MEKTOVI SIDE EFFECTS

Last updated on MDtodate: 10/7/2022

SIDE EFFECTS

The following adverse reactions are described elsewhere in the labeling:

  • Cardiomyopathy
  • Venous Thromboembolism
  • Ocular Toxicities
  • Interstitial Lung Disease
  • Hepatotoxicity
  • Rhabdomyolysis
  • Hemorrhage

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.

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 1.

Table 1: Adverse Reactions Occurring in ≥ 10% of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUSa

Adverse Reaction MEKTOVI
with encorafenib
N=192
Vemurafenib
N=186
All Grades
(%)
Grades 3 and 4b
(%)
All Grades
(%)
Grades 3 and 4b
(%)
General Disorders and Administration Site Conditions
  Fatiguec 43 3 46 6
  Pyrexiac 18 4 30 0
  Peripheral edemac 13 1 15 1
Gastrointestinal Disorders
  Nausea 41 2 34 2
  Diarrhea 36 3 34 2
  Vomitingc 30 2 16 1
  Abdominal painc 28 4 16 1
  Constipation 22 0 6 1
Skin and Subcutaneous Tissue Disorders
  Rashc 22 1 53 13
Nervous System Disorders
  Dizzinessc 15 3 4 0
Visual Disorders
  Visual impairmentc 20 0 4 0
  Serous retinopathy/RPEDc 20 3 2 0
Vascular Disorders
  Hemorrhagec 19 3 9 2
  Hypertensionc 11 6 11 3
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

Laboratory Abnormality MEKTOVI
with encorafenib
N=192
Vemurafenib
N=186
All Grades
(%)
Grades 3 and 4
(%)
All Grades
(%)
Grades 3 and 4
(%)
Hematology
  Anemia 36 3.6 34 2.2
  Leukopenia 13 0 10 0.5
  Lymphopenia 13 2.1 30 7
  Neutropenia 13 3.1 4.8 0.5
Chemistry
  Increased Creatinine 93 3.6 92 1.1
  Increased Creatine Phosphokinase 58 5 3.8 0
  Increased Gamma Glutamyl Transferase 45 11 34 4.8
  Increased ALT 29 6 27 2.2
  Increased AST 27 2.6 24 1.6
  Increased Alkaline Phosphatase 21 0.5 35 2.2
  Hyponatremia 18 3.6 15 0.5
a Grades per National Cancer Institute CTCAE v4.03.

 

 

SRC: NLM .