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MEKTOVI® (binimetinib) Adverse Reactions

6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

6.1 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 [see Warnings and Precautions (5)] 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 [see Clinical Studies (14)] 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.

The most common (≥ 25%) adverse reactions in patients receiving MEKTOVI in combination with encorafenib were fatigue, nausea, diarrhea, vomiting, and abdominal pain.

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 3.

Table 3: Adverse Reactions Occurring in ≥ 10% of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS*
Adverse ReactionMEKTOVI with encorafenib
N=192
Vemurafenib
N=186
All Grades
(%)
Grades 3 and 4
(%)
All Grades
(%)
Grades 3 and 4
(%)
*
Grades per National Cancer Institute CTCAE v4.03.
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.
Represents a composite of multiple, related preferred terms.
General Disorders and Administration Site Conditions
  Fatigue433466
  Pyrexia184300
  Peripheral edema131151
Gastrointestinal Disorders
  Nausea412342
  Diarrhea363342
  Vomiting302161
  Abdominal pain284161
  Constipation22061
Skin and Subcutaneous Tissue Disorders
  Rash2215313
Nervous System Disorders
  Dizziness15340
Visual Disorders
  Visual impairment20040
  Serous retinopathy/RPED20320
Vascular Disorders
  Hemorrhage19392
  Hypertension116113

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 4: Laboratory Abnormalities Occurring in ≥ 10% (All grades) of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS*
Laboratory AbnormalityMEKTOVI with encorafenib
N=192
Vemurafenib
N=186
All Grades
(%)
Grades 3 and 4
(%)
All Grades
(%)
Grades 3 and 4
(%)
*
Grades per National Cancer Institute CTCAE v4.03.
Hematology
  Anemia 363.6342.2
  Leukopenia 130100.5
  Lymphopenia 132.1307
  Neutropenia133.14.80.5
Chemistry
  Increased Creatinine933.6921.1
  Increased Creatine Phosphokinase 5853.80
  Increased Gamma Glutamyl Transferase 4511344.8
  Increased ALT 296272.2
  Increased AST 272.6241.6
  Increased Alkaline Phosphatase 210.5352.2
  Hyponatremia 183.6150.5

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