Encorafenib is a BRAF inhibitor primarily used to treat melanoma, colorectal cancer, and non-small cell lung cancer with BRAFV600E or V600K mutations. The usage and dosage should be adjusted according to the indications, and attention should be paid to the resistance mechanism and special precautions when using combination therapy. The following provides a detailed explanation from three aspects: usage and dosage, resistance mechanism, and precautions.

1. Usage and dosage of Conafenib

1.1 Recommended Dosage

The adult dose for melanoma is 450mg orally per day, in combination with bimertinib. The adult dose for colorectal cancer is 300mg orally per day, in combination with cetuximab. The adult dose for non-small cell lung cancer is 450mg orally per day, in combination with bimertinib. Continue treatment until disease progression or unacceptable toxicity occurs.

1.2 Dose adjustment

Gradually reduce the dosage according to the degree of adverse reactions: the first dose is reduced to 300mg/day, the second dose is reduced to 225mg/day, and the third dose is permanently discontinued. When used in combination with CYP3A4 inhibitors, the dosage should be reduced to 150mg/day for potent inhibitors.

2 Resistance mechanisms

Konafenib resistance is mainly associated with the reactivation of the MAPK pathway, including the production of BRAF splicing variants and the amplification of NRAS mutations. The combination of bimetinib can delay the onset of drug resistance, but ultimately may still lead to resistance caused by bypass activation or feedback enhancement.

3 Precautions

3.1 Newly developed malignant tumors

Skin and non skin malignant tumors need to be monitored. If non skin malignant tumors with positive RAS mutations occur, permanent discontinuation of medication is required.

3.2 Cardiomyopathy monitoring

LVEF should be regularly evaluated before and during treatment. If LVEF decreases by more than 20% from baseline and is lower than LLN, treatment should be reduced or suspended.

3.3 Hepatotoxicity Management

Baseline liver function test and monthly follow-up are required before treatment. When there is a 3-4 level increase in AST/ALT, the medication should be temporarily or permanently discontinued.

3.4 Other precautions

Including QT interval prolongation, bleeding risk, uveitis, etc. When relevant symptoms appear, the dosage should be adjusted or the medication should be stopped in a timely manner.