Enter drug's generic or brand name below. Results will appear here. Note: all drug related information obtained on this page is provided by RX List.
Using the RX LIST database:
(1) Enter the drug name in the search box below and hit ENTER
(2) The rx list web site will open here with the drug search completed. Next, scroll down the page to locate the link to the drug you are searching for and then click on the link.
Encorafenib is a kinase inhibitor. The chemical name is methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3( methanesulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2yl} carbamate. The molecular formula is C22H27ClFN7O4S and the molecular weight is 540 daltons. The chemical structure of encorafenib is shown below:
 |
Encorafenib is a white to almost white powder. In aqueous media, encorafenib is slightly soluble at pH 1, very slightly soluble at pH 2, and insoluble at pH 3 and higher.
BRAFTOVI (encorafenib) capsules for oral use contain 50 mg or 75 mg of encorafenib with the following inactive ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone, colloidal silicon dioxide, magnesium stearate (vegetable origin). The capsule shell contains gelatin, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink (pharmaceutical glaze, ferrosoferric oxide, propylene glycol).
BRAFTOVI is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test [see DOSAGE AND ADMINISTRATION].
BRAFTOVI is indicated, in combination with binimetinib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test [see DOSAGE AND ADMINISTRATION].
BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC [see WARNINGS AND PRECAUTIONS].
Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating BRAFTOVI [see WARNINGS AND PRECAUTIONS, Clinical Studies]. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: https://www.fda.gov/CompanionDiagnostics.
Confirm the presence of a BRAF V600E mutation in plasma or tumor tissue prior to initiating BRAFTOVI [see WARNINGS AND PRECAUTIONS, Clinical Studies]. If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of BRAF V600E mutations in CRC is available at: https://www.fda.gov/CompanionDiagnostics.
Confirm the presence of a BRAF V600E mutation in tumor or plasma specimens prior to initiating BRAFTOVI [see WARNINGS AND PRECAUTIONS, Clinical Studies]. If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: https://www.fda.gov/CompanionDiagnostics.
The recommended dosage of BRAFTOVI is 450 mg (six 75 mg capsules) orally once daily in combination with binimetinib until disease progression or unacceptable toxicity. Refer to the binimetinib prescribing information for recommended binimetinib dosing information.
The recommended dosage of BRAFTOVI is 300 mg (four 75 mg capsules) orally once daily in combination with biweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) [see Clinical Studies] or in combination with weekly cetuximab [see Clinical Studies] until disease progression or unacceptable toxicity.
BRAFTOVI may be taken with or without food [see CLINICAL PHARMACOLOGY]. Do not take a missed dose of BRAFTOVI within 12 hours of the next dose of BRAFTOVI.
Do not take an additional dose if vomiting occurs after BRAFTOVI administration but continue with the next scheduled dose.
If binimetinib is withheld, reduce BRAFTOVI to a maximum dose of 300 mg (four 75 mg capsules) once daily until binimetinib is resumed [see WARNINGS AND PRECAUTIONS].
Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 1.
Table 1: Recommended Dose Reductions for BRAFTOVI for Adverse Reactions — Melanoma or NSCLC
| Action | Recommended Dose |
| First Dose Reduction | 300 mg (four 75 mg capsules) orally once daily |
| Second Dose Reduction | 225 mg (three 75 mg capsules) orally once daily |
| Subsequent Modification | Permanently discontinue if unable to tolerate BRAFTOVI 225 mg (three 75 mg capsules) once daily |
If cetuximab is discontinued, discontinue BRAFTOVI.
Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 2.
Table 2: Recommended Dose Reductions for BRAFTOVI for Adverse Reactions — CRC
| Action | Recommended Dose |
| First Dose Reduction | 225 mg (three 75 mg capsules) orally once daily |
| Second Dose Reduction | 150 mg (two 75 mg capsules) orally once daily |
| Subsequent Modification | Permanently discontinue if unable to tolerate BRAFTOVI 150 mg (two 75 mg capsules) once daily |
Dosage modifications for adverse reactions associated with BRAFTOVI are presented in Table 3.
Table 3: Recommended Dosage Modifications for BRAFTOVI for Adverse Reactions
| Severity of Adverse Reactiona | Dose Modification for BRAFTOVI |
| New Primary Malignancies [see WARNINGS AND PRECAUTIONS] | |
| Noncutaneous RAS Mutation-positive Malignancies | Permanently discontinue BRAFTOVI. |
| Cardiomyopathy [see WARNINGS AND PRECAUTIONS] | |
|
Reduce BRAFTOVI by one dose level [see DOSAGE AND ADMINISTRATION].
|
| Hepatotoxicity [see WARNINGS AND PRECAUTIONS] | |
|
Maintain BRAFTOVI dose.
|
|
See Other Adverse Reactions. |
| Uveitis [see WARNINGS AND PRECAUTIONS] | |
|
If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold BRAFTOVI for up to 6 weeks.
|
|
Permanently discontinue BRAFTOVI. |
| QTc Prolongation [see WARNINGS AND PRECAUTIONS] | |
|
Withhold BRAFTOVI until QTcF less than or equal to 500 ms. Resume at reduced dose. • If more than one recurrence, permanently discontinue BRAFTOVI. |
|
Permanently discontinue BRAFTOVI. |
| Dermatologic [other than Hand-foot Skin Reaction (HFSR)] [see ADVERSE REACTIONS] | |
|
If no improvement within 2 weeks, withhold BRAFTOVI until Grade 0-1. Resume at same dose. |
|
Withhold BRAFTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent. |
|
Permanently discontinue BRAFTOVI. |
| Other Adverse Reactions (including Hemorrhage) [see WARNINGS AND PRECAUTIONS] and HFSR [see ADVERSE REACTIONS]b | |
|
Withhold BRAFTOVI for up to 4 weeks.
|
|
Permanently discontinue BRAFTOVI or Withhold BRAFTOVI for up to 4 weeks.
|
|
Consider permanently discontinuing BRAFTOVI. |
|
Permanently discontinue BRAFTOVI. |
| a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. b Dose modification of BRAFTOVI when administered with binimetinib or with cetuximab is not recommended for new primary cutaneous malignancies; ocular events other than uveitis, iritis, and iridocyclitis; interstitial lung disease/pneumonitis; creatine phosphokinase (CPK) elevation; rhabdomyolysis; and venous thromboembolism. |
|
Refer to the binimetinib or cetuximab prescribing information for dose modifications for adverse reactions associated with each product, as appropriate.
Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors. If coadministration is unavoidable, reduce the BRAFTOVI dose according to the recommendations in Table 4. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the BRAFTOVI dose that was taken prior to initiating the CYP3A4 inhibitor [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
Table 4: Recommended Dose Reductions for BRAFTOVI for Coadministration with Strong or Moderate CYP3A4 Inhibitors
| Current Daily Dosea | Dose for Coadministration with Moderate CYP3A4 Inhibitor | Dose for Coadministration with Strong CYP3A4 Inhibitor |
| 450 mg | 225 mg (three 75 mg capsules) | 150 mg (two 75 mg capsules) |
| 300 mg | 150 mg (two 75 mg capsules) | 75 mg |
| 225 mg | 75 mg | 75 mg |
| 150 mg | 75 mg | 75 mgb |
| a Current daily dose refers to recommended dose of BRAFTOVI based on indication or reductions for adverse reactions based on dosing recommendations in Table 1 (Melanoma) and Table 2 (CRC). b Encorafenib exposure at the 75 mg QD BRAFTOVI dosage when coadministered with a strong CYP3A4 inhibitor is expected to be higher than at the 150 mg QD dosage in the absence of a CYP3A4 inhibitor and similar to exposure at the 225 mg QD dosage in the absence of a CYP3A4 inhibitor. Monitor patients closely for adverse reactions and use clinical judgement when using BRAFTOVI with strong CYP3A4 inhibitors at the 150 mg dose level. |
||
Capsules: 75 mg, hard gelatin, stylized “A” on beige cap and “LGX 75mg” on white body.
BRAFTOVI (encorafenib) is supplied as 75 mg hard gelatin capsules.
75 mg: stylized “A” on beige cap and “LGX 75mg” on white body, available in cartons (NDC 70255-025-01) containing two bottles of 90 capsules each (NDC 70255-025-02) and cartons (NDC 70255-025-03) containing two bottles of 60 capsules each (NDC 70255-025-04).
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Do not use if safety seal under cap is broken or missing. Dispense in original bottle. Do not remove desiccant. Protect from moisture. Keep container tightly closed.
Distributed by: Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc., 3200 Walnut Street, Boulder, CO 80301. Revised: Mar 2025
The following adverse reactions are described elsewhere in the labeling:
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 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] 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 COLUMBUSa
| Adverse Reaction | BRAFTOVI with binimetinib N=192 |
Vemurafenib N=186 |
||
| All Grades (%) | Grades 3 and 4b (%) | All Grades (%) | Grades 3 and 4 (%) | |
| General Disorders and Administration Site Conditions | ||||
| Fatiguec | 43 | 3 | 46 | 6 |
| Pyrexiac | 18 | 4 | 30 | 0 |
| Gastrointestinal Disorders | ||||
| Nausea | 41 | 2 | 34 | 2 |
| Vomitingc | 30 | 2 | 16 | 1 |
| Abdominal painc | 28 | 4 | 16 | 1 |
| Constipation | 22 | 0 | 6 | 1 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Arthralgiac | 26 | 1 | 46 | 6 |
| Myopathyc | 23 | 0 | 22 | 1 |
| Pain in extremity | 11 | 1 | 13 | 1 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Hyperkeratosisc | 23 | 1 | 49 | 1 |
| Rashc | 22 | 1 | 53 | 13 |
| Dry skinc | 16 | 0 | 26 | 0 |
| Alopeciac | 14 | 0 | 38 | 0 |
| Pruritusc | 13 | 1 | 21 | 1 |
| Nervous System Disorders | ||||
| Headachec | 22 | 2 | 20 | 1 |
| Dizzinessc | 15 | 3 | 4 | 0 |
| Peripheral neuropathyc | 12 | 1 | 13 | 2 |
| Vascular Disorders | ||||
| Hemorrhagec | 19 | 3 | 9 | 2 |
| a Grades per National Cancer Institute CTCAE v4.03. b Grade 4 adverse reactions limited to fatigue (n=1), pruritus (n=1), and rash (n=1) in the BRAFTOVI with binimetinib arm. c Represents a composite of multiple, related preferred terms. |
||||
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
Table 6: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI in Combination with Binimetinib in COLUMBUSa
| Laboratory Abnormality | BRAFTOVI with binimetiniba N=192 |
Vemurafeniba 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 Gamma Glutamyl Transferase | 45 | 11 | 34 | 4.8 |
| Increased ALT | 29 | 6 | 27 | 2.2 |
| Increased AST | 27 | 2.6 | 24 | 1.6 |
| Hyperglycemia | 28 | 5 | 20 | 2.7 |
| Increased Alkaline Phosphatase | 21 | 0.5 | 35 | 2.2 |
| Hyponatremia | 18 | 3.6 | 15 | 0.5 |
| Hypermagnesemia | 10 | 1.0 | 26 | 0.5 |
| a Grades per National Cancer Institute CTCAE v4.03. | ||||
The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (500 mg/m² every 2 weeks) and mFOLFOX6 was evaluated in 231 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BREAKWATER) [see Clinical Studies]. BREAKWATER excluded 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.
Among patients who received BRAFTOVI, 54% were exposed for 6 months or longer and 18% were exposed for one year or longer.
Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Serious adverse reactions in >3% of patients included intestinal obstruction and pyrexia (3.5% each).
Fatal gastrointestinal perforation occurred in 0.9% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6.
Permanent discontinuation of BRAFTOVI due to an adverse reaction occurred in 12% of patients. Adverse reactions which resulted in permanent discontinuation of BRAFTOVI in ≥1% of patients included increased lipase.
Dosage interruptions of BRAFTOVI due to an adverse reaction occurred in 57% of patients. Adverse reactions which required dosage interruption in ≥5% included decreased neutrophil count, pyrexia, and anemia.
Dose reductions of BRAFTOVI due to an adverse reaction occurred in 22% of patients. Adverse reactions leading to dose reductions of BRAFTOVI in ≥2% of patients included increased lipase, nausea, and vomiting.
The most common (≥25%) adverse reactions of BRAFTOVI when used in combination with cetuximab and mFOLFOX6 were peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia.
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 BREAKWATER.
Table 7: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Cetuximab and mFOLFOX6 in BREAKWATERa
| Adverse Reaction | BRAFTOVI with cetuximab and mFOLFOX6 N=231 |
mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab N=228 |
||
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Nervous System Disorders | ||||
| Peripheral neuropathyb | 62 | 15 | 53 | 6 |
| Headache | 13 | <1 | 7 | 0 |
| Dysgeusia | 12 | 0 | 14 | 0 |
| Neurotoxicity | 11 | 5 | 8 | 0 |
| Gastrointestinal Disorders | ||||
| Nausea | 51 | 3 | 48 | 3 |
| Diarrhea | 34 | 1 | 47 | 4 |
| Vomiting | 33 | 4 | 21 | 2 |
| Abdominal painb | 26 | 4 | 27 | 1 |
| Constipation | 20 | <1 | 19 | <1 |
| General Disorders and Administration Site Conditions | ||||
| Fatigueb | 49 | 7 | 38 | 4 |
| Pyrexiab | 26 | 2 | 14 | <1 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 33 | 2 | 25 | 1 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Arthralgiab | 23 | 1 | 4 | 0 |
| Myopathyb | 14 | 0 | 7 | <1 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rashb | 31 | 1 | 4 | 0 |
| Alopecia | 21 | 0 | 10 | 0 |
| Dry skinb | 17 | 0 | 4 | 0 |
| Dermatitis acneiformb | 17 | 1 | 1 | 0 |
| Skin hyperpigmentation | 17 | 0 | 2 | 0 |
| Pruritus | 11 | 0 | 3 | <1 |
| Vascular Disorders | ||||
| Hemorrhageb | 30 | 3 | 18 | 1 |
| Psychiatric Disorder | ||||
| Insomniab | 11 | 0 | 7 | 0 |
| a Grades per National Cancer Institute CTCAE v4.03. b Represents multiple related terms. |
||||
Table 8: Laboratory Abnormalities Occurring in ≥20% (All Grades) of Patients Receiving BRAFTOVI in Combination with Cetuximab and mFOLFOX6 in BREAKWATERa
| Laboratory Abnormalityb | BRAFTOVI with cetuximab and mFOLFOX6 | mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab | ||
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Hematology | ||||
| Neutrophil count decreased | 63 | 36 | 60 | 34 |
| White blood cell decreased | 62 | 12 | 54 | 7 |
| Hemoglobin decreased | 60 | 13 | 47 | 5 |
| Platelet count decreased | 60 | 1 | 50 | 2 |
| Activated partial thromboplastin time prolonged | 57 | 3 | 38 | 1 |
| INR increased | 39 | 1 | 20 | 1 |
| Chemistry | ||||
| Lipase increased | 82 | 51 | 54 | 25 |
| Creatinine increased | 64 | 1 | 67 | 1 |
| Glucose increased | 49 | 11 | 35 | 2 |
| Alanine aminotransferase increased | 38 | 1 | 40 | 2 |
| Albumin decreased | 36 | 0 | 24 | 1 |
| Aspartate aminotransferase increased | 36 | 1 | 35 | 2 |
| Potassium decreased | 33 | 4 | 19 | 4 |
| Alkaline phosphatase increased | 31 | 2 | 31 | 1 |
| Calcium decreased | 24 | 4 | 16 | 2 |
| Magnesium decreased | 23 | 1 | 11 | 1 |
| a Grades per National Cancer Institute CTCAE v4.03. b The denominator used to calculate the rate varied from 220 to 227 based on the number of patients with a baseline and at least one post-treatment value. |
||||
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] 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 9 and Table 10 present adverse drug reactions and laboratory abnormalities, respectively, identified in BEACON CRC.
Table 9: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Cetuximab in BEACON CRCa
| Adverse Reaction | BRAFTOVI with cetuximab N=216 |
Irinotecan with cetuximab or FOLFIRI with cetuximab N=193 |
||
| All Grades (%) | ≥ Grade 3b (%) | All Grades (%) | ≥ Grade 3 (%) | |
| General Disorders and Administration Site Conditions | ||||
| Fatiguec | 51 | 7 | 50 | 8 |
| Pyrexiac | 17 | 1 | 15 | 1 |
| Gastrointestinal Disorders | ||||
| Nausea | 34 | 1 | 41 | 1 |
| Diarrheac | 33 | 2 | 48 | 10 |
| Abdominal painc | 30 | 4 | 32 | 5 |
| Vomiting | 21 | 1 | 29 | 3 |
| Constipation | 15 | 0 | 18 | 1 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 27 | 1 | 27 | 3 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Arthralgiac | 27 | 1 | 3 | 0 |
| Myopathyc | 15 | 1 | 4 | 0 |
| Pain in extremity | 10 | 0 | 1 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Dermatitis acneiformc | 32 | 1 | 43 | 3 |
| Rashc | 26 | 0 | 26 | 2 |
| Pruritusc | 14 | 0 | 6 | 0 |
| Melanocytic nevus | 14 | 0 | 0 | 0 |
| Dry skinc | 13 | 0 | 12 | 1 |
| Nervous System Disorders | ||||
| Headachec | 20 | 0 | 3 | 0 |
| Peripheral neuropathyc | 12 | 1 | 6 | 0 |
| Vascular Disorders | ||||
| Hemorrhagec | 19 | 2 | 9 | 0 |
| Psychiatric Disorders | ||||
| Insomniac | 13 | 0 | 6 | 0 |
| a Grades per National Cancer Institute CTCAE v4.03. b Grade 4-5 adverse reactions in the BRAFTOVI with cetuximab arm were limited to Grade 5 hemorrhage (n=1). c Represents a composite of multiple, related preferred terms. |
||||
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with cetuximab were:
Gastrointestinal disorders: Pancreatitis
Table 10: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI in Combination with Cetuximab in BEACON CRCa
| Laboratory Abnormalityb | BRAFTOVI with cetuximab | Irinotecan with cetuximab or FOLFIRI with cetuximab | ||
| All Grades (%) | Grades 3 and 4 (%) | All Grades (%) | Grades 3 and 4 (%) | |
| Hematology | ||||
| Anemia | 34 | 4 | 48 | 5 |
| Lymphopenia | 24 | 7 | 35 | 5 |
| Increased Activated Partial Thromboplastin Time | 13 | 1 | 7 | 1 |
| Chemistry | ||||
| Hypomagnesemia | 19 | 0 | 22 | 1 |
| Increased Alkaline Phosphatase | 18 | 4 | 30 | 7 |
| Increased ALT | 17 | 0 | 29 | 3 |
| Increased AST | 15 | 1 | 22 | 2 |
| Hypokalemia | 12 | 3 | 32 | 5 |
| Hyponatremia | 11 | 2 | 13 | 2 |
| a Grades per National Cancer Institute CTCAE v4.03. b Based on the number of patients with available baseline and at least one on-treatment laboratory test. |
||||
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] 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 11 and Table 12 present adverse drug reactions and laboratory abnormalities, respectively, identified in PHAROS.
Table 11: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Binimetinib in PHAROSa
| Adverse Reaction | BRAFTOVI with binimetinib N=98 |
|
| All Grades (%) | Grades 3 and 4b (%) | |
| General Disorders and Administration Site Conditions | ||
| Fatiguec | 61 | 8 |
| Edemad | 23 | 1 |
| Pyrexia | 22 | 0 |
| Gastrointestinal Disorders | ||
| Nausea | 58 | 3.1 |
| Diarrheae | 52 | 7 |
| Vomiting | 37 | 1 |
| Abdominal painf | 32 | 1 |
| Constipation | 27 | 0 |
| Eye Disorders | ||
| Visual impairmentg | 29 | 2 |
| Musculoskeletal and Connective Tissue Disorders | ||
| Musculoskeletal painh | 48 | 4.1 |
| Skin and Subcutaneous Tissue Disorders | ||
| Rashi | 27 | 3.1 |
| Pruritisj | 16 | 0 |
| Dry skin | 13 | 0 |
| Alopecia | 12 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Dyspneak | 27 | 8 |
| Coughl | 26 | 0 |
| Nervous System Disorders | ||
| Dizzinessm | 17 | 1 |
| Headache | 11 | 0 |
| Metabolism and Nutrition Disorders | ||
| Decreased appetite | 14 | 1 |
| Vascular Disorders | ||
| Hemorrhagebn | 12 | 4.1 |
| Hypertension | 10 | 5 |
| Cardiac Disorders | ||
| Left ventricular dysfunction/cardiomyopathyo | 11 | 1 |
| Investigations | ||
| Weight increased | 11 | 1 |
| Psychiatric Disorders | ||
| Insomnia | 10 | 0 |
| a Grades per National Cancer Institute CTCAE v4.03. b One Grade 5 adverse reaction of hemorrhage occurred. c Fatigue includes fatigue, asthenia. d Edema includes edema peripheral, generalized edema, swelling, localized edema, face edema. e Diarrhea includes diarrhea, colitis. f Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort. g Visual impairment includes vision blurred, visual impairment, vitreous floaters, photophobia, visual acuity reduced, photopsia. h Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal chest pain, noncardiac chest pain, neck pain. i Rash includes rash, rash macular, rash maculo-papular, rash papular, rash pustular, dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, eczema, skin exfoliation. j Pruritis includes pruritus, pruritus genital. k Dyspnea includes dyspnea, dyspnea exertional. l Cough includes cough, productive cough. m Dizziness includes dizziness, balance disorder. n Hemorrhage includes anal hemorrhage, hemothorax, gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhage intracranial, hyphema, small intestinal hemorrhage, upper gastrointestinal hemorrhage, vaginal hemorrhage. o Left ventricular dysfunction/cardiomyopathy includes ejection fraction decreased, cardiac failure, cardiac failure congestive. |
||
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
Table 12: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI with Binimetiniba
| Laboratory Abnormalityb | BRAFTOVI with binimetinib | |
| All Grades (%) | Grades 3 and 4 (%) | |
| Hematology | ||
| Anemia | 47 | 11 |
| Lymphopenia | 24 | 6 |
| Thrombocytopenia | 20 | 1.1 |
| Leukopenia | 12 | 0 |
| Neutropenia | 12 | 1.1 |
| Chemistry | ||
| Increased creatinine | 91 | 3.2 |
| Hyperglycemia | 48 | 6 |
| Increased creatine kinase | 41 | 3.3 |
| Lipase increased | 40 | 14 |
| Increased ALT | 34 | 9 |
| Hypoalbuminemia | 32 | 0 |
| Increased AST | 31 | 10 |
| Increased alkaline phosphatase | 31 | 3.2 |
| Hyperkalemia | 31 | 2.1 |
| Hyponatremia | 26 | 11 |
| Serum amylase increased | 22 | 1.1 |
| Hypocalcemia | 12 | 2.1 |
| a Grades per National Cancer Institute CTCAE v4.03. b Based on the number of patients with available baseline and at least one on-treatment laboratory test. |
||
Coadministration of BRAFTOVI with a strong or moderate CYP3A4 inhibitor increases encorafenib plasma concentrations [see CLINICAL PHARMACOLOGY] and may increase encorafenib adverse reactions. Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration is unavoidable, reduce the BRAFTOVI dose [see DOSAGE AND ADMINISTRATION].
Coadministration of BRAFTOVI with a strong CYP3A4 inducer may decrease encorafenib plasma concentrations [see CLINICAL PHARMACOLOGY] and may decrease encorafenib efficacy. Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers.
BRAFTOVI is a strong CYP3A4 inducer at steady-state. Concomitant use of BRAFTOVI may decrease the plasma concentrations of CYP3A4 substrates (including hormonal contraceptives), [see CLINICAL PHARMACOLOGY], which may reduce the efficacy of these substrates. Avoid the coadministration of BRAFTOVI with CYP3A4 substrates for which a decrease in plasma concentration may lead to reduced efficacy of the substrate. If the coadministration cannot be avoided, see the CYP3A4 substrate product labeling for recommendations.
Coadministration of BRAFTOVI with OATP1B1, OATP1B3, or BCRP substrates can result in increased concentrations of the substrates, and may increase toxicity of these agents. When used in combination, monitor patients closely for signs and symptoms of increased exposure and consider adjusting the dose of these substrates [see CLINICAL PHARMACOLOGY].
BRAFTOVI is associated with dose-dependent QTc interval prolongation [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY]. Avoid coadministration of BRAFTOVI with drugs known to prolong the QT/QTc interval.
Included as part of the PRECAUTIONS section.
New primary malignancies, cutaneous and noncutaneous, have been observed in patients treated with BRAF inhibitors and can occur with BRAFTOVI.
In COLUMBUS, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. Median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months) [see ADVERSE REACTIONS].
For patients who received BRAFTOVI as a single agent, cuSCC/KA was reported in 8%, basal cell carcinoma in 1%, and a new primary melanoma in 5% of patients.
In BEACON CRC, cuSCC/KA occurred in 1.4% of patients with CRC, and a new primary melanoma occurred in 1.4% of patients who received BRAFTOVI in combination with cetuximab.
In PHAROS, cuSCC and skin papilloma, each occurred in 2% of patients who received BRAFTOVI in combination with binimetinib.
In BREAKWATER, skin papilloma was reported in 2.6%, basal cell carcinoma in 1.3%, squamous cell carcinoma of skin in 0.9%, keratoacanthoma in 0.4% and malignant melanoma in situ in 0.4% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6.
Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies.
Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms [see WARNINGS AND PRECAUTIONS]. Monitor patients receiving BRAFTOVI for signs and symptoms of noncutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive noncutaneous malignancies [see DOSAGE AND ADMINISTRATION].
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating BRAFTOVI [see INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION].
Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with BRAFTOVI in combination with binimetinib. In COLUMBUS, evidence of cardiomyopathy (decreased in LVEF below the institutional LLN with an absolute decreased in LVEF ≥10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving BRAFTOVI plus binimetinib. Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving BRAFTOVI in combination with binimetinib was 3.6 months (range 0 to 21 months). Cardiomyopathy resolved in 87% of patients receiving BRAFTOVI plus binimetinib.
In PHAROS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥10% below baseline as detected by echocardiography or MUGA) occurred in 11% of patients receiving BRAFTOVI in combination with binimetinib. Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients receiving BRAFTOVI plus binimetinib.
Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and every 2 to 3 months during treatment. The safety of BRAFTOVI in combination with binimetinib has not been established in patients with baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with BRAFTOVI.
Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].
Hepatotoxicity can occur when BRAFTOVI is administered in combination with binimetinib. In COLUMBUS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with binimetinib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. In PHAROS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with binimetinib was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase.
In BREAKWATER, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 was 2.2% for alkaline phosphatase, 1.3% for ALT, and 0.9% for AST.
Monitor liver laboratory tests before initiation of BRAFTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].
In COLUMBUS, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with binimetinib; Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.
In BEACON CRC, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with cetuximab; Grade 3 or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal hemorrhage in 0.5% of patients. The most frequent hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%), and rectal hemorrhage (2.3%).
In PHAROS, hemorrhage occurred in 12% of patients receiving BRAFTOVI in combination with binimetinib including fatal hemorrhage intracranial (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each).
In BREAKWATER, hemorrhage occurred in 30% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6; Grade 3 or 4 hemorrhage occurred in 3% of patients.
Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].
Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI in combination with binimetinib. In COLUMBUS, the incidence of uveitis among patients treated with BRAFTOVI in combination with binimetinib was 4%. In PHAROS, the incidence of uveitis among patients treated with BRAFTOVI in combination with binimetinib was 1%.
Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].
BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients [see CLINICAL PHARMACOLOGY]. In COLUMBUS, an increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI in combination with binimetinib. In PHAROS, an increase in QTcF to >500 ms was measured in 2.1% (2/95) of patients who received BRAFTOVI in combination with binimetinib.
In BREAKWATER, an increase of QTcF >500 ms was measured in 3.6% (8/222) of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6.
Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].
Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman. Encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the recommended dose of 450 mg, with no clear findings at lower doses.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use an effective, nonhormonal method of contraception since BRAFTOVI can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the last dose of BRAFTOVI [see Use In Specific Populations].
BRAFTOVI when used as a single agent is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. In COLUMBUS, Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI single agent compared to 2% of patients treated with BRAFTOVI in combination with binimetinib [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended [see DOSAGE AND ADMINISTRATION].
BRAFTOVI is indicated for use as part of a regimen in combination with binimetinib, in combination with cetuximab, or in combination with cetuximab and mFOLFOX6. Refer to the prescribing information for binimetinib, cetuximab and individual product components of mFOLFOX6 for additional risk information.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients of the following:
Advise patients that BRAFTOVI increases the risk of developing new primary cutaneous and noncutaneous malignancies. Advise patients to contact their healthcare provider immediately for change in or development of new skin lesions [see WARNINGS AND PRECAUTIONS].
Advise patients of the need to confirm BRAF V600E or V600K mutation prior to initiating BRAFTOVI [see WARNINGS AND PRECAUTIONS].
Advise patients to report any symptoms of heart failure to their healthcare provider [see WARNINGS AND PRECAUTIONS].
Advise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment with BRAFTOVI. Instruct patients to report symptoms of liver dysfunction including jaundice, dark urine, nausea, vomiting, loss of appetite, fatigue, bruising, or bleeding [see WARNINGS AND PRECAUTIONS].
Advise patients to notify their healthcare provider immediately with any symptoms suggestive of hemorrhage, such as unusual bleeding [see WARNINGS AND PRECAUTIONS].
Advise patients to contact their healthcare provider if they experience any changes in their vision [see WARNINGS AND PRECAUTIONS].
Advise patients that BRAFTOVI can cause QTc interval prolongation and to inform their physician if they have any QTc interval prolongation symptoms, such as syncope [see WARNINGS AND PRECAUTIONS].
Advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the last dose [see Use In Specific Populations].
Advise males of reproductive potential that BRAFTOVI may impair fertility [see Use In Specific Populations].
Coadministration of BRAFTOVI with a strong or moderate CYP3A inhibitor may increase encorafenib concentrations; coadministration of BRAFTOVI with a strong CYP3A inducer may decrease encorafenib concentrations. Advise patients that they may need to avoid certain medications while taking BRAFTOVI and to inform their healthcare provider of all concomitant medications, including prescription medicines, over-thecounter drugs, vitamins, and herbal products. Advise patients to avoid grapefruit and grapefruit juice while taking BRAFTOVI [see DRUG INTERACTIONS].
BRAFTOVI is moisture sensitive. Advise patients to store BRAFTOVI in the original bottle with desiccant and to keep the cap of the bottle tightly closed. Do not remove the desiccants from the bottle.
Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats.
No dedicated fertility studies were performed with encorafenib in animals. In a general toxicology study in rats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No effects on reproductive organs were observed in either sex in any of the nonhuman primate toxicity studies.
Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. There are no available clinical data on the use of BRAFTOVI during pregnancy. In animal reproduction studies, encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the clinical dose of 450 mg, with no clear findings at lower doses (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Animal Data
In reproductive toxicity studies, administration of encorafenib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights, and increased incidence of total skeletal variations at a dose of 20 mg/kg/day (approximately 26 times the human exposure based on area under the concentration-time curve [AUC] at the recommended clinical dose of 450 mg once daily). In pregnant rabbits, administration of encorafenib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, increased incidence of total skeletal variations and increased post-implantation loss, including total loss of pregnancy at a dose of 75 mg/kg/day (approximately 178 times the human exposure based on AUC at the recommended clinical dose of 450 mg once daily). While formal placental transfer studies have not been performed, encorafenib exposure in the fetal plasma of both rats and rabbits was up to 1.7% and 0.8%, respectively, of maternal exposure.
There are no data on the presence of encorafenib or its metabolites in human milk or the effects of encorafenib on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child from BRAFTOVI, advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the last dose.
BRAFTOVI can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations].
Verify the pregnancy status of females of reproductive potential prior to initiating BRAFTOVI [see Use In Specific Populations].
Females
Advise females of reproductive potential to use effective contraception during treatment with BRAFTOVI and for 2 weeks after the last dose. Counsel patients to use a nonhormonal method of contraception since BRAFTOVI has the potential to render hormonal contraceptives ineffective [see DRUG INTERACTIONS].
Males
Based on findings in male rats at doses approximately 13 times the human exposure at the 450 mg clinical dose, use of BRAFTOVI may impact fertility in males [see Nonclinical Toxicology].
The safety and effectiveness of BRAFTOVI have not been established in pediatric patients.
Of the 690 patients with BRAF mutation-positive melanoma who received BRAFTOVI in combination with binimetinib across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older [see Clinical Studies].
Of the 231 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in combination with cetuximab and mFOLFOX6, 83 (36%) were 65 years of age and over and 16 (7%) were 75 years of age and over [see Clinical Studies].
Of the 216 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in combination with cetuximab, 62 (29%) were 65 years of age to up to 75 years of age, while 20 (9%) were 75 years of age and over [see Clinical Studies].
Of the 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received BRAFTOVI with binimetinib, 62 (63%) were 65 years of age and over and 20 (20%) were 75 years and over [see Clinical Studies].
No overall differences in the safety or effectiveness of BRAFTOVI plus binimetinib, BRAFTOVI plus cetuximab, or BRAFTOVI plus cetuximab and mFOLFOX6 were observed in older patients as compared to younger patients.
No BRAFTOVI dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Class A) [see CLINICAL PHARMACOLOGY]. A recommended dosage has not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.
No BRAFTOVI dosage adjustment is recommended in patients with mild to moderate renal impairment (CLcr 30 to <90 mL/min) [see CLINICAL PHARMACOLOGY]. A recommended dosage has not been established in patients with severe renal impairment (CLcr <30 mL/min).
Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with BRAFTOVI.
None.
Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and reduce ligand binding to these kinases at clinically achievable concentrations (≤0.9 μM).
Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression.
Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the coadministration compared to either drug alone.
In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. Coadministration of encorafenib and cetuximab had an anti-tumor effect greater than either drug alone, in a mouse model of colorectal cancer with mutated BRAF V600E.
A dedicated study to evaluate the QT prolongation potential of BRAFTOVI has not been conducted. BRAFTOVI is associated with dose-dependent QTc interval prolongation. Based on a central tendency analysis of QTc in a study of adult patients with melanoma who received the recommended dose of BRAFTOVI in combination with binimetinib, the largest mean (90% CI) QTcF change from baseline (ΔQTcF) was 18 (14 to 22) ms [see WARNINGS AND PRECAUTIONS].
The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or V600K mutation, BRAF V600E mutation-positive metastatic CRC. After a single dose, systemic exposure of encorafenib was dose proportional over the dose range of 50 mg to 700 mg (0.1 to 1.6 times the maximum recommended dose of 450 mg). After once-daily dosing, systemic exposure of encorafenib was less than dose proportional over the dose range of 50 mg to 800 mg (0.1 to 1.8 times the maximum recommended dose of 450 mg). Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%.
The median Tmax of encorafenib is 2 hours. At least 86% of the dose is absorbed.
Effect Of Food
Following administration of a single dose of BRAFTOVI 100 mg (0.2 times the maximum recommended dose of 450 mg) with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) the mean maximum encorafenib concentration (Cmax) decreased by 36% and there was no effect on AUC.
The geometric mean (CV%) of apparent volume of distribution is 164 L (70%). The protein binding of encorafenib is 86% in vitro. The blood-to-plasma concentration ratio is 0.58.
The mean (CV%) terminal half-life (t½) of encorafenib is 3.5 hours (17%), and the apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state at the maximum recommended dose of 450 mg.
Metabolism
Encorafenib is primarily metabolized by CYP3A4 (83%) and to a lesser extent by CYP2C19 (16%) and CYP2D6 (1%).
Excretion
Following a single radiolabeled dose of 100 mg encorafenib, 47% (5% unchanged) of the administered dose was recovered in feces and 47% (2% unchanged) in urine.
No clinically significant differences in the pharmacokinetics of encorafenib were observed based on age (19 to 94 years), sex, body weight (34 to 168 kg), mild hepatic impairment (Child-Pugh Class A), and mild or moderate renal impairment (CLcr 30 to <90 mL/min). The effect of race or ethnicity, moderate or severe hepatic impairment (Child-Pugh Class B or C), and severe renal impairment (CLcr <30 mL/min) on encorafenib pharmacokinetics have not been studied.
CYP3A4 Inhibitors
Coadministration of posaconazole (strong CYP3A4 inhibitor) or diltiazem (moderate CYP3A4 inhibitor) increased AUC of encorafenib by 3- and 2-fold, respectively, and increased Cmax by 68% and 45%, respectively, after a single dose of 50 mg BRAFTOVI (0.1 times the maximum recommended dose of 450 mg).
Strong CYP3A4 Inducers
The effect of a strong CYP3A4 inducer on encorafenib exposure has not been studied [see DRUG INTERACTIONS].
Moderate CYP3A4 Inducers
Repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily with modafinil, a moderate CYP3A4 inducer, decreased encorafenib steady-state AUC by 24% and Cmax by 20%, compared to BRAFTOVI alone.
Effect Of Encorafenib On CYP3A4 Substrates Repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily with a single dose of midazolam 2 mg, a sensitive CYP3A4 substrate, decreased midazolam AUC by 82% and Cmax by 74% relative to midazolam 2 mg alone.
Effect Of Encorafenib On Other CYP Substrates
There was no clinically significant effect of repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily on the exposure of substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6.
Proton Pump Inhibitors
No clinically significant differences in encorafenib pharmacokinetics were observed when coadministered with rabeprazole.
Binimetinib
No clinically significant differences in the pharmacokinetics of binimetinib (UGT1A1 substrate) were observed when coadministered with BRAFTOVI (UGT1A1 inhibitor).
Cetuximab
No clinically significant differences in the pharmacokinetics of encorafenib or cetuximab were observed when the recommended BRAFTOVI dose of 300 mg was coadministered with cetuximab.
Transporters
Repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily with a single dose of rosuvastatin (a sensitive substrate for OATP1B1, OATP1B3, and BCRP) increased rosuvastatin Cmax by 2.7-fold and AUC by 1.6-fold.
CYP/UGT Enzymes
Encorafenib is a reversible inhibitor of UGT1A1.
Transporters
Encorafenib is a substrate of P-glycoprotein (P-gp) but not of breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), organic anion transporting polypeptide (OATP1B1, OATP1B3) or organic cation transporter (OCT1) at clinically relevant plasma concentrations.
Encorafenib is an inhibitor of P-gp, BCRP, OCT2, organic anion transporter (OAT1, OAT3), OATP1B1, and OATP1B3, but not of OCT1 or MRP2 at clinically relevant plasma concentrations.
Adverse histopathology findings of hyperplasia and hyperkeratosis occurred in the stomach of rats at encorafenib doses of 20 mg/kg/day (approximately 14 times the human exposure at the 450 mg clinical dose based on AUC) or greater, in both 4 and 13-week studies.
BRAFTOVI in combination with binimetinib was evaluated in a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID™ BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus no).
Patients were randomized (1:1:1) to receive BRAFTOVI 450 mg once daily in combination with binimetinib 45 mg twice daily (BRAFTOVI in combination with binimetinib), BRAFTOVI 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved dosing (BRAFTOVI 450 mg in combination with binimetinib 45 mg) are described below.
The major efficacy outcome measure was progression-free survival (PFS), as assessed by a blinded independent central review, to compare BRAFTOVI in combination with binimetinib with vemurafenib. Additional efficacy outcome measures included overall survival (OS), as well as objective response rate (ORR) and duration of response (DoR) which were assessed by central review.
A total of 577 patients were randomized, 192 to the BRAFTOVI in combination with binimetinib arm, 194 to the BRAFTOVI arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the BRAFTOVI in combination with binimetinib or the vemurafenib arms, the median age was 56 years (20 to 89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-five percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH), 45% had ≥3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized testing, 100% of patients’ tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF V600K (11%), or both (<1%).
BRAFTOVI in combination with binimetinib demonstrated a statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table 13 and Figure 1.
Table 13: Efficacy Results for COLUMBUS
| BRAFTOVI with binimetinib N=192 |
Vemurafenib N=191 |
|
| Progression-Free Survival | ||
| Number of events (%) | 98 (51) | 106 (55) |
| Progressive disease | 88 (46) | 104 (54) |
| Death | 10 (5) | 2 (1) |
| Median PFS, months (95% CI) | 14.9 (11.0, 18.5) | 7.3 (5.6, 8.2) |
| HR (95% CI)a | 0.54 (0.41, 0.71) | |
| P-valueb | <0.0001 | |
| Overall Survivalc | ||
| Number of events (%) | 139 (72) | 147 (77) |
| Median OS, months (95% CI) | 33.6 (24.4, 39.2) | 16.9 (14.0, 24.5) |
| HR (95% CI)a | 0.67 (0.53, 0.84) | |
| Overall Response Rate | ||
| ORR (95% CI) | 63% (56%, 70%) | 40% (33%, 48%) |
| CR | 8% | 6% |
| PR | 55% | 35% |
| Duration of Response | ||
| Median DoR, months (95% CI) | 16.6 (12.2, 20.4) | 12.3 (6.9, 16.9) |
| CI = Confidence interval; CR = Complete response; DoR = Duration of response; HR = Hazard ratio; NE = Not estimable; ORR = Overall response rate; OS = Overall survival; PFS = Progression-free survival; PR = Partial response. a Estimated with Cox proportional hazard model adjusted by the following stratification factors: American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c) and Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1). b Log-rank test adjusted by the same stratification factors. c Based on a cutoff date of 82.4 months after the date of the PFS analysis. |
||
Figure 1: Kaplan-Meier Curves for Progression-Free Survival in COLUMBUS
 |
BRAFTOVI in combination with cetuximab and mFOLFOX6 was evaluated in a randomized, active-controlled, open-label, multicenter trial (BREAKWATER CRC; NCT04607421). Eligible patients were required to have BRAF V600E mutation-positive metastatic colorectal cancer (CRC), as detected using the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction (PCR) Kit. Other key eligibility criteria included no prior systemic treatment in the metastatic setting, absence of prior treatment with any selective BRAF inhibitor or EGFR inhibitor, tumor that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) unless the patient is ineligible to receive immune checkpoint inhibitors, tumor that is not RAS-mutated or for which RAS mutation status is unknown, and Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Randomization was stratified by ECOG performance status (0 versus 1) and region (US/Canada versus Europe versus Rest of World).
Patients were initially randomized 1:1:1 to one of the following treatment arms, and then 1:1 after discontinuation of enrollment of the BRAFTOVI+cetuximab arm (158 patients):
Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, lost to follow-up, or death. Only the results of the approved regimen (BRAFTOVI in combination with cetuximab and mFOLFOX6) are described below.
The major efficacy outcome measure was confirmed objective response rate (ORR) as assessed by BICR and was evaluated in the first 110 participants randomized in each arm. An additional efficacy outcome measure included duration of response (DoR) as assessed by BICR.
A total of 236 patients were randomized to the BRAFTOVI+cetuximab+mFOLFOX6 arm and 243 to the control arm. Of these patients, the median age was 61 years, 50% were female, 60% were White, 37% were Asian, 0.4% were Multiracial, 0.2% were Black or African American, and 2.5% were not reported. Twelve percent (12%) were Hispanic or Latino, 81% were not Hispanic or Latino, and 7% were not reported. Fifty-four percent (54%) had baseline ECOG performance status of 0.
BRAFTOVI in combination with cetuximab and mFOLFOX6 demonstrated a statistically significant improvement in ORR compared to the active comparator. Efficacy results are summarized in Table 14 below.
Table 14: Efficacy Results for BREAKWATER
| Efficacy Parameter | BRAFTOVI with cetuximab and mFOLFOX6 N=110 |
mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab N=110 |
| Objective Response Rate (per BICR) | ||
| ORR (95% CI) | 61% (52%, 70%) | 40% (31%, 49%) |
| CR | 2.7% | 1.8% |
| PR | 58% | 38% |
| P-valuea | 0.0008 | |
| Duration of Response (per BICR) | ||
| Median DoR, months (95% CI) | 13.9 (8.5, NE) | 11.1 (6.7, 12.7) |
| % with DoR ≥6 months | 69% | 34% |
| % with DoR ≥12 months | 22% | 11% |
| CI = Confidence interval; CR = Complete response; DoR = Duration of response; N = Number of patients; NE = Not estimable; ORR = Objective response rate; PR = Partial response. a Stratified by ECOG performance status and geographic region at randomization. Cochran-Mantel-Haenszel test; tested at 1-sided alpha level of 0.001. |
||
BRAFTOVI in combination with cetuximab was evaluated in a randomized, active-controlled, open-label, multicenter trial (BEACON CRC; NCT02928224). Eligible patients were required to have BRAF V600E mutation-positive metastatic colorectal cancer (CRC), as detected using the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction (PCR) Kit, with disease progression after 1 or 2 prior regimens. Other key eligibility criteria included absence of prior treatment with a RAF, MEK, or EGFR inhibitor, eligibility to receive cetuximab per local labeling with respect to tumor RAS status, and ECOG performance status (PS) 0-1. Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), prior use of irinotecan (yes versus no), and cetuximab product used (US-licensed versus EUapproved). Patients were randomized 1:1:1 to one of the following treatment arms:
The dosage of cetuximab in all patients was 400 mg/m² intravenously for the first dose followed by 250 mg/m² weekly.
Patients in the control arm received cetuximab with either irinotecan 180 mg/m² intravenously on Days 1 and 15 of each 28-day cycle or FOLFIRI intravenously (irinotecan 180 mg/m² on Days 1 and 15; folinic acid 400 mg/m² on Days 1 and 15; then fluorouracil 400 mg/m² bolus on Days 1 and 15 followed by fluorouracil 2400 mg/m²/day by continuous infusion over 2 days).
Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved regimen (BRAFTOVI in combination with cetuximab) are described below.
The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures included progression-free survival (PFS), overall response rate (ORR), and duration of response (DoR) as assessed by blinded independent central review (BICR). OS and PFS were assessed in all randomized patients. ORR and DoR were assessed in the subset of the first 220 patients included in the randomized portion of the BRAFTOVI/cetuximab and control arm of the study.
A total of 220 patients were randomized to the BRAFTOVI/cetuximab arm and 221 to the control arm. Of these 441 patients, the median age was 61 years; 53% were female; 80% were White, 15% were Asian, and 5% were other or not reported. Four percent (4%) were Hispanic or Latino, 90% were not Hispanic or Latino, and 6% were not reported or unknown. Fifty percent (50%) had baseline ECOG performance status of 0; 66% received 1 prior therapy and 34% received 2; 93% received prior oxaliplatin and 52% received prior irinotecan.
BRAFTOVI in combination with cetuximab demonstrated a statistically significant improvement in OS, ORR, and PFS compared to the active comparator. Efficacy results are summarized in Table 15 and Figure 2.
Table 15: Efficacy Results From BEACON CRC
| BRAFTOVI with cetuximab N=220 |
Irinotecan with cetuximab or FOLFIRI with cetuximab N=221 |
|
| Overall Survival | ||
| Number of Events (%) | 93 (42) | 114 (52) |
| Median OS, months (95% CI) | 8.4 (7.5, 11.0) | 5.4 (4.8, 6.6) |
| HR (95% CI)a,b | 0.60 (0.45, 0.79) | |
| P-valuea,c | 0.0003 | |
| Overall Response Rate (per BICR) | ||
| ORR (95% CI)d | 20% (13%, 29%) | 2% (0%, 7%) |
| CR | 5% | 0% |
| PR | 15% | 2% |
| P-valuea,e | <0.0001 | |
| Median DoR, months (95% CI) | 6.1 (4.1, 8.3) | NR (2.6, NR) |
| Progression Free Survival (per BICR) | ||
| Number of events (%) | 133 (60) | 128 (58) |
| Progressive disease | 110 (50) | 101 (46) |
| Death | 23 (10) | 27(12) |
| Median PFS, months (95% CI) | 4.2 (3.7, 5.4) | 1.5 (1.4, 1.7) |
| HR (95% CI)a,b | 0.40 (0.31, 0.52) | |
| P-valuea,f | <0.0001 | |
| CI = Confidence interval; CR = Complete response; DoR = Duration of response; HR = Hazard ratio; NR = Not reached; ORR = Overall response rate; OS = Overall survival; PFS = Progression-free survival; PR = Partial response. a Stratified by ECOG PS, source of cetuximab (US-licensed versus EU-approved) and prior irinotecan use at randomization. b Stratified Cox proportional hazard model. c Stratified log-rank test, tested at alpha level of 0.0084. d BRAFTOVI/cetuximab arm (n=113) and control arm (n=107). e Cochran-Mantel-Haenszel test; tested at alpha level of 0.05. f Stratified log-rank test, tested at alpha level of 0.0234. |
||
Figure 2: Kaplan-Meier Curves for Overall Survival in BEACON CRC
 |
BRAFTOVI in combination with binimetinib was evaluated in an open-label, multicenter, single-arm study in patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer (NSCLC) (PHAROS; NCT03915951). Eligible patients had a diagnosis of histologically-confirmed metastatic NSCLC with BRAF V600E mutation that was treatment-naive or had been previously treated with 1 prior line of systemic therapy in the metastatic setting (platinum-based chemotherapy and/or anti-PD-1/PD-L1 therapies), age 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Prior use of BRAF inhibitors or MEK inhibitors was not allowed.
Patients received BRAFTOVI 450 mg once daily and binimetinib 45 mg orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) per RECIST v1.1 and duration of response (DoR) as assessed by independent review committee (IRC).
In the efficacy population, BRAF V600E mutation status was determined by prospective local testing using tumor tissue (78%) or blood (22%) specimens. Of the 98 patients with BRAF V600E mutation, 6 patients were enrolled into the trial based on testing of their tumor tissue specimens with the FoundationOne CDx tissue test. Of the remaining 92 patients enrolled based on local testing, 68 patients had their tumor tissue specimens retrospectively confirmed as having BRAF V600E positive status by the FoundationOne CDx tissue test. The remaining patients had either BRAF V600E negative status (n=5) or had unevaluable results (n=19) by the FoundationOne CDx tissue test. In addition, plasma samples from 81 out of 98 patients were retrospectively tested using the FoundationOne Liquid CDx assay. Of the 81 patients, 48 were confirmed positive for BRAF V600E, while 33 patients were BRAF V600E mutation negative by FoundationOne Liquid CDx assay. The remaining 17 samples had unevaluable results with FoundationOne Liquid CDx assay.
The efficacy population included 59 treatment-naive patients and 39 previously-treated patients. Among these 98 patients, the median age was 70 years (range: 47 to 86); 53% female; 88% White, 7% Asian, 3% Black or African American, and 1% American Indian or Alaska Native; 99% were not Hispanic or Latino; 13% were current smokers and 57% were former smokers; 73% had ECOG PS of 1; and 97% had adenocarcinoma. All patients had metastatic disease, and 8% had brain metastases at baseline.
Efficacy results for patients with BRAF V600E mutation-positive metastatic NSCLC are summarized in Table 16.
Table 16: Efficacy Results for PHAROS
| Efficacy Parameter | BRAFTOVI with binimetinib | |
| Treatment naive (N=59) |
Previously treated (N=39) |
|
| Objective Response Ratea | ||
| ORR (95% CI) | 75% (62, 85) | 46% (30, 63) |
| CR | 15% | 10% |
| PR | 59% | 36% |
| Duration of Responsea,b | N=44 | N=18 |
| Range in months | 1.4, 51.6+ | 3.8, 45.8+ |
| % with DoR ≥12 months | 64% | 44% |
| % with DoR ≥24 months | 43% | 22% |
| CI = Confidence interval; CR = Complete response; DoR = Duration of response; N = Number of patients; NE = Not estimable; ORR = Objective response rate; PR = Partial response. a Assessed by Independent Central Review (ICR). b Based on observed duration of response. |
||
BRAFTOVI®
(braf-TOE-vee)
(encorafenib) capsules
Important information: BRAFTOVI is used in combination with other medicines, including binimetinib, cetuximab, or cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin). Read the Medication Guide that comes with binimetinib if BRAFTOVI is used with binimetinib. Talk to your healthcare provider about cetuximab, or cetuximab and mFOLFOX 6 if used with BRAFTOVI.
What is the most important information I should know about BRAFTOVI?
BRAFTOVI may cause serious side effects, including:
Risk of new skin cancers. BRAFTOVI when used alone, or with binimetinib or cetuximab, may cause skin cancers called cutaneous squamous cell carcinoma or basal cell carcinoma.
Talk to your healthcare provider about your risk for these cancers.
Check your skin and tell your healthcare provider right away about any skin changes, including a:
Your healthcare provider should check your skin before treatment with BRAFTOVI, every 2 months during treatment, and for up to 6 months after you stop treatment with BRAFTOVI to look for any new skin cancers.
Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider about any new symptoms that develop during treatment with BRAFTOVI.
See “What are the possible side effects of BRAFTOVI?” for more information about side effects.
What is BRAFTOVI?
BRAFTOVI is a prescription medicine used:
BRAFTOVI should not be used to treat people with wild-type BRAF melanoma, wild-type BRAF colorectal cancer, or wild-type BRAF NSCLC. Your healthcare provider will perform a test to make sure that BRAFTOVI is right for you.
It is not known if BRAFTOVI is safe and effective in children.
Before taking BRAFTOVI, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
BRAFTOVI and certain other medicines can affect each other, causing side effects or affecting how BRAFTOVI or the other medicines work.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take BRAFTOVI?
What are the possible side effects of BRAFTOVI?
BRAFTOVI may cause serious side effects, including:
Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with BRAFTOVI if you have certain side effects.
The most common side effects of BRAFTOVI when taken in combination with binimetinib for melanoma include:
The most common side effects of BRAFTOVI when taken in combination with cetuximab and mFOLFOX6 for colorectal cancer include:
The most common side effects of BRAFTOVI when taken in combination with cetuximab for colorectal cancer include:
The most common side effects of BRAFTOVI when taken in combination with binimetinib for NSCLC include:
BRAFTOVI may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.
These are not all of the possible side effects of BRAFTOVI.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to Pfizer Inc. at 1-800-438-1985.
How should I store BRAFTOVI?
Keep BRAFTOVI and all medicines out of the reach of children.
General information about the safe and effective use of BRAFTOVI.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BRAFTOVI for a condition for which it was not prescribed. Do not give BRAFTOVI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about BRAFTOVI that is written for health professionals.
What are the ingredients in BRAFTOVI?
Active ingredient: encorafenib
Inactive ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone, colloidal silicon dioxide, and magnesium stearate of vegetable origin
Capsule shell: gelatin, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink (pharmaceutical glaze, ferrosoferric oxide, propylene glycol)
This Medication Guide has been approved by the U.S. Food and Drug Administration.
