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.

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, Photosensitivity

Immune system disorders: Drug hypersensitivity

BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC) in Combination with Cetuximab and fluorouracil-based chemotherapy

The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (500 mg/m2 every 2 weeks) and mFOLFOX6 was evaluated in 232 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BREAKWATER) [see Clinical Studies (14.2)]. In a separate cohort of BREAKWATER (Cohort 3), 139 patients with BRAF V600E mutation-positive mCRC were evaluated; of which 71 patients received BRAFTOVI in combination with cetuximab (500 mg/m2 every 2 weeks) and FOLFIRI. Patients with pancreatitis, leptomeningeal disease, chronic inflammatory bowel disease requiring medical intervention, as well as clinically significant cardiovascular diseases [e.g., myocardial infarction, acute coronary syndromes, NYHA Class ≥II congestive heart failure, prolonged QTcF interval (≥480 ms), history of prolonged QT syndrome] and active infectious conditions were excluded.

BRAFTOVI in combination with cetuximab and mFOLFOX6

Among patients who received BRAFTOVI, 73% were exposed for 6 months or longer and 48% were exposed for one year or longer.

Serious adverse reactions occurred in 46% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Serious adverse reactions in >3% of patients included intestinal obstruction (4.7%), pyrexia (3.9%), sepsis (3.4%), and abdominal pain (3.4%).

Fatal intestinal obstruction occurred in 0.9%, and fatal large intestinal perforation and gastrointestinal perforation occurred in 0.4% (each) of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6.

Permanent discontinuation of BRAFTOVI due to an adverse reaction occurred in 14% of patients. Adverse reactions which resulted in permanent discontinuation of BRAFTOVI in ≥1% of patients included increased lipase and sepsis.

Dosage interruptions of BRAFTOVI due to an adverse reaction occurred in 68% of patients. Adverse reactions which required dosage interruption in ≥5% included neutropenia, anemia, pyrexia, COVID-19, and diarrhea.

Dose reductions of BRAFTOVI due to an adverse reaction occurred in 25% of patients. Adverse reactions leading to dose reductions of BRAFTOVI in ≥2% of patients included fatigue, anemia, arthralgia, increased lipase, nausea, neurotoxicity, and vomiting.

The most common (≥25%) adverse reactions of BRAFTOVI when used in combination with cetuximab and mFOLFOX6 were peripheral neuropathy, nausea, fatigue, diarrhea, decreased appetite, rash, vomiting, hemorrhage, abdominal pain, arthralgia, pyrexia, and constipation.

The most common Grade 3 or 4 laboratory abnormalities (≥10%) of BRAFTOVI when used in combination with cetuximab and mFOLFOX6 were increased lipase, decreased neutrophil count, decreased hemoglobin, decreased white blood cell count, and increased glucose.

Table 7 and Table 8 present adverse drug reactions and laboratory abnormalities, respectively, identified in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 in BREAKWATER.

Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6 were:

Immune system disorders: Drug hypersensitivity

Skin and subcutaneous tissue disorders: Hyperkeratosis

Gastrointestinal disorders: Pancreatitis

BRAFTOVI in combination with cetuximab and FOLFIRI

Among patients who received BRAFTOVI, 81% were exposed for 6 months or longer and 17% were exposed for one year or longer.

Serious adverse reactions occurred in 39% of patients who received BRAFTOVI in combination with cetuximab and FOLFIRI. Serious adverse reactions in >3% of patients included febrile neutropenia (5.6%) and infusion related reaction (4.2%).

Fatal gastrointestinal perforation occurred in 1.4% of patients who received BRAFTOVI in combination with cetuximab and FOLFIRI.

Permanent discontinuation of BRAFTOVI due to an adverse reaction occurred in 9% of patients. Adverse reactions which resulted in permanent discontinuation of BRAFTOVI in ≥1% of patients included completed suicide, diarrhea, dyspnea, gastrointestinal perforation, infusion related reaction and pyrexia.

Dosage interruptions of BRAFTOVI due to an adverse reaction occurred in 55% of patients. Adverse reactions which required dosage interruption in ≥5% included neutropenia, diarrhea, and febrile neutropenia.

Dose reductions of BRAFTOVI due to an adverse reaction occurred in 20% of patients. Adverse reactions leading to dose reductions of BRAFTOVI in ≥2% of patients included nausea, vomiting, decreased appetite, fatigue, and diarrhea.

The most common (≥25%) adverse reactions of BRAFTOVI when used in combination with cetuximab and FOLFIRI were nausea, diarrhea, fatigue, vomiting, alopecia, constipation, abdominal pain, decreased appetite, and rash.

The most common Grade 3 or 4 laboratory abnormalities (≥10%) of BRAFTOVI when used in combination with cetuximab and FOLFIRI were decreased neutrophil count, increased lipase, decreased white blood cell count, and decreased hemoglobin.

Table 9 and Table 10 present adverse drug reactions and laboratory abnormalities, respectively, identified in patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI in Cohort 3 of BREAKWATER.

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

Immune system disorders: Drug hypersensitivity

Skin and subcutaneous tissue disorders: Hyperkeratosis

Gastrointestinal disorders: Pancreatitis

Nervous system disorders: Peripheral neuropathy

BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) in Combination with Cetuximab

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 (14.3)] 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 11 and Table 12 present adverse drug reactions and laboratory abnormalities, respectively, identified in BEACON CRC.

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

Gastrointestinal disorders: Pancreatitis

BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

The safety of BRAFTOVI in combination with binimetinib was evaluated in 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received BRAFTOVI (450 mg once daily) in combination with binimetinib (45 mg twice daily) in an open-label, single-arm trial (PHAROS).

The PHAROS trial [see Clinical Studies (14.3)] excluded patients with abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of treatment for BRAFTOVI and binimetinib was 9.2 and 8.4 months, respectively.

The most common (≥25%) adverse reactions in patients receiving BRAFTOVI were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.

Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 59% of patients receiving BRAFTOVI; the most common (≥5%) were diarrhea (17%); nausea (13%); musculoskeletal pain, fatigue (8% each); AST increased (7%); ALT increased, anemia, hemorrhage, vomiting (6% each); and acute kidney injury (5%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 30% of patients receiving BRAFTOVI; the most common (≥5%) were diarrhea, nausea (8% each); AST increased and fatigue (5% each). A total of 16% of patients receiving BRAFTOVI experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the most common (≥2%) were diarrhea, musculoskeletal pain (3.1% each); fatigue, rash, nausea, visual impairment, and vomiting (2% each). None of the other adverse reactions leading to permanent discontinuation of BRAFTOVI occurred in more than 1 patient.

Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with binimetinib. Serious adverse reactions occurring in ≥2% of patients were hemorrhage (6%); diarrhea (4.1%); anemia, dyspnea, pneumonia (3.1% each); arrhythmia, device related infection, edema, myocardial infarction, and pleural effusion (2% each). Fatal adverse reactions occurred in 2% of patients who received BRAFTOVI (450 mg once daily) in combination with binimetinib, including intracranial hemorrhage and myocardial infarction (1% each).

Table 13 and Table 14 present adverse drug reactions and laboratory abnormalities, respectively, identified in PHAROS.

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

Nervous system disorders: Peripheral neuropathy, Dysgeusia, Facial paresis

Gastrointestinal disorders: Pancreatitis

Skin and subcutaneous tissue disorders: Hyperkeratosis, Erythema, Photosensitivity

Immune system disorders: Drug hypersensitivity