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BRAFTOVI®Adverse Reactions (encorafenib)

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.

BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

The safety of BRAFTOVI in combination with binimetinib is described in 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received BRAFTOVI (450 mg once daily) in combination with binimetinib (45 mg twice daily) in a randomized open-label, active-controlled trial (COLUMBUS).

The COLUMBUS trial [see Clinical Studies (14.1)] excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with BRAFTOVI in combination with binimetinib and 6.2 months for patients treated with vemurafenib.

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

Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 30% of patients receiving BRAFTOVI in combination with binimetinib; the most common were nausea (7%), vomiting (7%), and pyrexia (4%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 14% of patients receiving BRAFTOVI in combination with binimetinib; the most common were arthralgia (2%), fatigue (2%), and nausea (2%). Five percent (5%) of patients receiving BRAFTOVI in combination with binimetinib experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the most common were hemorrhage in 2% and headache in 1% of patients.

Table 5 and Table 6 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 BRAFTOVI in combination with binimetinib, as compared to vemurafenib, for any specific adverse reaction listed in Table 5.

Table 5: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Binimetinib in COLUMBUS*
Adverse ReactionBRAFTOVI with binimetinib
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 fatigue (n=1), pruritus (n=1) and rash (n=1) in the BRAFTOVI with binimetinib arm.
Represents a composite of multiple, related preferred terms.
General Disorders and Administration Site Conditions
  Fatigue433466
  Pyrexia184300
Gastrointestinal Disorders
  Nausea412342
  Vomiting302161
  Abdominal pain284161
  Constipation22061
Musculoskeletal and Connective Tissue Disorders
  Arthralgia261466
  Myopathy230221
  Pain in extremity111131
Skin and Subcutaneous Tissue Disorders
  Hyperkeratosis231491
  Rash2215313
  Dry skin160260
  Alopecia140380
  Pruritus131211
Nervous System Disorders
  Headache222201
  Dizziness15340
  Peripheral neuropathy121132
Vascular Disorders
  Hemorrhage19392

BRAFTOVI when used as a single agent increases the risk of certain adverse reactions compared to BRAFTOVI in combination with binimetinib. In patients receiving BRAFTOVI 300 mg orally once daily as a single agent, the following adverse reactions were observed at a higher rate (≥ 5%) compared to patients receiving BRAFTOVI in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51% vs. 7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs. 23%), back pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%).

Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with binimetinib were:

Nervous system disorders: Facial paresis

Gastrointestinal disorders: Pancreatitis

Skin and subcutaneous tissue disorders: Panniculitis

Immune system disorders: Drug hypersensitivity

Table 6: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI in Combination with Binimetinib in COLUMBUS*
Laboratory AbnormalityBRAFTOVI with binimetinib*
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
  Anemia363.6342.2
  Leukopenia130100.5
  Lymphopenia132.1307
  Neutropenia133.14.80.5
Chemistry
  Increased Creatinine933.6921.1
  Increased Gamma Glutamyl Transferase4511344.8
  Increased ALT296272.2
  Increased AST272.6241.6
  Hyperglycemia285202.7
  Increased Alkaline Phosphatase210.5352.2
  Hyponatremia183.6150.5
  Hypermagnesemia101.0260.5

BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)

The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (400 mg/m2 initial dose, followed by 250 mg/m2 weekly) was evaluated in 216 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BEACON CRC). The BEACON CRC trial [see Clinical Studies (14.2)] excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (> 480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 4.4 months for patients treated with BRAFTOVI in combination with cetuximab and 1.6 months for patients treated with either irinotecan or infusional 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI) in combination with cetuximab.

The most common (≥ 25%) adverse reactions in patients receiving BRAFTOVI in combination with cetuximab were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.

Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 33% of patients receiving BRAFTOVI in combination with cetuximab; the most common were vomiting (4%), fatigue (4%), nausea (4%), pyrexia (3%), and diarrhea (3%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 9% of patients receiving BRAFTOVI in combination with cetuximab; the most common were fatigue (2%), arthralgia (2%), and peripheral neuropathy (2%). Ten percent (10%) of patients receiving BRAFTOVI in combination with cetuximab experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI. None of the adverse reactions leading to permanent discontinuation of BRAFTOVI occurred in more than one patient (>0.5%).

Table 7 and Table 8 present adverse drug reactions and laboratory abnormalities, respectively, identified in BEACON CRC.

Table 7: Adverse Reactions Occurring in ≥ 10% of Patients Receiving BRAFTOVI in Combination with Cetuximab in BEACON CRC*
Adverse ReactionBRAFTOVI with cetuximab
N=216
Irinotecan with cetuximab or FOLFIRI with cetuximab
N=193
All Grades
(%)
≥ Grade 3
(%)
All Grades
(%)
≥ Grade 3
(%)
*
Grades per National Cancer Institute CTCAE v4.03.
Grade 4–5 adverse reactions in the BRAFTOVI with cetuximab arm were limited to Grade 5 hemorrhage (n=1).
Represents a composite of multiple, related preferred terms.
General Disorders and Administration Site Conditions
  Fatigue517508
  Pyrexia171151
Gastrointestinal Disorders
  Nausea341411
  Diarrhea3324810
  Abdominal pain304325
  Vomiting211293
  Constipation150181
Metabolism and Nutrition Disorders
  Decreased appetite271273
Musculoskeletal and Connective Tissue Disorders
  Arthralgia27130
  Myopathy15140
  Pain in extremity10010
Skin and Subcutaneous Tissue Disorders
  Dermatitis acneiform321433
  Rash260262
  Pruritus14060
  Melanocytic nevus14000
  Dry skin130121
Nervous System Disorders
  Headache20030
  Peripheral neuropathy12160
Vascular Disorders
  Hemorrhage19290
Psychiatric Disorders
  Insomnia13060

Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with cetuximab were:

Gastrointestinal disorders: Pancreatitis

Table 8: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI in Combination with Cetuximab in BEACON CRC*
Laboratory AbnormalityBRAFTOVI with cetuximabIrinotecan with cetuximab or FOLFIRI with cetuximab
All Grades
(%)
Grades 3 and 4
(%)
All Grades
(%)
Grades 3 and 4
(%)
*
Grades per National Cancer Institute CTCAE v4.03.
Based on the number of patients with available baseline and at least one on-treatment laboratory test.
Hematology
  Anemia344485
  Lymphopenia247355
  Increased Activated Partial Thromboplastin Time13171
Chemistry
  Hypomagnesemia190221
  Increased Alkaline Phosphatase184307
  Increased ALT170293
  Increased AST151222
  Hypokalemia123325
  Hyponatremia112132
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