Binimetinib

Liver laboratory abnormalities

• Grade 2 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3x - ≤ 5x upper limit of normal (ULN)

Binimetinib dose should be maintained.

If no improvement within 2 weeks, binimetinib should be withheld until improved to Grade 0 or 1 or to baseline levels, and then resumed at the same dose.

• First occurrence of Grade 3 (AST or ALT > 5x ULN and blood bilirubin > 2x ULN)

Binimetinib should be withheld for up to 4 weeks.

• If improved to Grade 0 or 1 or baseline level, binimetinib should be resumed at reduced dose, or

• If not improved, binimetinib should be permanently discontinued.

• First occurrence of Grade 4 (AST or ALT > 20 ULN)

Binimetinib should be withheld for up to 4 weeks.

• If improved to Grade 0 or 1 or baseline levels, binimetinib should be resumed at a reduced dose level, or

• If not improved, binimetinib should be permanently discontinued.

Or, binimetinib should be permanently discontinued.

• Recurrent Grade 3 (AST or ALT > 5x ULN and blood bilirubin > 2x ULN)

It should be considered to permanently discontinue binimetinib.

• Recurrent Grade 4 (AST or ALT > 20 ULN)

Binimetinib should be permanently discontinued.

Interstitial lung disease (ILD)/pneumonitis

• Grade 2

Binimetinib should be withheld for up to 4 weeks.

• If improved to Grade 0 or 1, binimetinib should be resumed at reduced dose, or

• If not resolved within 4 weeks, binimetinib should be permanently discontinued.

• Grade 3 or Grade 4

Binimetinib should be permanently discontinued.

a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03

Table 2: Recommended dose modifications for binimetinib (used in combination with encorafenib) for other adverse reactions

Severity of adverse reaction

Binimetinib

• Recurrent or intolerable Grade 2 adverse reactions

• First occurrence of Grade 3 adverse reactions

Binimetinib should be withheld for up to 4 weeks.

• If improved to Grade 0 or 1 or baseline level, binimetinib should be resumed at reduced dose, or

• If not improved, binimetinib should be permanently discontinued.

• First occurrence of Grade 4 adverse reactions

Binimetinib should be withheld for up to 4 weeks.

• If improved to Grade 0 or 1 or baseline levels, binimetinib should be resumed at a reduced dose level, or

• If not improved, binimetinib should be permanently discontinued.

Or, binimetinib should be permanently discontinued binimetinib

• Recurrent Grade 3 adverse reactions

It should be considered to permanently discontinue binimetinib.

• Recurrent Grade 4 adverse reactions

Binimetinib should be permanently discontinued.

Duration of treatment

Treatment should continue until the patient no longer derives benefit or the development of unacceptable toxicity.

Missed doses

If a dose of binimetinib is missed, it should not be taken if it is less than 6 hours until the next dose is due.

Vomiting

In case of vomiting after administration of binimetinib, the patient should not re-take the dose and should take the next scheduled dose.

Special populations

Elderly patients