tumors.
Based on its mechanism of action, encorafenib may promote malignancies associated with RAS activation through mutation or other mechanisms. Monitor patients receiving encorafenib for signs and symptoms of non-cutaneous malignant tumors. Discontinue BRAFTOVI (brand name of encorafenib) in case of RAS mutation-positive non-cutaneous malignant tumors.
In vitro studies have shown that exposure to BRAF inhibitors in BRAF wild-type cells leads to paradoxical activation of MAP kinase signaling and increased cell proliferation. Confirm the presence of BRAF V600E or V600K mutation before initiating encorafenib treatment.
Cardiomyopathy, manifested as left ventricular dysfunction associated with symptomatic or asymptomatic decreased ejection fraction, has been reported in patients receiving encorafenib in combination with binimetinib.
In the COLUMBUS trial:
7% of patients receiving encorafenib plus binimetinib developed evidence of cardiomyopathy.
The incidence of grade 3 left ventricular dysfunction was 1.6%.
The median time to first occurrence of left ventricular dysfunction was 3.6 months. Cardiomyopathy resolved in 87% of patients.
In the PHAROS trial:
11% of patients receiving encorafenib in combination with binimetinib developed evidence of cardiomyopathy.
The incidence of grade 3 left ventricular dysfunction was 1%.
Cardiomyopathy resolved in 82% of patients.
Assess ejection fraction via echocardiogram or MUGA scan before the start of treatment, 1 month after treatment initiation, and every 2–3 months during treatment. The safety of encorafenib in combination with binimetinib has not been established in patients with a baseline ejection fraction below 50% or below the institutional lower limit of normal. Patients with cardiovascular risk factors should be closely monitored while receiving encorafenib.
Suspend, reduce the dose, or permanently discontinue encorafenib based on the severity of adverse reactions.
Hepatotoxicity may occur when encorafenib is administered in combination with binimetinib.
In the COLUMBUS trial, among patients receiving encorafenib in combination with binimetinib, the incidence of grade 3 or 4 elevations in liver function laboratory parameters was:
ALT: 6%.
AST: 2.6%.
Alkaline phosphatase: 0.5%.
In the PHAROS trial, among patients receiving encorafenib in combination with binimetinib, the incidence of grade 3 or 4 elevations in liver function laboratory parameters was:
AST: 10%.
ALT: 9%.
Alkaline phosphatase: 3.2%.
In the BREAKWATER trial, among patients receiving encorafenib in combination with cetuximab and the mFOLFOX6 regimen, the incidence of grade 3 or 4 elevations in liver function laboratory parameters was:
Alkaline phosphatase: 2.2%.
ALT: 1.3%.
AST: 0.9%.
Monitor liver function laboratory tests before the start of encorafenib, monthly during treatment, and as clinically indicated. Suspend, reduce the dose, or permanently discontinue encorafenib based on the severity of adverse reactions.
In the COLUMBUS trial:
19% of patients receiving encorafenib in combination with binimetinib experienced bleeding.
The incidence of grade 3 or higher bleeding was 3.2%, including a 1.6% incidence of fatal intracranial hemorrhage in cases of new or progressive brain metastases.
The most common bleeding events were gastrointestinal bleeding.
In the BEACON CRC trial:
19% of patients receiving encorafenib in combination with cetuximab experienced bleeding.
The incidence of grade 3 or higher bleeding was 1.9%, including 0.5% fatal gastrointestinal bleeding.
The most common bleeding events were epistaxis, hematochezia, and rectal bleeding.
In the PHAROS trial:
12% of patients receiving encorafenib in combination with binimetinib experienced bleeding, including fatal intracranial hemorrhage (1%).
The incidence of grade 3 or 4 bleeding was 4.1%.
The most common bleeding events were anal bleeding and hemothorax.
In the BREAKWATER trial:
30% of patients receiving encorafenib in combination with cetuximab and the mFOLFOX6 regimen experienced bleeding.
The incidence of grade 3 or 4 bleeding was 3%.
Suspend, reduce the dose, or permanently discontinue encorafenib based on the severity of adverse reactions.
Uveitis (including iritis and iridocyclitis) has been reported in patients receiving encorafenib in combination with binimetinib.
In the COLUMBUS trial:
The incidence of uveitis was 4% among patients receiving encorafenib in combination with binimetinib.
In the PHAROS trial:
The incidence of uveitis was 1% among patients receiving encorafenib in combination with binimetinib.
Assess visual symptoms at each visit. Conduct regular ophthalmological evaluations and follow up on new or worsening visual disturbances and new or persistent ophthalmological findings. Suspend, reduce the dose, or permanently discontinue encorafenib based on the severity of adverse reactions.
Encorafenib is associated with dose-dependent QT interval prolongation in some patients.
In the COLUMBUS trial:
0.5% of patients receiving encorafenib in combination with binimetinib had a measured QTcF greater than 500 ms.
In the PHAROS trial:
2.1% of patients receiving encorafenib in combination with binimetinib had a measured QTcF greater than 500 ms.
In the BREAKWATER trial:
3.6% of patients receiving encorafenib in combination with cetuximab and the mFOLFOX6 regimen had a measured QTcF greater than 500 ms.
Monitor patients with a history of or significant risk factors for QTc prolongation. Correct hypokalemia and hypomagnesemia before and during encorafenib administration. Suspend, reduce the dose, or permanently discontinue encorafenib in patients with a QTc greater than 500 ms.
Based on its mechanism of action, encorafenib may cause fetal harm when administered to pregnant women. Encorafenib induced embryofetal developmental changes in rats and rabbits, and exhibited abortifacient effects in rabbits at doses ≥178 times the exposure at the recommended human dose of 450 mg.
Inform pregnant women and females of reproductive potential about the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment and for 2 weeks after the last dose of encorafenib, as encorafenib may render hormonal contraceptives ineffective.
Encorafenib monotherapy is associated with an increased risk of certain adverse reactions compared to encorafenib in combination with binimetinib. In the COLUMBUS trial:
The incidence of grade 3 or 4 cutaneous reactions was 21% in patients receiving encorafenib monotherapy, compared to 2% in patients receiving encorafenib in combination with binimetinib.
If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of encorafenib as recommended.
Encorafenib must be used as part of a regimen in combination with binimetinib, or with cetuximab, or with cetuximab and the mFOLFOX6 regimen. Refer to the prescribing information for each component (binimetinib, cetuximab, and mFOLFOX6) for additional risk information.
FDA，2025.03
