What are the precautions for Canafenib/Encofenib?

In clinical studies of canafenib/encorafenib for the treatment of a certain disease, warnings and precautions have emerged regarding new primary malignant tumors, tumor promotion BRAF wild-type tumors, cardiomyopathy, liver toxicity, bleeding, uveitis, QT prolongation, embryo-fetal toxicity, risks associated with being a single agent, risks associated with combination therapy, etc. Discontinue and resume at reduced dose upon recovery, or permanently discontinue based on severity.

1. New primary malignancies: New primary cutaneous and non-cutaneous malignancies have been observed in patients treated with BRAF inhibitors and may occur with canafenib. Cutaneous malignancies may include basal cell carcinoma, cutaneous squamous cell carcinoma (cuSCC) , including keratoacanthoma (KA), and dermatological evaluation is performed before starting treatment, every 2 months during treatment, and within 6 months after discontinuation of treatment. Suspected skin lesions are managed by excision and dermatopathological evaluation. No dose adjustment is recommended for new primary cutaneous malignancies.

Based on its mechanism of action, canafenib may promote malignancies associated with RAS activation through mutation or other mechanisms. Monitor patients receiving canafenib for signs and symptoms of noncutaneous malignancies. For RAS mutation-positive noncutaneous malignancies, discontinue canafenib.

2. Tumor promotion 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. Before starting canafenib, confirm evidence of BRAF V600E or V600K mutation.

3. Cardiomyopathy: Cardiomyopathy, characterized by left ventricular dysfunction with symptomatic or asymptomatic reduced ejection fraction, has been reported in patients receiving canafenib combination therapy. Ejection fraction is assessed by echocardiography or MUGA scan before starting treatment, one month after starting treatment, and every 2 to 3 months during treatment. Safety has not been established in patients with baseline ejection fraction less than 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with canafenib.

4. Hepatotoxicity: Hepatotoxicity may occur when canafenib is combined with binimetinib. Liver function laboratory tests include alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase. Monitor liver laboratory tests prior to initiating treatment, monthly during treatment, and as clinically indicated.

5. Bleeding: In clinical studies, the most common bleeding events are epistaxis and gastrointestinal bleeding, including rectal bleeding, blood in the stool and hemorrhoidal bleeding.

6. Uveitis: including iritis and iridocyclitis. Visual symptoms were assessed at each visit. Perform periodic ophthalmologic evaluations for new or worsening visual impairments and follow up on new or ongoing eye exam results.

7. QT prolongation: In some patients, canafenib is associated with dose-dependent QTc interval prolongation. Monitor patients who have QTc prolongation or who are at high risk for developing QTc prolongation, including patients with known long QT syndrome, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, and patients taking other drugs associated with QT prolongation. Correct hypokalemia and hypomagnesemia before and during administration of canafenib. For QTc>500ms, suspend, reduce dose, or permanently discontinue medication.

8. Embryo-Fetal Toxicity: Based on its mechanism of action, canafenib can cause fetal damage when administered to pregnant women. Canafenib produces embryonic-fetal developmental changes in rats and rabbits and is an abortifacient in rabbits at doses ≥causing approximately 26- and 178-fold the human exposure at the recommended dose of 450 mg, with no clear findings at lower doses. Inform pregnant women and women of reproductive potential of the potential risks to the fetus. Advise females of reproductive potential to use an effective non-hormonal method of contraception as canafenib can render hormonal contraceptives ineffective during treatment and for 2 weeks after the last dose.

9. Risks associated with being a single drug: Compared with the combined use of canafenib andbinimetinib, when used alone, there is an increased risk of certain adverse reactions.

10. Risks related to combination therapy: Canafenib is suitable for use as part of a combination regimen withbinimetinib or cetuximab.