The following adverse reactions are described elsewhere in the labeling:
- Venous Thromboembolism
- Ocular Toxicities
- Interstitial Lung Disease
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in Warnings and Precautions reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in a randomized open-label, active-controlled trial (COLUMBUS) or, for rare events, exposure of 690 patients with BRAF V600 mutation positive melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials.
The data described below reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in COLUMBUS.
The COLUMBUS trial excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (> 480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with MEKTOVI in combination with encorafenib and 6.2 months for patients treated with vemurafenib.
Adverse reactions leading to dose interruptions of MEKTOVI occurred in 33% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (6%) and serous retinopathy (5%). Adverse reactions leading to dose reductions of MEKTOVI occurred in 19% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (3%), serous retinopathy (3%), and colitis (2%). Five percent (5%) of patients receiving MEKTOVI in combination with encorafenib experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI. The most common adverse reactions resulting in permanent discontinuation of MEKTOVI were hemorrhage in 2% and headache in 1% of patients.
Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for MEKTOVI in combination with encorafenib, as compared to vemurafenib, for any specific adverse reaction listed in Table 1.
Table 1: Adverse Reactions Occurring in ≥ 10% of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUSa
|Grades 3 and 4b
|Grades 3 and 4b
|General Disorders and Administration Site Conditions|
|Skin and Subcutaneous Tissue Disorders|
|Nervous System Disorders|
|a Grades per National Cancer Institute CTCAE v4.03.
b Grade 4 adverse reactions limited to diarrhea (n=1) and hemorrhage (n=3) in the MEKTOVI with encorafenib arm and constipation (n=1) in the vemurafenib arm.
c Represents a composite of multiple, related preferred terms.
Other clinically important adverse reactions occurring in < 10% of patients who received MEKTOVI in combination with encorafenib were:
Gastrointestinal disorders: Colitis
Skin and subcutaneous tissue disorders: Panniculitis
Immune system disorders: Drug hypersensitivity
Table 2: Laboratory Abnormalities Occurring in ≥ 10% (All grades) of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUSa
|Grades 3 and 4
|Grades 3 and 4
|Increased Creatine Phosphokinase||58||5||3.8||0|
|Increased Gamma Glutamyl Transferase||45||11||34||4.8|
|Increased Alkaline Phosphatase||21||0.5||35||2.2|
|a Grades per National Cancer Institute CTCAE v4.03.|
SRC: NLM .