Renal dysfunction

Blood creatinine elevation and renal failure occurred when binimetinib was used in combination with encorafenib (see section 4.8 of encorafenib SmPC).

Liver laboratory abnormalities

The incidences of liver laboratory abnormalities reported in the pooled Combo 450 population are listed below:

• Increased transaminases: 15.7% (43/274) overall - Grade 3-4: 5.5% (15/274)

• Increased GGT: 14.6% (40/274) overall - Grade 3-4: 8.4% (23/274)

In Study CMEK162B2301-Part 2, in the Combo 300 arm, the incidences of liver laboratory abnormalities are listed below:

• Increased transaminases: 13.2% (34/257) overall - Grade 3-4: 5.4% (14/257)

• Increased GGT: 14.0% (36/257) overall - Grade 3-4: 4.7% (12/257)

Gastrointestinal disorders

In the pooled Combo 450 population, diarrhoea was observed in 38 % (104/274) of patients and was Grade 3 or 4 in 3.3 % (9/274) of patients. Diarrhoea led to dose discontinuation in 0.4 % of patients and to dose interruption or dose modification in 4.4 % of patients. Constipation occurred in 24.1 % (66/274) of patients and was Grade 1 or 2. Abdominal pain was reported in 27.4 % (75/274) of patients and was Grade 3 in 2.6 % (7/274) patients. Nausea occurred in 41.6 % (114/274) with Grade 3 or 4 observed in 2.6 % (7/274) of patients. Vomiting occurred in 28.1 % (77/274) of patients with Grade 3 or 4 reported in 2.2 % (6/274) of patients.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, nausea was observed in 27.2% (70/257) of patients and was Grade 3 in 1.6% (4/257) of patients. Vomiting occurred in 15.2% (39/257) of patients with Grade 3 reported in 0.4% (1/257) of patients. Diarrhoea occurred in 28.4% (73/257) of patients with Grade 3 reported in 1.6% (4/257) of patients.

Gastrointestinal disorders were typically managed with standard therapy.

Anaemia

In the pooled Combo 450 population, anaemia was reported in 19.7 % (54/274) of patients; 4.7 % (13/274) of patients had Grade 3 or 4. No patients discontinued treatment due to anaemia, 1.5 % (4/274) required dose interruption or dose modification.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, anaemia was observed in 9.7% (25/257) of patients with Grade 3-4 reported in 2.7% (7/257) patients.

Headache

In the pooled Combo 450 population, headache occurred in 21.5% (59/274) of patients including Grade 3 in 1.5% (4/274) of patients.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, headache was reported in 12.1% (31/257) of patients and was Grade 3 in 0.4% (1/257) of patients.

Fatigue

In the pooled Combo 450 population, fatigue occurred in 43.8% (120/274) of patients including Grade 3 in 2.9% (8/274) of patients.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, fatigue was observed in 33.5% (86/257) of patients with 1.6% (4/257) Grade 3-4 events.

Special populations

Elderly