Braftovi Drug Information

Patient Selection BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating BRAFTOVI. Information on FDA-authorized tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics. BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) Confirm the presence of a BRAF V600E mutation in plasma or tumor tissue prior to initiating BRAFTOVI.

If no mutation is detected in a plasma specimen, test tumor tissue. BRAF V600E Mutation-Positive Metastatic Non‑Small Cell Lung Cancer (NSCLC) Confirm the presence of a BRAF V600E mutation in tumor or plasma specimens prior to initiating BRAFTOVI.

Recommended Dosage for BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma and for BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) 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.

Recommended Dosage for BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) The recommended dosage of BRAFTOVI is 300 mg (four 75 mg capsules) orally once daily until disease progression or unacceptable toxicity in combination with: • biweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) or biweekly cetuximab and FOLFIRI (fluorouracil, leucovorin and irinotecan) • weekly cetuximab.

Administration BRAFTOVI may be taken with or without food

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.

Dosage Modifications for Adverse Reactions BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma or BRAF V600E Mutation-Positive Metastatic NSCLC If binimetinib is withheld, reduce BRAFTOVI to a maximum dose of 300 mg (four 75 mg capsules) once daily until binimetinib is resumed. 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 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) When BRAFTOVI is administered in combination with cetuximab and mFOLFOX6 or FOLFIRI • Continue BRAFTOVI with mFOLFOX6 or FOLFIRI if cetuximab is permanently discontinued. • Permanently discontinue BRAFTOVI if cetuximab and mFOLFOX6 or FOLFIRI are permanently discontinued.

Table 3: Recommended Dosage Modifications for BRAFTOVI for Adverse Reactions Severity of Adverse Reaction National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Dose Modification for BRAFTOVI New Primary Malignancies Noncutaneous RAS Mutation-positive Malignancies Permanently discontinue BRAFTOVI. Cardiomyopathy • Symptomatic congestive heart failure or absolute decrease in LVEF of greater than 20% from baseline that is also below LLN Reduce BRAFTOVI by one dose level. • If LVEF improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, continue BRAFTOVI at the reduced dose. • If no improvement, withhold BRAFTOVI until improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline and then resume at the reduced dose or reduce dose an additional dose level.

Hepatotoxicity Other Adverse Reactions (including Hemorrhage) and HFSR 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.

Dose Modifications for Coadministration with Strong or Moderate CYP3A4 Inhibitors 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.

Table 4: Recommended Dose Reductions for BRAFTOVI for Coadministration with Strong or Moderate CYP3A4 Inhibitors

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 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. 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 Grades per National Cancer Institute CTCAE v4.03. 3 9 2 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 ( % 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 COLUMBUS 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/m 2 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). Patients with pancreatitis, leptomeningeal disease, chronic inflammatory bowel disease requiring medical intervention, as well as clinically significant cardiovascular diseases 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. 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.

Table 7: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Cetuximab and mFOLFOX6 in BREAKWATER Grades per National Cancer Institute CTCAE v4.03. 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. 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. Adverse reactions leading to dose reductions of BRAFTOVI in ≥2% of patients included nausea, vomiting, decreased appetite, fatigue, and diarrhea.

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. 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. 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. Table 11: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Cetuximab in BEACON CRC Grades per National Cancer Institute CTCAE v4.03. 0 6 0 Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with cetuximab were: Gastrointestinal disorders: Pancreatitis Table 12: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI in Combination with Cetuximab in BEACON CRC Grades per National Cancer Institute CTCAE v4.03. 2 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 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. 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. 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. Table 13: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Binimetinib in PHAROS Grades per National Cancer Institute CTCAE v4.03. 0 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 14: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI with Binimetinib Grades per National Cancer Institute CTCAE v4.03.

Effect of Other Drugs on BRAFTOVI Strong or Moderate CYP3A4 Inhibitors Coadministration of BRAFTOVI with a strong or moderate CYP3A4 inhibitor increases encorafenib plasma concentrations 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.

Strong CYP3A4 Inducers Coadministration of BRAFTOVI with a strong CYP3A4 inducer may decrease encorafenib plasma concentrations and may decrease encorafenib efficacy. Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers.

Effect of BRAFTOVI on Other Drugs Sensitive CYP3A4 Substrates BRAFTOVI is a strong CYP3A4 inducer at steady-state. Concomitant use of BRAFTOVI may decrease the plasma concentrations of CYP3A4 substrates (including hormonal contraceptives),, 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. OATP1B1, OATP1B3, or BCRP Substrates 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.

Drugs That Prolong the QT Interval BRAFTOVI is associated with dose-dependent QTc interval prolongation. Avoid coadministration of BRAFTOVI with drugs known to prolong the QT/QTc interval.

Pregnancy Risk Summary Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman. 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 respectively. Data 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 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.

Pediatric Use The safety and effectiveness of BRAFTOVI have not been established in pediatric patients.

Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with BRAFTOVI.