ents led to discontinuation of treatment in 1.1 % (3/274) of patients. The most frequent haemorrhagic events were haematuria in 3.3 % (9/274) of patients, rectal haemorrhage in 2.9 % (8/274) and haematochezia in 2.9 % (8/274) of patients. Fatal gastric ulcer haemorrhage with multiple organ failure as a concurrent cause of death, occurred in one patient. Cerebral haemorrhage occurred in 1.5 % (4/274) of patients with fatal outcome in 3 patients. All events occurred in the setting of new or progressive brain metastases.
In Study CMEK162B2301-Part 2, in the Combo 300 arm, haemorrhagic events were observed in 6.6% (17/257) of patients and were Grade 3-4 in 1.6% (4/257) of patients.
Hypertension
New onset elevated blood pressure or worsening of pre-existing hypertension were reported in 11.7 % (32/274) of patients treated with the Combo 450. Hypertension events were reported as Grade 3 in 5.5 % (15/274) of patients, including hypertensive crisis (0.4 % (1/274)). Hypertension led to dose interruption or adjustment in 2.9 % of patients. Hypertensive adverse reactions required additional therapy in 8.0 % (22/274) of patients.
Venous thromboembolism
In patients treated with Combo 450, VTE occurred in 4.7 % (13/274) of patients, including 2.2 % (6/274) of patients who developed pulmonary embolism. In the pooled Combo 450 population, VTE was reported as Grade 1 or 2 in 3.6 % (10/274) of patients and Grade 3 or 4 in 1.1 % (3/274) of patients. VTE led to dose interruptions or dose modifications in 1.1 % (3/274) patients and to additional therapy in 4.7 % (13/274) of patients.
Pancreatitis
Pancreatitis was reported when binimetinib was used in combination with encorafenib (see section 4.8 of encorafenib SmPC).
Dermatologic reactions
Dermatologic reactions may occur when binimetinib is used in combination with encorafenib.
Rash
In the pooled Combo 450 population, rash occurred in 19.7 % (54/274) of patients. Most events were mild, with Grade 3 or 4 events reported in 0.7 % (2/274) of patients. Rash led to treatment discontinuation in 0.4 % (1/274) of patients and to dose interruption or dose modification in 1.1 % (3/274) of patients.
Dermatitis acneiform
In patients treated with Combo 450, dermatitis acneiform occurred in 4.4 % (12/274) of patients, was Grade 1 and 2 and no event led to treatment discontinuation. Dose modification was reported in 0.7 % (2/274) of patients.
Palmar-plantar erythrodysaesthesia syndrome
PPES can occur when binimetinib is used in combination with encorafenib (see section 4.8 of encorafenib SmPC).
Photosensitivity
In the pooled Combo 450 population, photosensitivity was observed in 4.0 % (11/274) of patients.
Most events were Grade 1-2, with Grade 3 reported in 0.4 % (1/274) of patients and no event led to discontinuation. Dose interruption or dose modification was reported in 0.4 % (1/274) of patients.
Facial paresis
Facial paresis was reported when binimetinib was used in combination with encorafenib (see section 4.8 of encorafenib SmPC).
CK elevation/rhabdomyolysis
In the pooled Combo 450 population, mostly mild asymptomatic blood CK elevation was reported in 27.0 % (74/274) of patients. The incidence of Grade 3 or 4 adverse reactions was 5.8 % (16/274). The median time to onset of the first event was 2.7 months (range: 0.5 to 17.5 months).
Rhabdomyolysis was reported in 0.4 % (1/274) of patients treated with encorafenib in combination with binimeti
