TAFINLAR^® is indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test [see Dosage and Administration (2.1)].

TAFINLAR is indicated, in combination with trametinib, for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection [see Dosage and Administration (2.1)].

TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test [see Dosage and Administration (2.1)].

TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options [see Dosage and Administration (2.1)].

TAFINLAR is indicated, in combination with trametinib, for the treatment of adult and 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 [see Dosage and Administration (2.1)]. This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DoR) [see Clinical Studies (14.6)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

TAFINLAR is indicated, in combination with trametinib, for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy [see Dosage and Administration (2.1)].

• TAFINLAR is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition [see Indications and Usage (1.6), Clinical Pharmacology (12.1)].
• TAFINLAR is not indicated for treatment of patients with wild-type BRAF solid tumors [see Warnings and Precautions (5.2)].

Melanoma

• Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR as a single agent [see Warnings and Precautions (5.2), Clinical Studies (14.1)].
• Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Warnings and Precautions (5.2), Clinical Studies (14.2, 14.3)].
• Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

NSCLC

• Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies (14.4)].
• Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

ATC

• Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies (14.5)]. An FDA-approved test for the detection of BRAF V600E mutation in ATC is not currently available.

Solid Tumors

• Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies (14.6)]. An FDA-approved test for the detection of BRAF V600E mutation in solid tumors other than melanoma and NSCLC is not currently available.

Low-Grade Glioma

• Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib [see Clinical Studies (14.7)]. An FDA-approved test for the detection of BRAF V600E mutation in LGG is not currently available.

TAFINLAR Capsules

Adult Patients

The recommended dosage for TAFINLAR capsules in adult patients is 150 mg taken orally twice daily [see Dosage and Administration (2.3)].

Pediatric Patients

The recommended dosage for TAFINLAR capsules in pediatric patients who weigh at least 26 kg is based on body weight (Table 1) [see Dosage and Administration (2.3)]. A recommended dosage of TAFINLAR capsules has not been established in patients who weigh less than 26 kg.

Table 1. Recommended Dosage for TAFINLAR Capsules in Pediatric Patients (Weight-based)

Body Weight	Recommended Dosage
26 to 37 kg	75 mg orally twice daily
38 to 50 kg	100 mg orally twice daily
51 kg or greater	150 mg orally twice daily

TAFINLAR Tablets for Oral Suspension

The recommended dosage for TAFINLAR tablets for oral suspension is based on body weight (Table 2) [see Dosage and Administration (2.3)].

Table 2. Recommended Dosage for TAFINLAR Tablets for Oral Suspension (Weight-based)

Body Weight	Recommended Dosage
8 to 9 kg	20 mg twice daily
10 to 13 kg	30 mg twice daily
14 to 17 kg	40 mg twice daily
18 to 21 kg	50 mg twice daily
22 to 25 kg	60 mg twice daily
26 to 29 kg	70 mg twice daily
30 to 33 kg	80 mg twice daily
34 to 37 kg	90 mg twice daily
38 to 41 kg	100 mg twice daily
42 to 45 kg	110 mg twice daily
46 to 50 kg	130 mg twice daily
≥ 51 kg	150 mg twice daily

• The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity.
• The recommended duration of treatment in the adjuvant melanoma setting is until disease recurrence or unacceptable toxicity for up to 1 year.
• The recommended duration of treatment for pediatric patients with LGG is until disease progression or until unacceptable toxicity.

Refer to the trametinib prescribing information for recommended trametinib dosing information.

• Take TAFINLAR at the same time each day, approximately 12 hours apart.
• Take TAFINLAR at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)].
• Do not take a missed dose of TAFINLAR within 6 hours of the next dose of TAFINLAR.
• If vomiting occurs after TAFINLAR administration, do not take an additional dose. Take the next dose at its scheduled time.

TAFINLAR Capsules

• Do not open, crush, or break TAFINLAR capsules.

TAFINLAR Tablets for Oral Suspension

• Prior to use of the oral suspension, instruct caregivers (and if appropriate, patients) on proper dosing and administration of TAFINLAR tablets for oral suspension.
• Do not swallow whole, chew or crush TAFINLAR tablets for oral suspension.

Preparation and Administration

• Prepare suspension with approximately 5 mL of water for 1 to 4 tablets, and approximately 10 mL of water for 5 to 15 tablets in the provided cup.
• Gently stir the water and prescribed number of tablets with the handle of a teaspoon until the tablets are fully dissolved. It may take at least 3 minutes to fully dissolve the tablets. Once the tablets for oral suspension are dissolved, the suspension will be cloudy white.
• Administer suspension immediately after preparation from cup, oral dosing syringe or feeding tube.
• Discard suspension if not administered within 30 minutes after preparation.

Dose reductions for adverse reactions associated with TAFINLAR are presented in Tables 3 and 4.

Table 3. Recommended Dosage Reductions for TAFINLAR Capsules for Adverse Reactions

Recommended Dosage	75 mg orally twice daily	100 mg orally twice daily	150 mg orally twice daily
First dose reduction	50 mg orally twice daily	75 mg orally twice daily	100 mg orally twice daily
Second dose reduction	N/A	50 mg orally twice daily	75 mg orally twice daily
Third dose reduction	N/A	N/A	50 mg orally twice daily
Subsequent modification	Permanently discontinue if unable to tolerate TAFINLAR capsules 50 mg orally twice daily.

Table 4. Recommended Dosage Reductions for TAFINLAR Tablets for Oral Suspension for Adverse Reactions

Body Weight (Recommended dosage)	First Dose Reduction	Second Dose Reduction	Third Dose Reduction
	Tablets for oral suspension twice daily
8 to 9 kg (20 mg twice daily)	10 mg twice daily	N/A	N/A
10 to 13 kg (30 mg twice daily)	20 mg twice daily	10 mg twice daily	N/A
14 to 17 kg (40 mg twice daily)	30 mg twice daily	20 mg twice daily	10 mg twice daily
18 to 21 kg (50 mg twice daily)	30 mg twice daily	20 mg twice daily	10 mg twice daily
22 to 25 kg (60 mg twice daily)	40 mg twice daily	30 mg twice daily	20 mg twice daily
26 to 29 kg (70 mg twice daily)	50 mg twice daily	40 mg twice daily	20 mg twice daily
30 to 33 kg (80 mg twice daily)	50 mg twice daily	40 mg twice daily	30 mg twice daily
34 to 37 kg (90 mg twice daily)	60 mg twice daily	50 mg twice daily	30 mg twice daily
38 to 41 kg (100 mg twice daily)	70 mg twice daily	50 mg twice daily	30 mg twice daily
42 to 45 kg (110 mg twice daily)	70 mg twice daily	60 mg twice daily	40 mg twice daily
46 to 50 kg (130 mg twice daily)	90 mg twice daily	70 mg twice daily	40 mg twice daily
≥ 51 kg (150 mg twice daily)	100 mg twice daily	80 mg twice daily	50 mg twice daily

Dosage modifications for adverse reactions associated with TAFINLAR are presented in Table 5.

Table 5. Recommended Dosage Modifications for TAFINLAR for Adverse Reactions

a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b See Tables 3 and 4 for recommended dose reductions of TAFINLAR. c Dose modifications are not recommended for TAFINLAR when administered with trametinib for the following adverse reactions of trametinib: retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), interstitial lung disease/pneumonitis, and uncomplicated venous thromboembolism. Dose modification of TAFINLAR is not required for new primary cutaneous malignancies.
Severity of Adverse Reactiona	Dosage Modification for TAFINLAR b
New Primary Malignancies [see Warnings and Precautions (5.1)]
Non-Cutaneous RAS Mutation-positive Malignancies	Permanently discontinue TAFINLAR.
Cardiomyopathy [see Warnings and Precautions (5.4)]
Symptomatic congestive heart failure Absolute decrease in left ventricular ejection fraction (LVEF) of greater than 20% from baseline that is below lower limit of normal (LLN)	Withhold TAFINLAR until LVEF improves to at least the institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, then resume at same dose.
Uveitis [see Warnings and Precautions (5.5)]
Uveitis, including iritis and iridocyclitis	For mild or moderate uveitis does not respond to ocular therapy, or for severe uveitis, withhold TAFINLAR for up to 6 weeks. If improved to Grade 0-1, then resume TAFINLAR at same or lower dose. If not improved, permanently discontinue TAFINLAR.
Febrile Reactions [see Warnings and Precautions (5.6)]
Fever of 100.4°F to 104°F (or first symptoms in case of recurrence)	Withhold TAFINLAR until fever resolves, then resume TAFINLAR at same or lower dose.
Fever higher than 104°F Fever complicated by rigors, hypotension, dehydration, or renal failure	Withhold TAFINLAR until febrile reactions resolve for at least 24 hours, then resume TAFINLAR at lower dose. Or Permanently discontinue TAFINLAR.
Skin Toxicities [see Warnings and Precautions (5.7)]
Intolerable Grade 2 Grade 3 or 4	Withhold TAFINLAR for up to 3 weeks. If improved, resume TAFINLAR at lower dose. If not improved, permanently discontinue TAFINLAR.
Severe cutaneous adverse reactions (SCARs)	Permanently discontinue TAFINLAR.
Other Adverse Reactionsc, including Hemorrhage [see Warnings and Precautions (5.3)]
Intolerable Grade 2 Any Grade 3	Withhold TAFINLAR. If improved to Grade 0-1, resume TAFINLAR at lower dose. If not improved, permanently discontinue TAFINLAR.
First occurrence of any Grade 4	Withhold TAFINLAR until improves to Grade 0-1, then resume at lower dose. Or Permanently discontinue TAFINLAR.
Recurrent Grade 4	Permanently discontinue TAFINLAR.

Refer to the trametinib prescribing information for dose modifications for adverse reactions associated with trametinib.

Cutaneous Malignancies

TAFINLAR Monotherapy (Adult): In the pooled safety population [see Adverse Reactions (6.1)], cutaneous squamous cell carcinomas (cuSCC), and keratoacanthomas occurred in 11% and 4% of patients, respectively. Basal cell carcinoma and new primary melanoma occurred in 4% and 1% of patients, respectively.

TAFINLAR Administered with Trametinib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], the incidence of cuSCC (including keratoacanthomas) occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and < 1% of patients, respectively.

TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, new primary melanoma occurred in < 1% of patients.

Perform dermatologic evaluations prior to initiation of TAFINLAR, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR.

Non-Cutaneous Malignancies

Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)].

In the pooled adult safety populations of TAFINLAR monotherapy and TAFINLAR administered with trametinib [see Adverse Reactions (6.1)], non-cutaneous malignancies occurred in 1% of patients.

Monitor patients receiving TAFINLAR for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies [see Dosage and Administration (2.4)].

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 status prior to initiation of TAFINLAR as a single agent or in combination with trametinib [see Indications and Usage (1.6), Dosage and Administration (2.1)].

Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is administered with trametinib. Fatal cases have been reported.

TAFINLAR Administered with Trametinib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], hemorrhagic events occurred in 17% of patients; gastrointestinal hemorrhage occurred in 3% of patients; intracranial hemorrhage occurred in 0.6% of patients; fatal hemorrhage occurred in 0.5% of patients. The fatal events were cerebral hemorrhage and brainstem hemorrhage.

TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, hemorrhagic events occurred in 25% of patients; the most common type of bleeding was epistaxis (16%). Serious events of bleeding occurred in 3.6% of patients and included gastrointestinal hemorrhage (1.2%), cerebral hemorrhage (0.6%) uterine hemorrhage (0.6%), post-procedural hemorrhage (0.6%), and epistaxis (0.6%).

Permanently discontinue TAFINLAR for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved, resume at the next lower dose level.

TAFINLAR Administered with Trametinib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥ 10% from baseline and below the institutional lower limit of normal (LLN), occurred in 6% of patients. Development of cardiomyopathy resulted in dose interruption or discontinuation of TAFINLAR in 3% and < 1% of patients, respectively. Cardiomyopathy resolved in 45 of 50 patients who received TAFINLAR administered with trametinib.

TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, cardiomyopathy, defined as a decrease in LVEF ≥ 10% from baseline and below the institutional LLN, occurred in 9% of patients.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with trametinib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold TAFINLAR for symptomatic cardiomyopathy or asymptomatic LV dysfunction of > 20% from baseline that is below institutional LLN. Resume TAFINLAR at the same dose level upon recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease ≤ 10% compared to baseline [see Dosage and Administration (2.4)].

TAFINLAR Monotherapy (Adult): In the pooled safety population [see Adverse Reactions (6.1)], uveitis occurred in 1% of patients.

TAFINLAR Administered with Trametinib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], uveitis occurred in 2% of patients.

TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, uveitis occurred in 1.2% of patients.

Treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If iritis is diagnosed, administer ocular therapy and continue TAFINLAR without dose modification. If severe uveitis (i.e., iridocyclitis) or if mild or moderate uveitis does not respond to ocular therapy, withhold TAFINLAR and treat as clinically indicated. Resume TAFINLAR at the same or lower dose if improves to Grade 0 or 1. Permanently discontinue TAFINLAR for persistent Grade 2 or greater uveitis of > 6 weeks [see Dosage and Administration (2.4)].

Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur with TAFINLAR.

The incidence and severity of pyrexia are increased when TAFINLAR is administered with trametinib compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].

TAFINLAR Monotherapy (Adult): In the pooled safety population [see Adverse Reactions (6.1)], fever (serious and non-serious) occurred in 30% of patients. Approximately 13% of these patients experienced 3 or more discrete episodes. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 6% of patients.

TAFINLAR Administered with Trametinib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration or renal failure occurred in 5% of patients. Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in < 1% of patients.

TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population [see Adverse Reactions (6.1)], pyrexia occurred in 66% of patients.

Withhold TAFINLAR when used as monotherapy, and both TAFINLAR and trametinib when used in combination, if the patient’s temperature is ≥ 100.4°F. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia [see Adverse Reactions (6.1)]. Fever may be complicated by hypotension, rigors or chills, dehydration, or renal failure. Evaluate for signs and symptoms of infection and monitor serum creatinine and other evidence of renal function during and following severe pyrexia. If appropriate, TAFINLAR, or both TAFINLAR and trametinib when used in combination, may be restarted if the patient has recovered from the febrile reaction for at least 24 hours, either at the same or lower dose [see Dosage and Administration (2.4)]. Administer antipyretics as secondary prophylaxis when resuming TAFINLAR if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., prednisone 10 mg daily) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia, or for pyrexia associated with complications, such as dehydration, hypotension, renal failure, or severe chills/rigors, and there is no evidence of active infection.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with TAFINLAR administered with trametinib [see Adverse Reactions (6.2)].

TAFINLAR Administered with Trametinib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], other serious skin toxicity occurred in < 1% of patients.

TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, serious adverse events of skin and subcutaneous tissue disorders occurred in 1.8% of patients.

Monitor for new or worsening serious skin reactions. Permanently discontinue TAFINLAR for SCARs [see Dosage and Administration (2.4)]. For other skin toxicities, withhold TAFINLAR for intolerable or severe skin toxicity. Resume TAFINLAR at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue TAFINLAR if skin toxicity has not improved within 3 weeks [see Dosage and Administration (2.4)].

TAFINLAR Monotherapy (Adult): In the pooled safety population [see Adverse Reactions (6.1)], 14% of patients with a history of diabetes that received TAFINLAR required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia occurred in 3% of patients.

TAFINLAR Administered with Trametinib (Adult): In the pooled safety population [see Adverse Reactions (6.1)], 15% of patients with a history of diabetes who had received TAFINLAR with trametinib required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia occurred in 2% of patients.

TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, Grade 3 and Grade 4 hyperglycemia events occurred in < 1% of patients.

Monitor serum glucose levels upon initiation and as clinically appropriate when TAFINLAR is administered in patients with preexisting diabetes or hyperglycemia. Initiate or optimize anti-hyperglycemic medications as clinically indicated.

TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Monitor patients with G6PD deficiency for signs of hemolytic anemia while taking TAFINLAR.

TAFINLAR is indicated for use in combination with trametinib. Review the prescribing information for trametinib for information on the serious risks of trametinib prior to initiation of TAFINLAR with trametinib.

Hemophagocytic lymphohistiocytosis (HLH) has been observed in the post-marketing setting when TAFINLAR was administered with trametinib. If HLH is suspected, interrupt treatment. If HLH is confirmed, discontinue treatment and initiate appropriate management of HLH.

Based on findings from animal studies and its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended adult clinical dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective non-hormonal contraception, since TAFINLAR can render hormonal contraceptives ineffective, during treatment with TAFINLAR and for 2 weeks after the last dose [see Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3)].

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 TAFINLAR monotherapy pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to TAFINLAR 150 mg orally, taken 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 for TAFINLAR administered with trametinib (Adult) 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 METRIC, MEK113583, MEK111504, 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) [see Clinical Studies (14.6, 14.7)]. 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 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/m² intravenously every 3 weeks (n = 63) [see Clinical Studies (14.1)]. 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
Papillomac	27	0	2	0
cuSCCd	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 [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4)]^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	6b	14	2
Increased alkaline phosphatase	19	0	14	2
Hyponatremia	8	2	3	0

Other clinically important adverse reactions observed in less than 10% of patients (N = 586) treated with TAFINLAR were:

Gastrointestinal: Pancreatitis

Immune System: Hypersensitivity manifesting as bullous rash

Renal and Urinary: Interstitial nephritis

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 [see Clinical Studies (14.2)].

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 0 and 28% had ECOG performance status 1, 64% had M1c stage 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 [see Clinical Studies (14.2)]. 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 folliculitis.
	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	1.9
Chills	31	0.5	31	0	17	0.5
Skin and subcutaneous tissue
Rashc	32	1.1	42	0	27	1.4
Dry skin	10	0	12	0	16	0
Nervous system
Headache	30	0.9	33	0.5	30	1.4
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:

Gastrointestinal: Colitis, gastrointestinal perforation, pancreatitis

Immunologic: Sarcoidosis

Skin and subcutaneous tissue: Panniculitis

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	4.3
Hypophosphatemia	38	6	38	3.8	35	7
Hyponatremia	25	8	24	6	14	2.9
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 [see Clinical Studies (14.3)]. 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 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
Pyrexiab	63	5	11	< 1
Fatiguec	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
Headached	39	1	24	0
Skin and subcutaneous tissue
Rashe	37	< 1	16	< 1
Musculoskeletal and connective tissue
Arthralgia	28	< 1	14	0
Myalgiaf	20	< 1	14	0

Other clinically important adverse reactions observed in less than 20% of patients in the COMBI-AD study who received TAFINLAR administered with trametinib were: blurred vision (6%), ejection fraction decreased (5%), rhabdomyolysis (< 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 Trametiniba N = 435		Placeboa 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 [see Clinical Studies (14.4)].

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 0 and 61% had ECOG performance status 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
Fatigueb	51	5
Edemac	28	0
Chills	23	1.1
Gastrointestinal
Nausea	45	0
Vomiting	33	3.2
Diarrhea	32	2.2
Decreased appetite	29	0
Skin and subcutaneous tissue
Dry skin	31	1.1
Rashd	28	3.2
Vascular
Hemorrhagee	23	3.2
Respiratory system
Cough	22	0
Dyspnea	20	5

Other clinically important adverse reactions for TAFINLAR observed in less than 10% of patients with NSCLC receiving TAFINLAR administered with trametinib were:

Gastrointestinal: Pancreatitis

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	1.1
Hepatic a
Increased blood alkaline phosphatase	64	0
Increased AST	61	4.4
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 [see Clinical Studies (14.5, 14.6)]. 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 0 and 60% had ECOG performance status 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

aNCI CTCAE version 4.0. bIncludes fatigue, asthenia, and malaise. cIncludes peripheral edema and peripheral swelling. dIncludes rash, rash maculo-papular, rash erythematous, rash pustular, and rash papular. eIncludes 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. fIncludes cough and productive cough. gIncludes myalgia, musculoskeletal chest pain, and musculoskeletal pain.
Adverse Reactions	TAFINLAR plus Trametiniba (N = 206)
	All Grades (%)	Grade 3 or 4 (%)
General
Pyrexia	55	4.9
Fatigueb	50	5
Chills	30	0.5
Peripheral edemac	22	0
Gastrointestinal
Nausea	40	1.5
Constipation	27	0
Vomiting	27	1.5
Diarrhea	26	2.9
Skin and subcutaneous tissue
Rashd	40	2.4
Nervous system
Headache	30	1.5
Vascular
Hemorrhagee	29	4.4
Respiratory system
Coughf	29	0
Musculoskeletal and connective tissue
Myalgiag	24	0.5
Arthralgia	23	0.5

Clinically relevant adverse reactions in < 20% of adult patients who received TAFINLAR in combination with trametinib included ejection fraction decreased (8%), uveitis (1.9%) and hypersensitivity (1.9%).

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 Trametiniba
	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Hyperglycemia	61	8
Decreased sodium	35	10
Decreased magnesium	24	0
Increased creatinine	21	1.5
Hepatic
Increased alkaline phosphatase	51	5
Increased AST	51	4.6
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 [see Clinical Studies (14.6)]. 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 ejection fraction decreased (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 ALT increased (6%), AST increased (4.2%) and ejection fraction decreased (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%), ejection fraction decreased (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 Trametiniba (N = 48)
	All Grades (%)	Grade 3 or 4 (%)
General
Pyrexia	75	17
Fatigueb	48	0
Skin and subcutaneous tissue
Rashc	73	2.1
Dry skin	48	0
Dermatitis acneiformd	40	0
Gastrointestinal
Vomiting	52	4.2
Diarrhea	42	2.1
Abdominal paine	33	4.2
Nausea	33	2.1
Constipation	23	0
Respiratory system
Cough	44	0
Nervous system
Headache	35	0
Vascular
Hemorrhagef	33	0
Infections and infestations
Paronychia	23	0

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. aThe 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 Trametiniba
	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Hyperglycemia	65	2.2
Hypoalbuminemia	48	2.1
Hypocalcemia	40	2.1
Decreased phosphate	38	0
Decreased magnesium	33	2.1
Hypernatremia	27	0
Hypokalemia	21	2.1
Hepatic
Increased AST	55	4.2
Increased ALT	40	6
Increased alkaline phosphatase	28	6
Increased total bilirubin	21	2.1
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/m² and 1.5 mg/m², 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
Diarrheab	29	0	18	6
Nausea	25	0	45	0
Abdominal painc	25	0	24	0
Constipation	12	0	36	0
Stomatitisd	10	0	18	0
General
Pyrexiae	68	8	18	3
Fatiguef	33	0	39	0
Nervous system
Headacheg	47	1	33	3
Dizzinessh	15	0	9	3
Peripheral neuropathyi	7	0	45	6
Vascular
Hemorrhagej	25	0	12	0
Skin and subcutaneous tissue
Rashk	51	2.7	18	3
Dry skin	26	0	3	0
Dermatitis acneiforml	22	0	0	0
Alopecia	3	0	24	0
Musculoskeletal and connective tissue
Musculoskeletal painm	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	3.1
Decreased lymphocytes	16	1.4	56	6

The following adverse reactions have been identified during postapproval 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.

Dermatologic: SCAR (including DRESS and SJS) [see Warnings and Precautions (5.7)]

Immune System: Hemophagocytic lymphohistiocytosis (HLH) [see Warnings and Precautions (5.11)]

Strong inhibitors of CYP3A4 or CYP2C8 may increase the concentration of dabrafenib [see Clinical Pharmacology (12.3)]. 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.

Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. 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 [see Use in Specific Populations (8.1, 8. 3 )]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

Risk Summary

Based on findings from animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)], 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 [approximately three times the human exposure at the recommended adult dose based on area under the curve (AUC)]. 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.

Risk Summary

There are no data on the presence of dabrafenib in human milk, or the effects of dabrafenib on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with TAFINLAR and for 2 weeks following the last dose.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating TAFINLAR.

Contraception

Based on data from animal studies and its mechanism of action, TAFINLAR can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1 )].

Females

Advise female patients of reproductive potential to use effective contraception during treatment with TAFINLAR and for 2 weeks after the last dose. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective [see Drug Interactions (7.2)].

Males

To avoid potential drug exposure to pregnant partners and female partners of reproductive potential, advise male patients (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with TAFINLAR and for 2 weeks after the last dose.

Infertility

Females

Advise female patients of reproductive potential that TAFINLAR may impair fertility. A reduction in fertility was observed in female rats at dose exposures equivalent to the human exposure at the recommended adult dose. A reduction in the number of corpora lutea was noted in pregnant rats at dose exposures approximately three times the human exposure at the recommended adult dose [see Nonclinical Toxicology (13.1)].

Males

Advise male patients of the potential risk for impaired spermatogenesis which may be irreversible. Effects on spermatogenesis have been observed in animals treated with dabrafenib at dose exposures up to three times the human exposure at the recommended adult dose [see Nonclinical Toxicology (13.1)].

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) 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 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6, 14.7)].

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.

Of the 586 patients with various solid tumors who received single agent TAFINLAR, 22% were aged 65 years and older. Of the 187 patients with melanoma who received single-agent TAFINLAR in the BREAK-3 study, 21% were aged 65 years or older [see Clinical Studies (14.1)]. No overall differences in the effectiveness or safety of TAFINLAR were observed between geriatric patients as compared to younger adults in the BREAK-3 study.

Of the 994 patients with melanoma who received TAFINLAR plus trametinib in the COMBI-d, COMBI-v, and COMBI-AD studies [see Clinical Studies (14.2, 14.3)], 21% were aged 65 years and older and 5% were aged 75 years and older. No overall differences in the effectiveness of TAFINLAR plus trametinib were observed in geriatric patients as compared to younger adults across these melanoma studies. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) were increased in geriatric patients as compared to younger adults in these studies.

Of the 171 patients with NSCLC who received TAFINLAR in Study BRF113928, there were insufficient numbers of geriatric patients to determine whether they respond differently from younger adults [see Clinical Studies (14.4)].

Of the 26 patients with ATC who received TAFINLAR in Study BRF117019, 77% were aged 65 years and older, and 31% were aged 75 years and older [see Clinical Studies (14.5)]. This study in ATC did not include sufficient numbers of younger adults to determine whether they respond differently compared to geriatric patients.

Dose adjustment is not recommended for patients with mild (bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or bilirubin > 1x to 1.5x ULN and any AST) hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate (bilirubin > 1.5x to 3x ULN and any AST) to severe (bilirubin > 3x to 10x ULN and any AST) hepatic impairment may have increased exposure. An appropriate dosage has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].

Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC₅₀ values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC₅₀ values of 3.2 and 5.0 nM, respectively, and other kinases, such as SIK1, NEK11, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth [see Indications and Usage (1)]. Dabrafenib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.

Dabrafenib and trametinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of dabrafenib and trametinib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation-positive tumor xenografts compared with either drug alone.

In the setting of BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors [see Indications and Usage (1.8)].

Cardiac Electrophysiology

The potential effect of TAFINLAR on QT interval was assessed in a dedicated multiple-dose study in 32 patients with BRAF V600 mutation-positive tumors. No large changes in the mean QT interval (i.e., > 20 ms) were detected with dabrafenib 300 mg administered twice daily (two times the recommended dosage).

In clinical trials, QTc (heart rate-corrected QT) prolongation to ≥ 500 ms occurred in 0.8% of 264 patients who received TAFINLAR with trametinib and in 1.5% of patients who received TAFINLAR as a single agent. The QTc was increased > 60 ms from baseline in 3.8% of patients who received TAFINLAR with trametinib and 3% of patients treated with TAFINLAR as a single agent.

Following administration of TAFINLAR capsules, dabrafenib C_max and AUC increased in a dose-proportional manner across the dose range of 12 mg (0.08 times the approved recommended adult dose) to 300 mg (2 times the approved recommended adult dose), but the increase was less than dose-proportional after steady state twice-daily dosing. After twice-daily dosing, the mean accumulation ratio was 0.7, and the inter-subject variability (CV%) of AUC at steady-state was 38%.

Absorption

The median time to achieve peak plasma concentration (T_max) is 2 hours. Mean absolute bioavailability of TAFINLAR capsules is 95% and TAFINLAR tablets for oral suspension is 76%.

Effect of Food

Following administration of TAFINLAR capsules, a high-fat meal (approximately 1000 calories, 58-75 grams fat, 58 grams carbohydrates, and 33 grams protein) decreased C_max by 51%, decreased AUC by 31%, and delayed median T_max by 3.6 hours as compared with the fasted state.

Distribution

Dabrafenib is 99.7% bound to human plasma proteins. The apparent volume of distribution (V_c/F) is 70.3 L.

Elimination

The mean terminal half-life is 8 hours. Hydroxy-dabrafenib terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl-dabrafenib metabolites exhibit longer half-lives (21 to 22 hours). The apparent clearance of dabrafenib is 17 L/h after a single dose and 34 L/h after twice-daily dosing for 2 weeks.

Metabolism

The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites. Mean metabolite-to-parent AUC ratios following repeat-dose administration are 0.9, 11, and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on systemic exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib.

Excretion

Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only.

Specific Populations

Age (18 to 93 years), sex, weight (36 to 170 kg), and renal impairment (eGFR 15 to 89 mL/min/1.73 m²) have no clinically relevant effect on the pharmacokinetics of dabrafenib.

Pediatric Patients

The pharmacokinetics of dabrafenib in glioma and other solid tumors were evaluated in 243 patients aged 1 to < 18 years following a single dose or multiple doses. Pharmacokinetic parameters in patients aged 1 to < 18 years are within range of values previously observed in adults give the same dose based on weight. Weight (6 to 156 kg) had a statistically significant effect on dabrafenib oral clearance in this population.

Patients with Hepatic Impairment

Mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1x to 1.5x ULN and any AST) has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with moderate (bilirubin > 1.5x to 3x ULN and any AST) or severe (bilirubin > 3x to 10x ULN and any AST) hepatic impairment.

Drug Interaction Studies

Effect of Trametinib on Dabrafenib: Coadministration of TAFINLAR 75 mg twice daily with trametinib 2 mg daily resulted in a 23% increase in AUC of dabrafenib, a 33% increase in AUC of desmethyl-dabrafenib, and no change in AUC of hydroxy-dabrafenib as compared with administration of dabrafenib.

Effect of Strong Inhibitors of CYP3A4 or CYP2C8 on Dabrafenib: Coadministration of TAFINLAR 75 mg twice daily and ketoconazole (a strong CYP3A4 inhibitor) for 4 days increased dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%.

Coadministration of TAFINLAR 75 mg twice daily and gemfibrozil (a strong CYP2C8 inhibitor) for 4 days increased dabrafenib AUC by 47%, with no change in the AUC of dabrafenib metabolites.

Effect of Strong Inducers of CYP3A4 or Moderate Inducers of CYP2C8 on Dabrafenib:  Coadministration of TAFINLAR 150 mg twice daily and rifampin (a strong CYP3A4 and moderate CYP2C8 inducer) for 10 days decreased dabrafenib AUC by 34% and desmethyl-dabrafenib AUC by 30%, and had no effect on hydroxy-dabrafenib AUC.

Effect of Acid Reducing Agents on Dabrafenib: Coadministration of TAFINLAR 150 mg twice daily and rabeprazole for 4 days did not result in clinically relevant changes in exposures to dabrafenib and its metabolites.

Effect of Dabrafenib on CYP Substrates: Coadministration of TAFINLAR 150 mg twice daily for 15 days and a single dose of midazolam (a CYP3A4 substrate) decreased midazolam AUC by 65%. Coadministration of TAFINLAR 150 mg twice daily for 15 days and a single dose of warfarin decreased the AUC of S-warfarin (a CYP2C9 substrate) by 37% and the AUC of R-warfarin (CYP3A4/CYP1A2 substrate) by 33%.

In vitro data demonstrate that dabrafenib is an inducer of CYP3A4 and CYP2B6 via activation of the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) nuclear receptors. Dabrafenib may also induce CYP2C enzymes via the same mechanism.

Effect of Transporters on Dabrafenib: Dabrafenib and its metabolites, hydroxyl-dabrafenib and desmethyl-dabrafenib, are substrates of human P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) but are not substrates of organic cation transporter (OCT1) or organic anion transporting polypeptide (OATP1A2, OATP1B1, OATP1B3, OATP2B1) in vitro.

Effect of Dabrafenib on Transporters: Coadministration of TAFINLAR 150 mg twice daily with a single dose of rosuvastatin (a sensitive OATP1B1 and OATP1B3 substrate) increased rosuvastatin C_max by 2.6-fold but did not change its AUC.

Dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl-dabrafenib, are inhibitors of organic anion transporter (OAT1 and OAT3) in vitro. Dabrafenib and desmethyl-dabrafenib are inhibitors of OCT2 and BCRP in vitro.

Carcinogenicity studies with dabrafenib have not been conducted. TAFINLAR increased the risk of cuSCCs in patients in clinical trials.

Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay and was not clastogenic in an in vivo rat bone marrow micronucleus test.

In a combined female fertility and embryo-fetal development study in rats, a reduction in fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human exposure at the recommended adult dose based on AUC). A reduction in the number of ovarian corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately three times the human exposure at the recommended adult dose based on AUC).

Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to and three times the human exposure at the recommended adult dose based on AUC, respectively.

Adverse cardiovascular effects were noted in dogs at dabrafenib doses of 50 mg/kg/day (approximately five times the human exposure at the recommended adult dose based on AUC) or greater, when administered for up to 4 weeks. Adverse effects consisted of coronary arterial degeneration/necrosis and hemorrhage, as well as cardiac atrioventricular valve hypertrophy/hemorrhage.

BREAK-3 Study

The safety and efficacy of TAFINLAR as a single agent were evaluated in an international, multi-center, randomized (3:1), open-label, active-controlled trial (the BREAK-3 study; NCT01227889) conducted in 250 patients with previously untreated BRAF V600E mutation-positive, unresectable or metastatic melanoma. Patients with any prior use of BRAF inhibitors or MEK inhibitors were excluded. Patients were randomized to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1000 mg/m² intravenously every 3 weeks (n = 63). Randomization was stratified by disease stage at baseline [unresectable Stage III (regional nodal or in-transit metastases), M1a (distant skin, subcutaneous, or nodal metastases), or M1b (lung metastases) versus M1c melanoma (all other visceral metastases or elevated serum LDH)]. The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. In addition, an independent radiology review committee (IRRC) assessed the following efficacy outcome measures in pre-specified supportive analyses: PFS, confirmed overall response rate (ORR), and duration of response (DoR).

The median age of patients in the BREAK-3 study was 52 years. The majority of the trial population was male (60%), White (99%), had an ECOG performance status of 0 (67%), M1c disease (66%), and normal LDH (62%). All patients had tumor tissue with mutations in BRAF V600E as determined by a clinical trial assay at a centralized testing site. Tumor samples from 243 patients (97%) were tested retrospectively, using an FDA-approved companion diagnostic test, THxID™-BRAF assay.

The median durations of follow-up prior to initiation of alternative treatment in patients randomized to receive TAFINLAR was 5.1 months and in the dacarbazine arm was 3.5 months. Twenty-eight (44%) patients crossed over from the dacarbazine arm at the time of disease progression to receive TAFINLAR.

The BREAK-3 study demonstrated a statistically significant increase in progression-free survival in the patients treated with TAFINLAR. Table 20 and Figure 1 summarize the PFS results.

Table 20. Investigator-Assessed Progression-Free Survival and Confirmed Overall Response Results in the BREAK-3 Study

Abbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached. a Pike estimator, stratified by disease state. b Stratified log-rank test.
Investigator-Assessed Endpoints	TAFINLAR N  =   187	Dacarbazine N  =   63
Progression- F ree Survival
Number of events (%)	78 (42%)	41 (65%)
Progressive disease	76	41
Death	2	0
Median, months (95% CI)	5.1 (4.9, 6.9)	2.7 (1.5, 3.2)
HRa (95% CI)	0.33 (0.20, 0.54)
P valueb	< 0.0001
Confirmed Tumor Responses
Overall response rate (95% CI)	52% (44%, 59%)	17% (9%, 29%)
Complete response, n (%)	6 (3%)	0
Partial response, n (%)	91 (48%)	11 (17%)
Duration of response
Median DoR, months (95% CI)	5.6 (5.4, NR)	NR (5.0, NR)

In supportive analyses based on IRRC assessment and in an exploratory subgroup analysis of patients with retrospectively confirmed V600E mutation-positive melanoma with the THxID™-BRAF assay, the PFS results were consistent with those of the primary efficacy analysis.

BREAK-MB Study

The activity of TAFINLAR for the treatment of BRAF V600E mutation-positive melanoma, metastatic to the brain was evaluated in a single-arm, open-label, two-cohort multi-center trial (the BREAK-MB study; NCT01266967). All patients received TAFINLAR 150 mg twice daily. Patients in Cohort A (n = 74) had received no prior local therapy for brain metastases, while patients in Cohort B (n = 65) had received at least one local therapy for brain metastases, including, but not limited to, surgical resection, whole brain radiotherapy, or stereotactic radiosurgery, such as gamma knife, linear-accelerated-based radiosurgery, or charged particles. In addition, patients in Cohort B were required to have evidence of disease progression in a previously treated lesion or an untreated lesion. Additional eligibility criteria were at least one measurable lesion of 0.5 cm or greater in largest diameter on contrast-enhanced MRI, stable or decreasing corticosteroid dose, and no more than two prior systemic regimens for treatment of metastatic disease. The major efficacy outcome measure was estimation of the overall intracranial response rate (OIRR) in each cohort.

The median age of patients in Cohort A was 50 years, 72% were male, 100% were White, 59% had a pre-treatment ECOG performance status of 0, and 57% had an elevated LDH value at baseline. The median age of patients in Cohort B was 51 years, 63% were male, 98% were White, 66% had a pre-treatment ECOG performance status of 0, and 54% had an elevated LDH value at baseline. The intracranial response rate as determined by an independent radiology review committee, masked to investigator response assessments, was 18% (95% CI: 10%, 28%) in Cohort A and 18% (95% CI: 10%, 30%) in Cohort B. The median duration of intracranial response was 4.6 months in both cohorts.

COMBI-d Study and COMBI-v Study

The safety and efficacy of TAFINLAR administered with trametinib were evaluated in two international, randomized, active-controlled trials: one double-blind trial (the COMBI-d study; NCT01584648) and one open-label trial (the COMBI-v study; NCT01597908). 

The COMBI-d study compared TAFINLAR and trametinib to TAFINLAR and placebo as first-line therapy for patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive TAFINLAR 150 mg twice daily and trametinib 2 mg once daily or TAFINLAR 150 mg twice daily plus matching placebo. Randomization was stratified by LDH level (> ULN vs. ≤ ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR).

The COMBI-v study compared TAFINLAR and trametinib to vemurafenib as first-line treatment therapy for patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Patients were randomized (1:1) to receive TAFINLAR 150 mg twice daily and trametinib 2 mg once daily or vemurafenib 960 mg twice daily. Randomization was stratified by lactate dehydrogenase (LDH) level (> ULN vs. ≤ ULN) and BRAF mutation subtype (V600E vs. V600K). The major efficacy outcome measure was overall survival. Additional efficacy outcome measures were PFS and ORR as assessed by investigator per RECIST v1.1.

In the COMBI-d study, 423 patients were randomized to TAFINLAR plus trametinib (n = 211) or TAFINLAR plus placebo (n = 212). The median age was 56 years (range: 22 to 89), 53% were male, > 99% were White, 72% had ECOG performance status of 0, 4% had Stage IIIC, 66% had M1c disease, 65% had a normal LDH, and 2 patients had a history of brain metastases. All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing with the FDA-approved companion diagnostic test; 85% with BRAF V600E mutations and 15% with BRAF V600K mutations.

In the COMBI-v study, 704 patients were randomized to TAFINLAR plus trametinib (n = 352) or single-agent vemurafenib (n = 352). The median age was 55 years (range: 18 to 91), 96% were White, and 55% were male, 6% percent of patients had Stage IIIC, 61% had M1c disease, 67% had a normal LDH, 70% had ECOG performance status of 0, 89% had BRAF V600E mutation-positive melanoma, and one patient had a history of brain metastases.

The COMBI-d and COMBI-v studies demonstrated statistically significant improvements in OS and PFS. Table 21 and Figures 2 and 3 summarize the efficacy results.

Table 21. Efficacy Results in Patients with BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma^a

Abbreviations: DoR, duration of response; ORR, overall response rate; CI, confidence interval; HR, hazard ratio; NR, not reached. a P-value is comparing with the allocated alpha of 0.021 for the interim analysis based on 77% information. b PFS and ORR were assessed by investigator.
Endpoint	COMBI-d Study		COMBI-v Study
	TAFINLAR plus Trametinib N   =   211	TAFINLAR plus Placebo N   =   212	TAFINLAR plus Trametinib N   =   352	Vemurafenib N   =   352
Overall Survival
Number of deaths (%)	99 (47%)	123 (58%)