Tafinlar Drug Information

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. Adult Safety Pools The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to TAFINLAR 150 mg orally, twice daily as a single agent in 586 patients with various solid tumors, including BRAF V600 mutation-positive unresectable or metastatic melanoma, enrolled in BREAK-2, BREAK-3, BREAK-MB, BRF113220, and BRF112680. Among these 586 patients who received TAFINLAR as a single agent, 46% were exposed for 6 months or longer and 15% were exposed for greater than one year. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to TAFINLAR 150 mg orally, twice daily, administered in combination with trametinib 2 mg orally, once daily, in 1087 patients enrolled in COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma, or NSCLC. Among these 1087 patients who received TAFINLAR administered with trametinib, 70% were exposed for 6 months or longer and 21% were exposed for greater than one year.

Pediatric Safety Pool The pediatric pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to weight-based TAFINLAR orally, twice daily administered in combination with trametinib in 166 pediatric patients across two trials: a multi-center, open-label, multi-cohort study in pediatric patients with BRAF V600E mutation-positive glioma requiring systemic therapy (Study G2201; n = 123) and a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors with MAPK pathway activation (Study X2101; n = 43) . Among 166 patients who received TAFINLAR administered with trametinib, 84% were exposed for 6 months or longer and 70% were exposed for greater than one year. The most common (> 20%) adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common (> 2%) Grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%). Unresectable or Metastatic BRAF V600E or V600K Mutation-Positive Melanoma TAFINLAR as a Single Agent The safety of TAFINLAR was evaluated in BREAK-3, a multi-center, international, open-label, randomized (3:1), controlled trial that allocated 250 patients with unresectable or metastatic BRAF V600E mutation-positive melanoma to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1000 mg/m 2 intravenously every 3 weeks (n = 63) . The trial excluded patients with abnormal LVEF or cardiac valve morphology (≥ Grade 2), corrected QT interval ≥ 480 milliseconds on electrocardiogram, or a known history of G6PD deficiency. The median duration on treatment was 4.9 months for patients treated with TAFINLAR and 2.8 months for dacarbazine-treated patients.

The population exposed to TAFINLAR was 60% male, 99% White, and had a median age of 53 years. The most common adverse reactions (≥ 20%) in patients treated with TAFINLAR were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES). The incidence of adverse events resulting in permanent discontinuation of study medication in the BREAK-3 study was 3% for patients treated with TAFINLAR and 3% for patients treated with dacarbazine. The most frequent (≥ 2%) adverse reactions leading to dose reduction of TAFINLAR were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%). Table 6 and Table 7 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR as a single agent in the BREAK-3 study.

Table 6. Select Adverse Reactions Occurring in ≥ 10% (All Grades) or ≥ 2% (Grades 3 or 4) of Patients Treated with TAFINLAR in the BREAK-3 Study a Abbreviations: cuSCC, cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma; NA, not applicable. a Adverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1). c Includes skin papilloma and papilloma. d Cases of cuSCC were required to be reported as Grade 3 per protocol. TAFINLAR N = 187 Dacarbazine N = 59 Adverse Reactions All Grades (%) Grades 3 and 4 b (%) All Grades (%) Grades 3 and 4 (%) Skin and subcutaneous tissue Hyperkeratosis 37 1 0 0 Alopecia 22 NA 2 NA Palmar-plantar erythrodysesthesia syndrome 20 2 2 0 Rash 17 0 0 0 Nervous system Headache 32 0 8 0 General Pyrexia 28 3 10 0 Musculoskeletal and connective tissue Arthralgia 27 1 2 0 Back pain 12 3 7 0 Myalgia 11 0 0 0 Neoplasms Papilloma c 27 0 2 0 cuSCC d 7 4 0 0 Respiratory system Cough 12 0 5 0 Gastrointestinal Constipation 11 2 14 0 Infections and infestations Nasopharyngitis 10 0 3 0 Table 7. Laboratory Abnormalities Worsening from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in the BREAK-3 Study a a Adverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. b Grade 4 laboratory abnormality limited to hypophosphatemia (n = 1). TAFINLAR N = 187 Dacarbazine N = 59 Laboratory Abnormality All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Hyperglycemia 50 6 43 0 Hypophosphatemia 37 6 b 14 2 Increased alkaline phosphatase 19 0 14 2 Hyponatremia 8 2 3 0 Other clinically important adverse reactions for TAFINLAR in a pool of TAFINLAR monotherapy clinical studies observed in less than 10% of patients who received TAFINLAR were: Gastrointestinal: Pancreatitis Immune System: Hypersensitivity manifesting as bullous rash Nervous System: Peripheral neuropathy Renal and Urinary: Interstitial nephritis Skin and Subcutaneous Tissue: Photosensitivity TAFINLAR with Trametinib The safety of TAFINLAR when administered with trametinib was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600E or V600K mutation-positive melanoma who received TAFINLAR in two trials, the COMBI-d study (n = 209), a multi-center, double-blind, randomized (1:1), active-controlled trial and the COMBI-v study (n = 350), a multi-center, open-label, randomized (1:1), active-controlled trial. In both trials, patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity.

Both trials excluded patients with abnormal LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED), QTcB interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, or known history of G6PD deficiency. Among these 559 patients, 199 (36%) were exposed to TAFINLAR for > 6 months to 12 months while 185 (33%) were exposed to TAFINLAR for ≥ 1 year. The median age was 55 years (range: 18 to 91), 57% were male, 98% were White, 72% had baseline ECOG performance status of 0 and 28% had ECOG performance status of 1, 64% had M1c disease, 35% had elevated lactate dehydrogenase (LDH) at baseline, and 0.5% had a history of brain metastases.

The most common adverse reactions (≥ 20%) for TAFINLAR in patients who received TAFINLAR plus trametinib in the COMBI-d and COMBI-v studies were: pyrexia, rash, chills, headache, arthralgia, and cough. The demographics and baseline tumor characteristics of patients enrolled in the COMBI-d study are summarized in Clinical Studies . Patients who received TAFINLAR plus trametinib had a median duration of exposure of 11 months (range: 3 days to 30 months) to TAFINLAR. Among the 209 patients who received TAFINLAR plus trametinib, 26% were exposed to TAFINLAR for > 6 months to 12 months while 46% were exposed to TAFINLAR for > 1 year. In the COMBI-d study, adverse reactions leading to discontinuation of TAFINLAR occurred in 11% of patients who received TAFINLAR plus trametinib; the most frequent was pyrexia (1.9%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 26% of patients who received TAFINLAR plus trametinib; the most frequent were pyrexia (14%), neutropenia (1.9%), rash (1.9%), and chills (1.9%). Adverse reactions leading to dose interruptions of TAFINLAR occurred in 56% of patients who received TAFINLAR plus trametinib; the most frequent were pyrexia (35%), chills (11%), vomiting (7%), nausea (5%), and decreased ejection fraction (5%). Table 8 and Table 9 present adverse reactions and laboratory abnormalities, respectively, observed in the COMBI-d study.

Table 8. Select Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Treated with TAFINLAR Administered with Trametinib in the COMBI-d Study a a NCI CTCAE version 4.0. b Grade 4 adverse reactions limited to headache (n = 1). c Includes rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, rash maculo-papular, and rash follicular. Pooled TAFINLAR plus Trametinib N = 559 COMBI-d Study TAFINLAR plus Trametinib N = 209 TAFINLAR N = 211 Adverse Reactions All Grades (%) Grades 3 and 4 b (%) All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) General Pyrexia 54 5 57 7 33

Chills 31 0.5 31 0 17 0.5 Skin and subcutaneous tissue Rash

c 32 1.1 42 0 27

Dry skin 10 0 12 0 16 0 Nervous system Headache 30

0.9 33 0.5 30

Dizziness 11 0.2 14 0 7 0 Musculoskeletal and connective tissue Arthralgia

25 0.9 26 0.9 31 0 Myalgia 15 0.2 13 0.5 13 0 Respiratory system Cough 20 0 21 0 21 0 Gastrointestinal Constipation 13 0.2 13 0.5 10 0 Infections and infestations Nasopharyngitis 12 0 12 0 10 0 Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies (N = 559) observed in less than 10% of patients who received TAFINLAR administered with trametinib were: Cardiac: Atrioventricular block, bundle branch block Gastrointestinal: Colitis, gastrointestinal perforation, pancreatitis Immune System: Sarcoidosis Nervous System: Peripheral neuropathy, Guillain-Barré syndrome Skin and Subcutaneous Tissue: Panniculitis, photosensitivity Table 9. Select Laboratory Abnormalities Worsening from Baseline Occurring at ≥ 10% (All Grades) of Patients Who Received TAFINLAR with Trametinib in the COMBI-d Study a For these laboratory tests, the denominator is 556. b For these laboratory tests, the denominator is 208 for the combination arm, 208-209 for the TAFINLAR arm. c Grade 4 adverse reactions limited to hyperglycemia (n = 4), hyponatremia and hypophosphatemia (each n = 1) in the pooled combination arm; hyperglycemia (n = 1) in the COMBI-d study combination arm; hypophosphatemia (n = 1) in the TAFINLAR arm. Laboratory Abnormalities Pooled TAFINLAR plus T rametinib N = 559 a COMBI-d Study TAFINLAR plus Trametinib N = 209 b TAFINLAR N = 211 b All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) Chemistry Hyperglycemia 60 4.7 65 6 57

Hypophosphatemia 38 6 38 3.8 35 7 Hyponatremia 25 8 24 6

14

Hepatic Increased blood alkaline phosphatase 49 2.7 50 1.0 25 0.5 Adjuvant

Treatment of BRAF V600E or V600K Mutation-Positive Melanoma The safety of TAFINLAR when administered with trametinib was evaluated in 435 patients with Stage III melanoma with BRAF V600E or V600K mutations following complete resection who received at least one dose of study therapy in the COMBI-AD study . Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily for 12 months. The trial excluded patients with abnormal LVEF; history of acute coronary syndromes, coronary angioplasty, or stenting within 6 months; Class II or greater congestive heart failure (New York Heart Association); QTc interval ≥ 480 msec; treatment refractory hypertension; uncontrolled arrhythmias; or history of RVO. Patients who received TAFINLAR in combination with trametinib had a median duration of exposure of 11 months (range: 0 to 12) to TAFINLAR. Among the 435 patients receiving TAFINLAR in combination with trametinib, 71% were exposed to TAFINLAR for > 6 months. The median age of patients who received TAFINLAR administered with trametinib was 50 years (range: 18 to 89), 56% were male, 99% were White, 92% had baseline ECOG performance status of 0, and 8% had baseline ECOG performance status of 1. The most common adverse reactions (≥ 20%) in patients who received TAFINLAR administered with trametinib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.

Adverse reactions resulting in discontinuation, dose reduction, or dose interruption of TAFINLAR occurred in 25%, 35%, and 66% of patients, respectively; the most frequent for each were pyrexia and chills. Table 10 summarizes the adverse reactions that occurred in at least 20% of patients who received TAFINLAR administered with trametinib. Table 10. Adverse Reactions Occurring in ≥ 20% of Patients in the COMBI-AD Study a a NCI CTCAE version 4.0. b Includes pyrexia and hyperpyrexia. c Includes fatigue, asthenia, and malaise. d Includes headache and tension headache. e Includes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular. f Includes myalgia, musculoskeletal pain, and musculoskeletal chest pain.

Adverse Reactions TAFINLAR plus Trametinib N = 435 Placebo N = 432 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) General Pyrexia b 63 5 11 < 1 Fatigue c 59 5 37 < 1 Chills 37 1 4 0 Gastrointestinal Nausea 40 < 1 20 0 Diarrhea 33 < 1 15 < 1 Vomiting 28 < 1 10 0 Nervous system Headache d 39 1 24 0 Skin and subcutaneous tissue Rash e 37 < 1 16 < 1 Musculoskeletal and connective tissue Arthralgia 28 < 1 14 0 Myalgia f 20 < 1 14 0 Other clinically important adverse reactions for TAFINLAR in the COMBI-AD study observed in less than 20% of patients who received TAFINLAR administered with trametinib were: blurred vision (6%), decreased ejection fraction (5%), peripheral neuropathy (2.5%), rhabdomyolysis (< 1%), atrioventricular block (< 1%), Guillain-Barré syndrome (< 1%), and sarcoidosis (< 1%). The laboratory abnormalities are summarized in Table 11. Table 11. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the COMBI-AD Study Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement: TAFINLAR plus Trametinib (range: 429 to 431) and Placebo arm (range: 426 to 428). Laboratory Abnormality TAFINLAR plus Trametinib a N = 435 Placebo a N = 432 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Chemistry Hyperglycemia 63 3 47 2 Hypophosphatemia 42 7 10 < 1 Hypoalbuminemia 25 < 1 < 1 0 Hepatic Increased AST 57 6 11 < 1 Increased ALT 48 5 18 < 1 Increased blood alkaline phosphatase 38 1 6 < 1 Hematology Neutropenia 47 6 12 < 1 Lymphopenia 26 5 6 < 1 Anemia 25 < 1 6 < 1 Trial COMBI-aPlus (Pyrexia Management Study) COMBI-aPlus evaluated the impact of pyrexia-related outcomes of a revised pyrexia management algorithm in patients who received dabrafenib administered with trametinib in the adjuvant treatment of BRAF V600 mutation-positive melanoma after complete resection. The pyrexia management algorithm interrupted both dabrafenib and trametinib when patient’s temperature is ≥ 100.4°F. Grade 3-4 pyrexia occurred in 4.3% of patients, hospitalizations due to pyrexia occurred in 5.1% of patients, pyrexia with complications (dehydration, hypotension, renal dysfunction, syncope, severe chills) occurred in 2.2% of patients, and treatment discontinuation due to pyrexia occurred in 2.5% of patients. Metastatic, BRAF V600E Mutation-Positive Non-Small Cell Lung Cancer The safety of TAFINLAR when administered with trametinib was evaluated in 93 patients with previously untreated (n = 36) and previously treated (n = 57) metastatic BRAF V600E mutation-positive NSCLC in a multi-center, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity.

The trial excluded patients with abnormal LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of interstitial lung disease or pneumonitis, or history or current RVO. Among these 93 patients, 53 (57%) were exposed to TAFINLAR and trametinib for > 6 months and 27 (29%) were exposed to TAFINLAR and trametinib for ≥ 1 year. The median age was 65 years (range: 41 to 91); 46% were male; 85% were White; 32% had baseline ECOG performance status of 0 and 61% had ECOG performance status of 1; 98% had non-squamous histology; and 12% were current smokers, 60% were former smokers, and 28% had never smoked. The most common adverse reactions (≥ 20%) in these 93 patients were: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.

Adverse reactions leading to discontinuation of TAFINLAR occurred in 18% of patients; the most frequent were pyrexia (2.2%), decreased ejection fraction (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 35% of patients; the most frequent were pyrexia (10%), diarrhea (4.3%), nausea (4.3%), vomiting (4.3%), and neutropenia (3.2%). Adverse reactions leading to dose interruptions of TAFINLAR occurred in 62% of patients; the most frequent were pyrexia (27%), vomiting (11%), neutropenia (8%), and chills (6%). Table 12 and Table 13 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR administered with trametinib in Study BRF113928. Table 12. Adverse Reactions Occurring in ≥ 20% (All Grades) of Patients Treated with TAFINLAR Administered with Trametinib in Study BRF113928 a a NCI CTCAE version 4.0. b Includes fatigue, malaise, and asthenia. c Includes peripheral edema, edema, and generalized edema. d Includes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular. e Includes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage. Adverse Reactions TAFINLAR plus T rametinib N = 93 All Grades (%) Grades 3 and 4 (%) General Pyrexia 55 5 Fatigue b 51 5 Edema c 28 0 Chills 23

Gastrointestinal Nausea 45 0 Vomiting 33 3.2 Diarrhea 32 2.2 Decreased appetite

29 0 Skin and subcutaneous tissue Dry skin 31

Rash d 28 3.2 Vascular Hemorrhage e 23 3.2 Respiratory system Cough

22 0 Dyspnea 20 5 Other clinically important adverse reactions for TAFINLAR in Study BRF113928 observed in less than 20% of patients who received TAFINLAR administered with trametinib were: Cardiac: Atrioventricular block Gastrointestinal: Pancreatitis Nervous System: Peripheral neuropathy Renal and Urinary: Tubulointerstitial nephritis Table 13. Treatment-Emergent Laboratory Abnormalities Occurring in ≥ 20% (All Grades) of Patients Who Received TAFINLAR with Trametinib in Study BRF113928 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a For these laboratory tests, the denominator is 90. b For these laboratory tests, the denominator is 91. Laboratory Abnormality TAFINLAR plus Trametinib N = 93 All Grades (%) Grades 3 and 4 (%) Chemistry a Hyperglycemia 71 9 Hyponatremia 57 17 Hypophosphatemia 36 7 Increased creatinine 21

Hepatic a Increased blood alkaline phosphatase 64 0 Increased

AST 61

Increased

ALT 32 6 Hematology b Leukopenia 48 8 Anemia 46 10 Neutropenia 44 8 Lymphopenia 42 14 Advanced BRAF V600E Mutation-Positive Tumors Study BRF117019 The safety of TAFINLAR when administered with trametinib was evaluated in a multi-cohort, multi-center, non-randomized, open-label study in adult patients with cancers with the BRAF V600E mutation (Study BRF117019). A total of 206 patients were enrolled in the trial, 36 of whom were enrolled in the ATC cohort, 105 were enrolled in specific solid tumor cohorts, and 65 in other malignancies . Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 206 patients, 103 (50%) were exposed to TAFINLAR for ≥ 1 year and 101 (49%) were exposed to trametinib for ≥ 1 year. The median age was 60 years (range: 18 to 89); 56% were male; 79% were White; and 34% had baseline ECOG performance status of 0 and 60% had ECOG performance status of 1. Serious adverse reactions occurred in 45% of patients who received TAFINLAR in combination with trametinib.

Serious adverse reactions in > 5% of patients included pyrexia (11%) and pneumonia (6%). Fatal adverse reactions occurred in 3.9% of patients who received TAFINLAR in combination with trametinib. Fatal adverse reactions that occurred in > 1% of patients included sepsis (1.9%). Permanent treatment discontinuation due to an adverse reaction occurred in 13% of patients. Adverse reactions which resulted in permanent treatment discontinuation in > 1% of patients included nausea (1.5%). Dosage interruptions due to an adverse reaction occurred in 55% of patients.

Adverse reactions which required dosage interruption in > 5% of patients included pyrexia (22%), chills (9%), fatigue (6%), neutropenia (6%), and nausea (5%). Dose reductions due to an adverse reaction occurred in 44% of patients. Adverse reactions which required dose reductions in > 5% of patients included pyrexia (18%), chills (8%), and fatigue (6%). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, are listed in Table 14 and Table 15. Table 14 summarizes the adverse reactions in Study BRF117019. Table 14. Adverse Reactions (≥ 20%) in Adult Patients Treated with TAFINLAR Plus Trametinib in Study BRF117019 a NCI CTCAE version 4.0. b Includes fatigue, asthenia, and malaise. c Includes peripheral edema and peripheral swelling. d Includes rash, rash maculo-papular, rash erythematous, rash pustular, and rash papular. e Includes epistaxis, hematuria, contusion, hematoma, hemoptysis, conjunctival hemorrhage, hematochezia, rectal hemorrhage, hemorrhoidal hemorrhage, melena, purpura, eye contusion, eye hemorrhage, gastric hemorrhage, gingival bleeding, hematemesis, hemorrhage intracranial, hemorrhagic stroke, hemothorax, increased tendency to bruise, large intestinal hemorrhage, mouth hemorrhage, petechiae, pharyngeal hemorrhage, prothrombin time prolonged, pulmonary hematoma, retinal hemorrhage, vaginal hemorrhage, and vitreous hemorrhage. f Includes cough and productive cough. g Includes myalgia, musculoskeletal chest pain, and musculoskeletal pain. Adverse Reactions TAFINLAR plus Trametinib a (N = 206) All Grades (%) Grade 3 or 4 (%) General Pyrexia 55

Fatigue b 50 5 Chills 30 0.5 Peripheral edema c 22 0

Gastrointestinal Nausea 40

Constipation 27 0 Vomiting 27 1.5 Diarrhea 26 2.9 Skin and subcutaneous

tissue Rash d 40

Nervous system Headache 30 1.5 Vascular Hemorrhage e 29 4.4 Respiratory system

Cough f 29 0 Musculoskeletal and connective tissue Myalgia g 24

Arthralgia 23 0.5 Clinically relevant adverse reactions for

TAFINLAR in Study BRF117019 observed in less than 20% of patients who received TAFINLAR in combination with trametinib were: peripheral neuropathy (9%), decreased ejection fraction (8%), atrioventricular block (2.9%), uveitis (1.9%), hypersensitivity (1.9%), Guillain-Barré syndrome (< 1%), and sarcoidosis (< 1%). Table 15 summarizes the laboratory abnormalities in Study BRF117019. Table 15. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Adult Patients Treated with TAFINLAR Plus Trametinib in Study BRF117019 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 199 to 202 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality TAFINLAR plus Trametinib a All Grades (%) Grade 3 or 4 (%) Chemistry Hyperglycemia 61 8 Decreased sodium 35 10 Decreased magnesium 24 0 Increased creatinine 21

Hepatic Increased alkaline phosphatase 51 5 Increased

AST 51

Increased

ALT 39 3 Hematology Decreased hemoglobin 44 9 BRAF V600E Mutation-Positive Solid Tumors in Pediatric Patients Study CTMT212X2101 (X2101) The safety of TAFINLAR when administered with trametinib was evaluated in Study X2101, a multi-center, open-label, multi-cohort study in pediatric patients (n = 48) with refractory or recurrent solid tumors . The median duration of exposure to TAFINLAR in Parts C (dose escalation) and D (cohort expansion) was 20.8 and 24.9 months, respectively. The median duration of exposure to trametinib in Parts C and D was 20.8 and 24.4 months, respectively. The median age of pediatric patients who received TAFINLAR with trametinib was 9 years (range: 1 to 17). Serious adverse reactions occurred in 46% of patients who received TAFINLAR in combination with trametinib.

Serious adverse reactions in > 5% of patients included pyrexia (25%) and decreased ejection fraction (6%). Permanent treatment discontinuation due to an adverse reaction occurred in 21% of patients. Adverse reactions which resulted in permanent treatment discontinuation in > 3% of patients included increased ALT (6%), increased AST (4.2%) and decreased ejection fraction (4.2%). Dosage interruptions due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dosage interruption in > 5% of patients included pyrexia (56%), vomiting (19%), neutropenia (13%), rash (13%), decreased ejection fraction (6%), and uveitis (6%). Dose reductions due to an adverse reaction occurred in 25% of patients.

Adverse reactions which required dose reductions in > 5% of patients included pyrexia (13%). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, are listed in Table 16 and Table 17. Table 16 summarizes the adverse reactions in Study X2101. Table 16. Adverse Reactions (≥ 20%) in Pediatric Patients Treated with TAFINLAR Plus Trametinib in Study X2101 a a NCI CTCAE version 4.0. b Includes fatigue, asthenia, and malaise. c Includes rash, rash maculo-papular, rash erythematous, rash papular, rash pustular, and rash macular. d Includes dermatitis acneiform and acne. e Includes abdominal pain and abdominal pain upper. f Includes epistaxis, hematuria, contusion, hematoma, petechiae, rectal hemorrhage, and red blood cell count decreased. Adverse Reactions TAFINLAR plus Trametinib a (N = 48) All Grades (%) Grade 3 or 4 (%) General Pyrexia 75 17 Fatigue b 48 0 Skin and subcutaneous tissue Rash c 73

Diarrhea 42 2.1 Abdominal pain e 33 4.2 Nausea 33 2.1 Constipation

23 0 Respiratory system Cough 44 0 Nervous system Headache 35 0 Vascular Hemorrhage f 33 0 Infections and infestations Paronychia 23 0 Clinically relevant adverse reactions for TAFINLAR in Study X2101 observed in less than 20% of patients (N=48) who received TAFINLAR in combination with trametinib were: atrioventricular block (2.1%). Table 17 summarizes the laboratory abnormalities in Study X2101. Table 17. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Pediatric Patients Treated with TAFINLAR Plus Trametinib in Study X2101 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 39 to 48 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality TAFINLAR plus Trametinib a All Grades (%) Grade 3 or 4 (%) Chemistry Hyperglycemia 65

Hypoalbuminemia 48 2.1 Hypocalcemia 40 2.1 Decreased phosphate 38 0 Decreased magnesium

33

Hypernatremia 27 0 Hypokalemia 21 2.1 Hepatic Increased

AST 55

Increased

ALT 40 6 Increased alkaline phosphatase 28 6 Increased total bilirubin 21

Hematology Decreased hemoglobin 60 6 Decreased neutrophils 49 28

BRAF V600E Mutation-Positive Low-Grade Glioma in Pediatric Patients Study CDRB436G2201 (G2201) The safety of TAFINLAR in combination with trametinib was evaluated in pediatric patients 1 to < 18 years of age in Study G2201. Patients with low-grade glioma (LGG) who required first systemic therapy were randomized (2:1) to TAFINLAR plus trametinib (n = 73) or carboplatin plus vincristine (n = 33). Nine patients crossed over from the carboplatin plus vincristine arm to the TAFINLAR and trametinib arm. Pediatric patients received weight-based TAFINLAR orally twice daily administered in combination with trametinib until disease progression or intolerable toxicity. Patients in the control arm received carboplatin and vincristine at doses of 175 mg/m 2 and 1.5 mg/m 2, respectively in 10-week induction course followed by eight 6-week cycles of maintenance therapy or until disease progression or intolerable toxicity.

Among patients with low-grade glioma who were randomized to TAFINLAR plus trametinib (n = 73), 95% were exposed for 6 months or longer and 71% were exposed for greater than one year. The median age of these patients was 10 years (range: 1 to 17); 60% female; 75% White, 7% Asian, 2.7% Black or African American, 4% other race, and 11% where race was unknown or not reported. Serious adverse reactions occurred in 40% of these patients.

Serious adverse reactions in > 3% of patients included pyrexia (14%) and vomiting (4%). Permanent discontinuation of TAFINLAR due to an adverse reaction occurred in 4% of patients. Adverse reactions which resulted in permanent discontinuation of TAFINLAR included chills, fatigue, pyrexia, weight increased, and headache. Dosage interruptions of TAFINLAR due to an adverse reaction occurred in 73% of patients.

Adverse reactions which required dosage interruption in > 5% of patients included pyrexia (53%). Dose reductions of TAFINLAR due to an adverse reaction occurred in 48% of patients. Adverse reactions which required dose reductions in > 2% of patients included rash (2.7%). The most common (≥ 15%) adverse reactions were pyrexia (68%), rash (51%), headache (47%), vomiting (34%), musculoskeletal pain (34%), fatigue (33%), diarrhea (29%), dry skin (26%), nausea (25%), hemorrhage (25%), abdominal pain (25%), dermatitis acneiform (22%), dizziness (15%), upper respiratory tract infection (15%), and weight increased (15%). The most common (≥ 20%) laboratory abnormalities that worsened from baseline were leukopenia (59%), increased alkaline phosphatase (55%), anemia (46%), decreased neutrophils (44%), increased AST (37%), decreased magnesium (34%), increased magnesium (32%), decreased platelets (30%), increased ALT (29%), and increased lymphocytes (24%). Table 18 summarizes the adverse reactions in Study G2201. Table 18. Adverse Reactions (≥ 15%) in Pediatric LGG Patients Who Received TAFINLAR in Combination with Trametinib in Study G2201 a a NCI CTCAE version 4.03. b Includes diarrhea, colitis, enterocolitis, and enteritis. c Includes abdominal pain and upper abdominal pain. d Includes stomatitis, cheilitis, mouth ulceration, aphthous ulcer, and glossitis. e Includes pyrexia and body temperature increased. f Includes fatigue and asthenia. g Includes headache and migraine with aura. h Includes dizziness and vertigo. i Includes peripheral neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia, neuralgia, hypoaesthesia, and peripheral sensory neuropathy. j Includes epistaxis, post-procedural hemorrhage, hematuria, upper gastrointestinal hemorrhage, and hemorrhage intracranial. k Includes rash, rash macular, rash maculo-papular, rash pustular, rash papular, rash erythematous, eczema, erythema multiforme, dermatitis, dermatitis exfoliative, skin exfoliation, palmar-plantar erythrodysaesthesia syndrome, and dermatitis bullous. l Includes dermatitis acneiform, acne, and acne pustular. m Includes back pain, myalgia, pain in extremity, arthralgia, bone pain, non-cardiac chest pain, neck pain, and musculoskeletal stiffness. Adverse Reactions TAFINLAR plus Trametinib N = 73 Carboplatin plus Vincristine N = 33 All Grades (%) Grade ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Gastrointestinal Vomiting 34 1 48 3 Diarrhea b 29 0 18 6 Nausea 25 0 45 0 Abdominal pain c 25 0 24 0 Constipation 12 0 36 0 Stomatitis d 10 0 18 0 General Pyrexia e 68 8 18 3 Fatigue f 33 0 39 0 Nervous system Headache g 47 1 33 3 Dizziness h 15 0 9 3 Peripheral neuropathy i 7 0 45 6 Vascular Hemorrhage j 25 0 12 0 Skin and subcutaneous tissue Rash k 51 2.7 18 3 Dry skin 26 0 3 0 Dermatitis acneiform l 22 0 0 0 Alopecia 3 0 24 0 Musculoskeletal and connective tissue Musculoskeletal pain m 34 0 30 0 Pain in jaw 1.4 0 18 0 Metabolism and nutrition Decreased appetite 5 0 24 0 Respiratory, thoracic and mediastinal Oropharyngeal pain 11 0 18 0 Psychiatric Anxiety 1.4 0 15 3 Immune system Hypersensitivity 0 0 15 3 Infections and infestations Upper respiratory tract infection 15 0 6 0 Injury, poisoning and procedural complications Infusion-related reaction 0 0 15 3 Investigations Weight increased 15 7 0 0 Table 19 summarizes the laboratory abnormalities in Study G2201. Table 19. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Pediatric LGG Patients Who Received TAFINLAR in Combination with Trametinib in Study G2201 a Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 70 to 73 in D + T arm and 9 to 33 in C + V arm based on the number of patients with a baseline value and at least one post-treatment value.

Laboratory Abnormality TAFINLAR plus Trametinib N = 73 Carboplatin plus Vincristine N = 33 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hepatic Increased alkaline phosphatase 55 0 13 0 Increased AST 37 1.4 55 0 Increased ALT 29 3 61 9 Chemistry Decreased magnesium 34 4.1 76 6 Increased magnesium 32 0 24 3 Increased potassium 15 4.2 21 6 Decreased calcium 14 4.1 22 9 Decreased potassium 8 1.4 70 0 Decreased phosphate 7 2.7 33 3 Decreased sodium 5 1.4 27 6 Increased serum fasting glucose 0 0 44 0 Hematology Decreased leukocytes 59 0 91 18 Decreased hemoglobin 46 0 94 36 Decreased neutrophils 44 17 84 75 Decreased platelets 30 0 73 18 Increased lymphocytes 24 0 13

Decreased lymphocytes 16 1.4 56 6 6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of TAFINLAR in combination with trametinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac: Atrioventricular block complete Immune System: Hemophagocytic lymphohistiocytosis (HLH) Skin and Subcutaneous Tissue: SCAR (including DRESS and SJS)

Effects of Other Drugs on

TAFINLAR Strong inhibitors of CYP3A4 or CYP2C8 may increase the concentration of dabrafenib . Substitution of strong inhibitors of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors.

Effects of

TAFINLAR on Other Drugs Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) . Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy . Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

Pregnancy Risk Summary Based on findings from animal reproduction studies and its mechanism of action , TAFINLAR can cause fetal harm when administered to a pregnant woman. There is insufficient data in pregnant women exposed to TAFINLAR to assess the risks. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended adult clinical dose of 150 mg twice daily (see Data). Advise pregnant women 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. Data Animal Data In a combined female fertility and embryo-fetal development study in rats conducted during the period of organogenesis, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day. At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended adult dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

Pediatric Use BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors and LGG The safety and effectiveness of TAFINLAR in combination with trametinib have been established in pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options; or with LGG with BRAF V600E mutation who require systemic therapy. Use of TAFINLAR in combination with trametinib for these indications is supported by evidence from studies X2101 and G2201 that enrolled 171 patients (1 to < 18 years of age) with BRAF V600 mutation-positive advanced solid tumors, of which 4 (2.3%) patients were 1 to < 2 years of age, 39 (23%) patients were 2 to < 6 years of age, 54 (32%) patients were 6 to < 12 years of age, and 74 (43%) patients were 12 to < 18 years of age . The safety and effectiveness of TAFINLAR in combination with trametinib have not been established for these indications in pediatric patients less than 1 year old. The safety and effectiveness of TAFINLAR as a single agent in pediatric patients have not been established.

Juvenile Animal Toxicity Data In a repeat-dose toxicity study in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC.

There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR.