WO2014193589A1

WO2014193589A1 - Cancer treatment method

Info

Publication number: WO2014193589A1
Application number: PCT/US2014/035991
Authority: WO
Inventors: Roya Behbahani; Robin L. CARSON; Mark J. CORNFELD; Christine E. DABROWSKI; Tona M. Gilmer; Vicki L. GOODMAN; Mary E. GUCKERT; Angela HUGHES-EARLE; Stephen R. LANE; Jeffrey J. Legos; Anne-Marie MARTIN; Daniele OUELLET; Kiran A. PATEL; Eric M. RICHARDS; Lauren E. RICHARDS-PETERSON; Sharon RUDO; Peng Sun; R. Suzanne SWANN
Original assignee: Glaxosmithkline Llc
Priority date: 2013-05-29
Filing date: 2014-04-30
Publication date: 2014-12-04

Abstract

Invented are methods for treating cancer in a human in need thereof which comprises the administration of a therapeutically effective amount of a combination of: N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, or a salt or solvate thereof; and N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide or a salt or solvate thereof, to such human. Also invented are methods of treating cancer in a human in need thereof which comprises the administration of a therapeutically effective amount of a combination of: N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethyl sulfoxide and N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate, to such human.

Description

CANCER TREATMENT METHOD

FIELD OF THE INVENTION

This invention relates to a method of treating cancer in a human by the in vivo administration of: N- {3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin- 1 -yljphenyl} acetamide dimethyl sulfoxide solvate, represented r referred to as Compound A:

(Compound A);

in combination with: N- {3-[5-(2-Amino-4-pyrimidinyl)-2-(l,l-dimethylethyl)-l,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate, represented by the following formula (II) and hereinafter referred to as Compound C:

(Compound C).

BACKGROUND OF THE INVENTION

Effective treatment of hyperproliferative disorders including cancer is a continuing goal in the oncology field. Generally, cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death. Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer. One of the most commonly studied pathways, which involves kinase regulation of apoptosis, is cellular signaling from growth factor receptors at the cell surface to the nucleus (Crews and Erikson, Cell, 74:215-17, 1993).

Mitogen-activated protein (MAP) Kinase/extracellular signal-regulated kinase (ERK) kinase (hereinafter referred to as MEK) is known to be involved in the regulation of numerous cellular processes. The Raf family (B-Raf, C-Raf etc.) activates the MEK family (MEK- 1 , MEK-2 etc.) and the MEK family activates the ERK family (ERK- 1 and ERK-2). Broadly, the signaling activity of the RAF/MEK/ERK pathway controls mRNA translation. This includes genes related to the cell cycle. Hence, hyperactivation of this pathway can lead to uncontrolled cell proliferation. Deregulation of the RAF/MEK/ERK pathway by ERK hyperactivation is seen in approximately 30% of all human malignancies (Allen, LF, et al. Semin. Oncol. 2003. 30(5 Suppl 16): 105-16). RAS, which can signal through both the PI3K/AKT and RAF/MEK/ERK, has a mutated oncogenic protein in 15% of all cancers (Davies, H. et al. Nature. 2002. 417:949-54). Also, activating BRAF mutations have been identified at a high frequency in specific tumor types (e.g., melanomas) (Davies, H. et al. Nature. 2002. 417:949-54). Although activating mutations in MEK itself don't appear to frequently occur in human cancers, MEK is thought to be an important drug target for treating human cancer because of its central role in the ERK pathway. Further, MEK inhibitory activity effectively induces inhibition of ERK 1/2 activity and suppression of cell proliferation (The Journal of Biological Chemistry, vol. 276, No. 4, pp. 2686-2692, 2001), and the compound is expected to show effects on diseases caused by undesirable cell proliferation, such as tumor genesis and/or cancer.

N- {3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido[4,3-d]pyrimidin- l-yl]phenyl}acetamide, as the un-solvated compound (hereinafter Compound B) is a compound which is disclosed and claimed, along with

pharmaceutically acceptable salts and solvates thereof, as being useful as an inhibitor of MEK activity, particularly in treatment of cancer, in International Application No. PCT/JP2005/01 1082, having an International filing date of June 10, 2005; International Publication Number WO 2005/121 142 and an International Publication date of December 22, 2005, the entire disclosure of which is hereby incorporated by reference. Compound B is the compound of Example 4-1.

Compound B can be prepared as described in International Application No. PCT/JP2005/01 1082. Compound B can be prepared as described in United States Patent Publication No. US

2006/0014768, Published January 19, 2006, the entire disclosure of which is hereby incorporated by reference. Compound B is the compound of Example 4-1.

Suitably, Compound B is in the form of a dimethyl sulfoxide solvate, or Compound A as defined herein. Suitably, Compound B is in the form of a solvate selected from: hydrate, acetic acid, ethanol, nitromethane, chlorobenzene, 1-pentanol, isopropyl alcohol, ethylene glycol and 3- methyl- 1 -butanol. Solvates and salt forms can be prepared by one of skill in the art, for example from the description in International Application No. PCT/JP2005/01 1082 or United States Patent Publication No. US 2006/0014768. Compound A is prepared in Example 4- 149 of United States Patent Publication No. US 2006/0014768. Mutations in various Ras GTPases and the B-Raf kinase have been identified that can lead to sustained and constitutive activation of the MAPK pathway, ultimately resulting in increased cell division and survival. As a consequence of this, these mutations have been strongly linked with the establishment, development, and progression of a wide range of human cancers. The biological role of the Raf kinases, and specifically that of B-Raf, in signal transduction is described in Davies, H., et al., Nature (2002) 9: 1-6; Garnett, M.J. & Marais, R., Cancer Cell (2004) 6:313- 319; Zebisch, A. & Troppmair, J., Cell. Mol. Life Sci. (2006) 63: 1314-1330; Midgley, R.S. & Kerr, D.J., Crit. Rev. Onc/Hematol. (2002) 44: 109-120; Smith, R.A., et al., Curr. Top. Med. Chem. (2006) 6: 1071-1089; and Downward, J., Nat. Rev. Cancer (2003) 3: 1 1-22.

Naturally occurring mutations of the B-Raf kinase that activate MAPK pathway signaling have been found in a large percentage of human melanomas (Davies (2002) supra) and thyroid cancers (Cohen et al J. Nat. Cancer Inst. (2003) 95(8) 625-627 and Kimura et al Cancer Res. (2003) 63(7) 1454-1457), as well as at lower, but still significant, frequencies in the following:

Barret's adenocarcinoma (Garnett et al., Cancer Cell (2004) 6 313-319 and Sommerer et al Oncogene (2004) 23(2) 554-558), billiary tract carcinomas (Zebisch et al., Cell. Mol. Life Sci. (2006) 63 1314-1330), breast cancer (Davies (2002) supra), cervical cancer (Moreno-Bueno et al Clin. Cancer Res. (2006) 12(12) 3865-3866), cholangiocarcinoma (Tannapfel et al Gut (2003) 52(5) 706-712), central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas and ependymomas (Knobbe et al Acta Neuropathol. (Berl.) (2004) 108(6) 467-470, Davies (2002) supra, and Garnett et al., Cancer Cell (2004) supra) and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system), colorectal cancer, including large intestinal colon carcinoma (Yuen et al Cancer Res. (2002) 62(22) 6451 -6455, Davies (2002) supra and Zebisch et al., Cell. Mol. Life Sci. (2006), gastric cancer (Lee et al Oncogene (2003) 22(44) 6942-6945), carcinoma of the head and neck including squamous cell carcinoma of the head and neck (Cohen et al J. Nat. Cancer Inst.

(2003) 95(8) 625-627 and Weber et al Oncogene (2003) 22(30) 4757-4759), hematologic cancers including leukemias (Garnett et al., Cancer Cell (2004) supra, particularly acute lymphoblastic leukemia (Garnett et al., Cancer Cell (2004) supra and Gustafsson et al Leukemia (2005) 19(2) 310-312), acute myelogenous leukemia (AML) (Lee et al Leukemia (2004) 18(1) 170- 172, and Christiansen et al Leukemia (2005) 19(12) 2232-2240), myelodysplasia syndromes (Christiansen et al Leukemia (2005) supra) and chronic myelogenous leukemia (Mizuchi et al Biochem. Biophys. Res. Commun. (2005) 326(3) 645-651); Hodgkin's lymphoma (Figl et al Arch. Dermatol. (2007) 143(4) 495-499), non-Hodgkin's lymphoma (Lee et al Br. J. Cancer (2003) 89(10) 1958-1960), megakaryoblastic leukemia (Eychene et al Oncogene (1995) 10(6) 1 159-1 165) and multiple myeloma (Ng et al Br. J. Haematol. (2003) 123(4) 637-645), hepatocellular carcinoma (Garnett et al., Cancer Cell (2004), lung cancer (Brose et al Cancer Res. (2002) 62(23) 6997-7000, Cohen et al J. Nat. Cancer Inst. (2003) supra and Davies (2002) supra), including small cell lung cancer (Pardo et al EMBO J. (2006) 25(13) 3078-3088) and non-small cell lung cancer (Davies (2002) supra), ovarian cancer (Russell & McCluggage J. Pathol. (2004) 203(2) 617-619 and Davies (2002) supr), endometrial cancer (Garnett et al., Cancer Cell (2004) supra, and Moreno-Bueno et al Clin. Cancer Res. (2006) supra), pancreatic cancer (Ishimura et al Cancer Lett. (2003) 199(2) 169-173), pituitary adenoma (De Martino et al J. Endocrinol. Invest. (2007) 30(1) RCl-3), prostate cancer (Cho et al Int. J. Cancer (2006) 1 19(8) 1858-1862), renal cancer (Nagy et al Int. J. Cancer (2003) 106(6) 980-981), sarcoma (Davies (2002) supra), and skin cancers (Rodriguez- Viciana et al Science (2006) 31 1(5765) 1287-1290 and Davies (2002) supra). Overexpression of c-Raf has been linked to AML (Zebisch et al., Cancer Res. (2006) 66(7) 3401-3408, and Zebisch (Cell. Mol. Life Sci. (2006)) and erythroleukemia (Zebisch et la., Cell. Mol. Life Sci. (2006).

By virtue of the role played by the Raf family kinases in these cancers and exploratory studies with a range of preclinical and therapeutic agents, including one selectively targeted to inhibition of B-Raf kinase activity (King A.J., et al., (2006) Cancer Res. 66: 1 1 100- 1 1 105), it is generally accepted that inhibitors of one or more Raf family kinases will be useful for the treatment of such cancers or other condition associated with Raf kinase.

Mutation of B-Raf has also been implicated in other conditions, including cardio-facio cutaneous syndrome (Rodriguez-Viciana et al Science (2006) 31 1(5765) 1287- 1290) and polycystic kidney disease (Nagao et al Kidney Int. (2003) 63(2) 427-437).

N- {3-[5-(2-Amino-4-pyrimidinyl)-2-(l , 1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2- fluorophenyl}-2,6-difluorobenzenesulfonamide, as the unsalted compound and as the

methanesulfonate salt (Collectively used herein as Compound C) are compounds which are disclosed and claimed, along with pharmaceutically acceptable salts thereof, as being useful as inhibitors of BRAF activity, particularly in treatment of cancer, in PCT application

PCT/US09/42682. Compound C is embodied by Examples 58a through 58e of the application. The PCT application was published on 12 November 2009 as publication WO2009/137391, and is hereby incorporated by reference.

It would be advantageous to provide an improved method of treating cancer.

It would be advantageous to provide an improved method of administering Compound A in combination with Compound C.

SUMMARY OF THE INVENTION This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account adverse reactions of the compound.

This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account the toxicology of the compound.

This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account the risk for Retinal Vein Occlusion caused by the combination.

This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account use in specific populations for the combination.

This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account Skin Toxicity caused by the combination.

This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account Retinal Pigment Epithelial Detachment caused by the combination.

This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account Cardiomyopathy caused by the combination.

This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account Interstitial Lung Disease and/or pneumonitis caused by the combination.

This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account the clinical pharmacology of the combination.

This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account Drug Interactions of the compound.

This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account febrile reactions caused by the combination. This invention comprises a method of administering Compound A, or Compound B or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound C; which method takes into account thromboembolic events caused by the combination. DETAILED DESCRIPTION OF THE INVENTION

PRESCRIBING INFORMATION - TAFINLAR

TAFINLAR (dabrafenib) Capsules, for oral use Initial U.S. Approval: 2013

RECENT MAJOR CHANGES INCLUDE

Indications and Usage (1.1-1.3),

Dosage and Administration (2.1-2.3)

Warnings and Precautions (5.1, 5.3-5.5) INDICATIONS AND USAGE

• TAFINLAR is a kinase inhibitor indicated as single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA- approved test. (1.1, 2.1)

• TAFINLAR in combination with trametinib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation as detected by an FDA-approved test. (1.2, 2.1) This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated with TAFINLAR in combination with trametinib. (1.2, 14.1) Limitation of use: TAFINLAR is not indicated for treatment of patients with wild- type BRAF melanoma. (1.3, 5.2)

DOSAGE AND ADMINISTRATION

• Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR as a single agent. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with TAFINLAR in combination with trametinib (2.1)

• The recommended dose as a single agent or in combination with trametinib is 150 mg orally twice daily taken at least 1 hour before or at least 2 hours after a meal. (2.2)

DOSAGE FORMS AND STRENGTHS

Capsules: 50 mg, 75 mg. (3) CONTRAINDICATIONS- • None. (4) WARNINGS AND PRECAUTIONS

• New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib. Monitor patients for cutaneous and non-cutaneous malignancies prior to initiation of therapy, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. (5.1)

• Tumor Promotion in BRAF Wild- Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors. (5.2)

• Hemorrhage: Major hemorrhagic events can occur in patients receiving TAFINLAR in combination with trametinib. Monitor for signs and symptoms of bleeding. (5.3, 2.3)

· Thromboembolic Events: Deep vein thrombosis and pulmonary embolism can occur in patients receiving TAFINLAR in combination with trametinib. (5.4, 2.3)

• Visual Changes: Retinal Pigment Epithelial Detachment (RPED), Uveitis and Iritis: Perform ophthalmologic evaluation for any visual disturbances. (5.5, 2.3)

• Serious Febrile Reactions: Incidence and severity of pyrexia are increased when TAFINLAR is used in combination with trametinib. (5.7, 2.3)

• Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia. (5.9)

• Glucose-6-Phosphate Dehydrogenase Deficiency: Closely monitor for hemolytic anemia. (5.10)

• Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus. TAFINLAR may render hormonal contraceptives less effective and an alternative method of contraception should be used. (5.1 1, 8.1)

ADVERSE REACTIONS

• Most common adverse reactions (>20%) for TAFINLAR as a single agent are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. (6.1)

• Most common adverse reactions (>20%) for TAFINLAR in combination with trametinib are pyrexia, chills, fatigue, nausea, vomiting, diarrhea, cough, headache, peripheral edema, rash, arthralgia, night sweats, decreased appetite, constipation, and myalgia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825- 5249 or FDA at 1-800-FDA-1088 or ww.fda.gov/medwatch.

DRUG INTERACTIONS

· Avoid concurrent administration of strong inhibitors of CYP3A4 or CYP2C8. (7.1)

• Avoid concurrent administration of strong inducers of CYP3A4 or CYP2C8. (7.1)

• Drugs that increase gastric pH may decrease dabrafenib concentrations. (7.1)

• Concomitant use with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents. (7.2)

USE IN SPECIFIC POPULATIONS

• Nursing Mothers: Discontinue drug or nursing. (8.3)

• Females and Males of Reproductive Potential: Advise female patients to use highly effective contraception during treatment and for 4 weeks following discontinuation of treatment. Advise male patients of potential risk for impaired spermatogenesis. (8.6)

FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE

1.1 BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma

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

1.2 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

TAFINLAR, in combination with trametinib, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate [see

Clinical Studies (14.2)]. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with trametinib.

1.3 Limitation of Use

TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)] . 2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

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)]. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with

TAFINLAR in combination with trametinib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at:

http://ww'w.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosing

The recommended dosage regimens of TAFINLAR are:

• 150 mg orally taken twice daily taken approximately 12 hours apart as a single agent

• 150 mg orally taken twice daily taken approximately 12 hours apart in combination with

trametinib 2 mg orally taken once daily

Continue treatment until disease progression or unacceptable toxicity occurs. Take TAFINLAR as a single agent, or TAFINLAR in combination with trametinib, 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. Do not open, crush, or break TAFINLAR Capsule.

When administered in combination with trametinib, take the once-daily dose of trametinib at the same time each day with either the morning dose or the evening dose of TAFINLAR.

2.3 Dose Modifications

For New Primary Cutaneous Malignancies: No dose modifications are recommended.

For Dose modifications for Retinal Vein Occlusion and Interstitial Lung Disease, see Full Prescribing Information for trametinib.

Table 1. Recommended Dose Reductions of TAFINLAR and Trametinib Administered Either as a Single Agent or in Combination

Table 2. Recommended Dose Modifications for Single-agent or for TAFINLAR in Combination With Trametinib

Cutaneous • Grade 2 skin toxicity Do not modify the dose of TAFINLAR.

If TAFINLAR is used in combination with trametinib, do not modify the dose of either TAFINLAR or trametinib.

• Intolerable Grade 2 skin toxicity If TAFINLAR is used as a single agent,

• Grade 3 or 4 skin toxicity withhold TAFINLAR for up to 3 weeks.

If improved within 3 weeks, resume TAFINLAR at the same or reduced dose level.

or

If TAFINLAR is used in combination with trametinib, withhold trametinib for up to 3 weeks and also interruption of TAFINLAR should be considered for recurrent events.

If improved within 3 weeks, resume trametinib at a reduced dose level. Then resume TAFINLAR at the same or at a reduced dose level.

• Intolerable Grade 2, or Grade 3 If TAFINLAR is administered as a or 4 skin toxicity that does not single agent, permanently discontinue improve within 3 weeks despite TAFINLAR.

withholding treatment, and

If TAFINLAR is used in combination reducing treatment to the lowest

with trametinib, permanently recommended dose

discontinue trametinib.

Cardiac • Asymptomatic, absolute decrease Do not modify TAFLINAR dose.

in LVEF of 10% or greater from

If TAFINLAR is used in combination baseline and is below

with trametinib, withhold trametinib for institutional lower limits of

up to 4 weeks. Do not modify the dose normal (LLN) from pretreatment

of TAFLINAR.

value

• Asymptomatic, absolute decrease Do not modify TAFLINAR dose in LVEF of 10% or greater from

If TAFINLAR is used in combination baseline and is below LLN that with trametinib, resume trametinib at a improves to normal LVEF value reduced dose level. Do not modify the within 4 weeks following dose of TAFINLAR.

interruption of TAFINLAR

• Symptomatic congestive heart Withhold TAFINLAR for up to 4 failure weeks, if improved, resume

• Absolute decrease in LVEF of TAFINLAR at the same dose. and greater than 20% from baseline

If TAFINLAR is used in combination that is below LLN

with trametinib, permanently

• Absolute decrease in LVEF of

discontinue trametinib.

10% or greater from baseline and

is below LLN that does not

improve to normal LVEF value

within 4 weeks following

interruption of TAFINLAR

Visual Changes • Grade 2-3 retinal pigment Do not modify TAFINLAR dose.

epithelial detachments (RPED)

If TAFINLAR is used in combination with trametinib, withhold trametinib for up to 3 weeks. Do not modify the dose of TAFINLAR

If improved to Grade 0- 1 within 3 weeks, resume trametinib at a reduced dose level. If not improved, permanently discontinue trametinib.

• Grade 2-3 RPED that improves Do not modify TAFINLAR dose to Grade 0- 1 within 3 weeks If TAFINLAR is used in combination with trametinib, resume trametinib at a reduced dose level

• Uveitis and Iritis Withhold TAFINLAR until uveitis/iritis resolves to Grade 0-1

If TAFINLAR is used in combination with trametinib, do not modify the trametinib dose.

Other⁰ • Intolerable Grade 2 adverse Withhold TAFINLAR for up to 3 reaction weeks.

• Any Grade 3 adverse reaction If TAFINLAR is used in combination with trametinib, withhold trametinib for up to 3 weeks (see next row).

• If Grade 3 adverse reaction If adverse reaction improved within 3 improves to Grade 0-1 weeks, resume TAFINLAR at a lower following interruption dose level.

If used in combination with trametinib and adverse reaction improved within 3 weeks, resume trametinib at a reduced dose level.

• Grade 4 adverse reaction Permanently discontinue TAFINLAR.

• Intolerable Grade 2 or any

and

Grade 3 adverse reaction that

If TAFINLAR is used in combination does not improve to Grade 0- 1

with trametinib, permanently within 3 weeks or at the lowest

discontinue trametinib.

recommended dose

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version

4.0.

b See Table 1 for recommended dose reductions of TAFINLAR and trametinib.

3 DOSAGE FORMS AND STRENGTHS

50 mg Capsules: Dark red capsule imprinted with 'GS TEW and '50 mg'.

75 mg Capsules: Dark pink capsule imprinted with 'GS LHF' and '75 mg'.

4 CONTRAINDICATIONS

None. 5 WARNINGS AND PRECAUTIONS

The following serious adverse reactions of single-agent trametinib, which may occur when

TAFINLAR is used in combination with trametinib, are not described in the TAFINLAR Full Prescribing Information:

• Retinal Vein Occlusion

· Interstitial Lung Disease 5.1 New Primary Malignancies

New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib.

Cutaneous Malignancies: TAFINLAR as single-agent results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma. TAFINLAR when used in combination with trametinib results in an increased incidence of basal cell carcinoma.

In Trial 1, cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC) occurred in 7% (14/187) of patients treated with TAFINLAR and in none of the patients treated with dacarbazine.

Across clinical trials of TAFINLAR (n = 586), the incidence of cuSCC was 1 1%. The median time to first cuSCC was 9 weeks (range: 1 to 53 weeks). Of those patients who developed new cuSCC, approximately 33% developed one or more cuSCC with continued TAFINLAR administration. The median time between diagnosis of the first cuSCC and the second cuSCC was 6 weeks.

In Trial 1, the incidence of new primary malignant melanomas was 2% (3/187) for patients receiving TAFINLAR while no dacarbazine-treated patient was diagnosed with new primary malignant melanoma.

In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with trametinib, with 9% (5/55) incidence in patients receiving TAFINLAR in combination with trametinib compared to 2% (1/53) incidence in patients receiving single-agent TAFINLAR. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with trametinib and was 197 days for the patient receiving single-agent dabrafenib.

Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with trametinib and 19% of patients receiving single-agent TAFINLAR. The range of time to diagnosis of cuSCC was 136 tol97 days in the combination arm and was 9 to - 197 days in the single-agent TAFINLAR arm.

New primary melanoma occurred in 2% (1/53) of patients receiving single-agent TAFINLAR and in none of the 55 patients receiving TAFINLAR in combination with trametinib.

Perform dermato logic evaluations prior to initiation of TAFINLAR as a single-agent or in combination with trametinib, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or trametinib are recommended in patients who develop new primary cutaneous malignancies.

Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with trametinib at the recommended dose, four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of other malignancies. Permanently discontinue TAFINAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with trametinib, no dose modification is needed for trametinib in patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type Melanoma

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 combination therapy [see Indications and Usage (1), Dosage and Administration (2.1)].

5.3 Hemorrhage

Hemorrhages, including major hemorrhages, defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with trametinib.

In Trial 2, treatment with TAFINLAR in combination with trametinib resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with trametinib compared with 2% (1/53) of patients treated with single-agent

TAFINLAR. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with trametinib compared with none of the 53 patients treated with single-agent TAFINLAR. Intracranial hemorrhage was fatal in two (4%) patients receiving the combination of TAFINLAR and trametinib.

For Grade 3 hemorrhagic events, withhold TAFINLAR for up to 3 weeks and if improved resume at a reduced dose. For all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve, permanently discontinue TAFINLAR. If used in combination with trametinib, similar dose modifications will apply to trametinib [see Dosage and Administration (2.3), Table 2, Other].

5.4 Venous Thromboembolism

Venous thromboembolism can occur when TAFINLAR is used in combination with trametinib.

In Trial 2, treatment with TAFINLAR in combination with trametinib resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with trametinib compared with none of the 53 patients treated with single-agent TAFINLAR. Pulmonary embolism was fatal in one (2%) patient receiving the combination of TAFINLAR and trametinib.

Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and trametinib for life -threatening PE. For uncomplicated DVT or PE, do not modify the dose of TAFINLAR and withhold trametinib for up to 3 weeks; If improved, trametinib may be resumed at a reduced dose.

5.5 Cardiomyopathy

Cardiomyopathy can occur when TAFINLAR is used in combination with trametinib and with trametinib as a single-agent [refer to the trametinib Full Prescribing Information] .

In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with trametinib and in none of patients treated with single-agent TAFINLAR. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with trametinib was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with trametinib in 2 of 5 patients. In all five patients, cardiomyopathy resolved and resulted in dose reduction.

Across clinical trials of TAFINLAR administered in combination with trametinib (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF >10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of >20% below baseline.

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 with the combination. Withhold treatment with trametinib if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, ermanently discontinue trametinib. If TAFINLAR is used in combination with trametinib, withhold TAFINLAR for up to 4 weeks, resume TAFINLAR at a same dose level [see Dosage and Administration (2.3)J.

5.6 Visual Changes

Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with trametinib and with single-agent trametinib [refer to the trametinib Full Prescribing Information] . Retinal detachments resulting from trametinib are often bilateral and multifocal, occurring in the macular region of the retina.

In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. One patient (2%) receiving trametinib in combination with dabrafenib developed RPED. Across clinical trials of TAFINLAR administered in combination with trametinib (N = 202), the incidence of RPED was 1% (2/202).

Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. Withhold trametinib if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume trametinib at a reduced dose [see Dosage and Administration (2.4)]. Discontinue trametinib if no improvement after 3 weeks. If TAFINLAR is used in combination with trametinib, do not modify the dose of

TAFINLAR.

Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib.

Uveitis (including iritis) occurred in 1% (6/586) of patients treated with single-agent TAFINLAR and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with trametinib. Symptomatic 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 diagnosed, withhold TAFINLAR until uveitis/iritis resolves to Grade 0- 1. If TAFINLAR is used in combination with trametinib, do not modify the dose of trametinib.

5.7 Serious Febrile Reactions

Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib. The incidence and severity of pyrexia are increased when TAFINLAR is administered in combination with trametinib [see Adverse Reactions (6.1)] . In Trial 1, the incidence of fever (serious and non-serious) was 28% in patients treated with TAFINLAR and 10% in patients treated with dacarbazine. In patients treated with TAFINLAR, the median time to initial onset of fever (any severity) was 1 1 days (range: 1 to 202 days) and the median duration of fever was 3 days (range: 1 to 129 days). Febrile reactions reported as Serious Adverse Events (SAEs) included events of fever of any severity accompanied by hypotension, rigors or chills and occurred in 3.7% (7/187) of patients treated with TAFINLAR and in none of the 59 patients treated with dacarbazine. In Trial 2, febrile reactions reported as Serious Adverse Events (SAEs) included events of fever of any severity accompanied by hypotension, rigors or chills and occurred in 25% (14/55) of patients treated with TAFINLAR in combination with trametinib compared with 2% (1/53) of patients treated with single-agent TAFINLAR. Fever was complicated by dehydration in 9% (5/55), renal failure in 4% (2/55), and chills/rigors in 51 % (28/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with trametinib, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with single-agent

TAFINLAR; the median duration of fever was 6 days with the combination compared with 4 days with single- agent TAFINLAR.

Withhold TAFINLAR for fever of 101.3°F or for any serious febrile reaction or fever a by accompanied hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Also withhold trametinib if used in combination with TAFINLAR for any fever higher than 104°F or any serious febrile drug reaction. Refer to Table 2 for recommended dose modifications for adverse reactions [see Dosage and Administration (2.4)]. Prophylaxis with antipyretics may be required when resuming TAFINLAR. Use of oral corticosteroids should be considered in patients with recurrent pyrexia for whom anti-pyretics are insufficient.

5.8 Serious Skin Toxicity

Serious skin toxicity can occur when TAFINLAR is used in combination with trametinib and with single-agent trametinib [refer to the trametinib Full Prescribing Information] .

Across all clinical trials of TAFINLAR in combination with trametinib (n = 202), severe skin toxicity requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with trametinib.

In Trial 2, the incidence of any skin toxicity, the most common of which were rash, dermatitis acneiform rash, palmar-plantar erythrodysesthesia syndrome, or erythema was similar for patients receiving TAFINLAR in combination with trametinib (65% [36/55]) compared with patients receiving single-agent TAFINLAR (68% [36/53]).

The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with trametinib was 37 days (range 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required reduction in the dose of TAFINLAR and trametinib or permanent discontinuation of TAFINLAR and trametinib for skin toxicity.

When TAFINLAR is administered as a single agent, withhold for events of severe skin toxicities. Resume TAFINLAR at the same or reduced dose, if skin toxicities improve within 3 weeks. Discontinue permanently if there is no improvement within this time period. When TAFINLAR is used in combination with trametinib, withhold trametinib for intolerable or severe skin toxicity. Consider interruption of the dose of TAFINLAR in recurrent events [see Dosage and

Administration (2.3)] .

5.9 Hyperglycemia

Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib.

In Trial 1, 5 of 12 patients with a history of diabetes required more intensive hypoglycemic therapy while taking TAFINLAR. The incidence of Grade 3 hyperglycemia based on laboratory values was 6% (12/187) in patients treated with TAFINLAR compared with none of the dacarbazine -treated patients.

In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with trametinib compared with 2% (1/53) in patients treated with single-agent TAFINLAR.

Monitor serum glucose levels as clinically appropriate during treatment with TAFINLAR in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase Deficiency

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

5.11 Embryofetal Toxicity

Based on 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 clinical dose. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Advise female patients of reproductive potential to use a highly effective non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective, during treatment and for at least 2 weeks after treatment with TAFINLAR or for 4 months after treatment with TAFINLAR in combination with trametinib. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Drug

Interactions (7.2), Use in Specific Populations (8.6)]. 6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in another section of the label:

• New Primary Cutaneous Malignancies [see Warnings and Precautions (5.1)]

· Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)]

• Hemorrhage [see Warnings and Precautions (5.3)]

• Venous Thromboembolism [see Warnings and Precautions (5.4)]

• Cardiomyopathy [see Warnings and Precautions (5.5)]

• Visual Changes [see Warnings and Precautions (5.6)] · Serious Febrile Drug Reactions [see Warnings and Precautions (5.7)]

• Serious Skin Toxicity [see Warnings and Precautions (5.8)]

• Hyperglycemia [see Warnings and Precautions (5.9)]

• Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)]

6.1 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.

The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with trametinib.

BRAF V600 E Unresectable or Metastatic Melanoma: The safety of TAFINLAR as a single agent was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 1 18 to 300 mg).

Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from analyses of Trial 1 [see Clinical Studies (14)]. Trial 1, a multicenter, 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 1 ,000 mg/m² intravenously every 3 weeks (n = 63). The trial excluded patients with abnormal left ventricular ejection fraction or cardiac valve morphology (>Grade 2), corrected QT interval >480 milliseconds on electrocardiogram, or a known history of glucose-6-phosphate dehydrogenase 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 commonly occurring 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 Trial 1 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 3. Selected Common Adverse Reactions Occurring in >10% (All Grades) or >2% (Grades 3 or 4) of Patients Treated With TAFINLAR"

Adverse drug reactions, reported using MedDRA and graded using 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 Includes squamous cell carcinoma of the skin and keratoacanthoma.

e Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.

f NA = not applicable.

Table 4. Incidence of Laboratory Abnormalities Increased From Baseline Occurring at a Higher Incidence in Patients Treated With TAFINLAR in Trial 1 [Between Arm Difference of >5% (All Grades) or >2% (Grades 3 or 4)]

Grade 4 laboratory abnormality limited to hypophosphatemia (n = 1).

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

Gastrointestinal Disorders: Pancreatitis.

Immune System Disorders: Hypersensitivity manifesting as bullous rash.

Renal and Urinary Disorders: Interstitial nephritis.

BRAF V600 E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with trametinib was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received

TAFINLAR 150 mg orally twice daily in combination with trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to trametinib for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to trametinib for greater than one year. The median age was 54 years, 57% were male, and >99% were white. Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg twice daily in combination with trametinib 2 mg orally once daily (N = 55), TAFLINAR 150 mg orally twice daily in combination with trametinib 1 mg once daily (N = 54), and single-agent TAFLINAR 150 mg orally twice daily [see Clinical Studies (14.2)]. Patients with abnormal

LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval >480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and trametinib (2 mg orally once daily treatment group) when used in combination, 10.6 months for both TAFINLAR and trametinib (1 mg orally once daily treatment group) when used in combination, and 6.1 months for single-agent TAFINLAR.

In Trial 2, 13% of patients receiving TAFINLAR in combination with trametinib experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with trametinib. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and trametinib when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in >10% at (All Grades) or >5%

(Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With Trametinib in Trial 2

Abdominal pain^b 33 2 24 2 21 2

Constipation 22 0 17 2 1 1 0

Dry mouth 1 1 0 1 1 0 6 0

Nervous system disorders

Headache 29 0 37 2 28 0

Dizziness 16 0 13 0 9 0

Respiratory, thoracic, and mediastinal disorders

Cough 29 0 1 1 0 21 0

Oropharyngeal pain 13 0 7 0 0 0

Musculoskeletal, connective tissue, and bone disorders

Arthralgia 27 0 44 0 34 0

Myalgia 22 2 24 0 23 2

Muscle spasms 16 0 2 0 4 0

Pain in extremity 16 0 1 1 2 19 0

Metabolism and nutritional disorders

Decreased appetite 22 0 30 0 19 0

Dehydration 1 1 0 6 2 2 0

Vascular disorders

Hemorrhage⁶ 16 5 1 1 0 2 0

Infections and infestations

Urinary tract infection 13 2 6 0 9 2

Renal and urinary disorders

Renal failure^d 7 7 2 0 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.

Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.

Includes the following terms: peripheral edema, edema, and lymphedema.

Includes the following terms: renal failure and renal failure acute.

Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhag epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with trametinib were:

Neoplasms Benign, Malignant, and Unspecified (including cvsts and polyps): Skin papilloma.

Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.

Vascular Disorders: Hypertension.

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.

Eve Disorders: Vision blurred, transient blindness.

Gastrointestinal Disorders: Stomatitis, pancreatitis.

General Disorders and Administration Site Conditions: Asthenia.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at >10% (All Grades) or >2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With Trametinib in Trial 2

ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase. 7 DRUG INTERACTIONS

7.1 Effects of Other Drugs on Dabrafenib

Drugs That Inhibit or Induce Drug-Metabolizing Enzymes: Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

Drugs That Affect Gastric pH: Drugs that alter the pH of the upper GI tract (e.g., proton pump inhibitors, H₂-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of dabrafenib. When TAFINLAR is coadministered with a proton pump inhibitor, H₂-receptor antagonist, or antacid, systemic exposure of dabrafenib may be decreased and the effect on efficacy of TAFINLAR is unknown.

7.2 Effects of Dabrafenib on Other Drugs

Dabrafenib induces CYP3A4 and CYP2C9. 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, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 Trametinib

Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D. Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses 3 times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.7)] .

Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately 3 times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

8.3 Nursing Mothers

It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of TAFINLAR have not been established in pediatric patients.

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.

8.5 Geriatric Use

One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were >65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with trametinib, there were insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 1 1 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older. 8.6 Females and Males of Reproductive Potential

Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 week after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with trametinib. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.7), Drug Interactions (7.1), Use in Specific Populations (8.1)] .

Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that

TAFINLAR taken in combination with trametinib may impair fertility in female patients.

Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

8.7 Hepatic Impairment

No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].

8.8 Renal Impairment

No formal pharmacokinetic trial in patients with renal impairment has been conducted. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

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. 11 DESCRIPTION

Dabrafenib mesylate is a kinase inhibitor. The chemical name for dabrafenib mesylate is N- {3-[5- (2-Amino-4-pyrimidinyl)-2-(l , 1-dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl} -2,6- difluorobenzene sulfonamide, methanesulfonate salt. It has the molecular formula C₂₃H₂oF₃N₅0₂S₂»CH₄0₃S and a molecular wei ht of 615.68. Dabrafenib mesylate has the

following chemical structure:

Dabrafenib mesylate is a white to slightly colored solid with three pK_as: 6.6, 2.2, and -1.5. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.

TAFINLAR (dabrafenib) capsules are supplied as 50-mg and 75-mg capsules for oral

administration. Each 50-mg capsule contains 59.25 mg dabrafenib mesylate equivalent to 50 mg of dabrafenib free base. Each 75-mg capsule contains 88.88 mg dabrafenib mesylate equivalent to 75 mg of dabrafenib free base.

The inactive ingredients of TAFINLAR are colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose. Capsule shells contain hypromellose, red iron oxide (El 72), and titanium dioxide (El 71).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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 IC₅o values of 3.2 and 5.0 nM, respectively, and other kinases such as SIK1, NEK1 1, 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 (I)]. Dabrafenib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo. Dabrafenib and trametinib target two different tyrosine 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 melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone. 12.3 Pharmacokinetics

Absorption: After oral administration, median time to achieve peak plasma concentration (T_max) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95%. Following a single dose, dabrafenib exposure (C^ and AUC) increased in a dose-proportional manner across the dose range of 12 to 300 mg, but the increase was less than dose-proportional after repeat twice-daily dosing. After repeat twice-daily dosing of 150 mg, the mean accumulation ratio was 0.73 and the inter-subject variability (CV%) of AUC at steady-state was 38%.

Administration of dabrafenib with a high- fat meal decreased C_maxby 51%, decreased AUC by 31%, and delayed median by 3.6 hours as compared with the fasted state [see Dosage and Administration (2.2)] .

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

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. Hydroxy-dabrafenib terminal half- life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl- dabrafenib metabolites exhibited longer half- lives (21 to 22 hours). Mean metabolite-to-parent AUC ratios following repeat-dose administration are 0.9, 1 1, 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.

Elimination: The mean terminal half-life of dabrafenib is 8 hours after oral administration. The apparent clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after 2 weeks of twice-daily dosing.

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, Body Weight, and Gender: Based on the population pharmacokinetics analysis, age has no effect on dabrafenib pharmacokinetics. Pharmacokinetic differences based on gender and on weight are not clinically relevant.

Pediatric: Pharmacokinetics of dabrafenib has not been studied in pediatric patients.

Renal: No formal pharmacokinetic trial in patients with renal impairment has been conducted. The pharmacokinetics of dabrafenib were evaluated using a population analysis in 233 patients with mild renal impairment (GFR 60 to 89 mL/min/1.73 m²) and 30 patients with moderate renal impairment (GFR 30 to 59 mL/min/1.73 m²) enrolled in clinical trials. Mild or moderate renal impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with severe renal impairment.

Hepatic: No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. The pharmacokinetics of dabrafenib was evaluated using a population analysis in 65 patients with mild hepatic impairment enrolled in clinical trials. Mild hepatic impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with moderate to severe hepatic impairment.

Drug Interactions:

In vitro studies show that dabrafenib is a substrate of CYP3A4 and CYP2C8 while hydroxy- dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Coadministration of dabrafenib 75 mg twice daily and ketoconazole 400 mg once daily (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 dabrafenib 75 mg twice daily and gemfibrozil 600 mg twice daily (a strong CYP2C8 inhibitor) for 4 days increased dabrafenib AUC by 47%, with no change in the AUC of dabrafenib metabolites. Dabrafenib is a substrate of human P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro.

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. Coadministration of dabrafenib 150 mg twice daily for 15 days and a single dose of midazolam 3 mg (a CYP3A4 substrate) decreased midazolam AUC by 74%. Coadministration of dabrafenib 150 mg twice daily for 15 days and a single dose of warfarin 15 mg decreased the AUC of S-warfarin (a CYP2C9 substrate) by 37% and the AUC of R-warfarin (a CYP3A4/CYP1A2 substrate) by 33% [see Drug Interactions (7.2)] . Dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl- dabrafenib, are inhibitors of human organic anion transporting polypeptide OATPIBI, OATP1B3 and organic anion transporter OAT1 and OAT3 in vitro. Dabrafenib and desmethyl-dabrafenib are inhibitors of BCRP in vitro.

Coadministration of trametinib 2 mg daily with dabrafenib 150 mg twice daily resulted in a 23% increase in AUC of dabrafenib, a 33% increase in AUC of desmethyl-dabrafenib, and no change in AUC of trametinib or hydroxy-dabrafenib as compared with administration of either drug alone.

12.4 QT Prolongation

In Trial 2, QTcF increased from baseline to >501 msec in 4% (2/55) of patients treated with MEKINIST in combination with dabrafenib compared with 2% (1/53) of patients treated with single-agent dabrafenib.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with dabrafenib have not been conducted. TAFINLAR increased the risk of cutaneous squamous cell carcinomas 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 embryofetal 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 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 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 3 times the human exposure at the recommended dose based on AUC, respectively.

13.2 Animal Toxicology and/or Pharmacology

Adverse cardiovascular effects were noted in dogs at dabrafenib doses of 50 mg/kg/day

(approximately 5 times the human exposure at the recommended 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. 14 CLINICAL STUDIES

14.1 BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma

In Trial 1 , the safety and efficacy of TAFINLAR as a single agent were demonstrated in an international, multicenter, randomized (3: 1), open- label, active-controlled trial 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 by mouth twice daily (n = 187) or dacarbazine 1 ,000 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), Mia (distant skin, subcutaneous, or nodal metastases), or Mlb (lung metastases) vs. Mlc 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 objective response rate (ORR), and duration of response.

The median age of patients in Trial 1 was 52 years. The majority of the trial population was male (60%), white (99%), had an ECOG performance status of 0 (67%), Mlc 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 the patients treated with 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.

Trial 1 demonstrated a statistically significant increase in progression- free survival in the patients treated with TAFINLAR. Table 7 and Figure 1 summarize the PFS results.

Table 7. Investigator- Assessed Progression-Free Survival and Confirmed Objective

Response Results in Trial 1

a Pike estimator, stratified by disease state.

b Stratified log-rank test.

CI = Confidence interval; CR = Complete response; HR = Hazard ratio; NR = Not reached; PR = Partial response.

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.

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 (Trial 3). 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, charged particles, or CyberKnife. 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 primary 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. Efficacy results as determined by an independent radiology review committee, masked to investigator response assessments, are provided in Table 8.

Table 8. Efficacy Results in Patients With BRAF V600E Melanoma Brain Metastases (Trial 3)

IRRC = Independent radiology review committee; CI = Confidence interval; NR = Not reached. 14.2 BRAF V600E or V600K Unresectable or Metastatic Melanoma

Trial 2 was a multicenter, open- label, randomized (1 : 1 : 1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with trametinib (at two different doses) and to compare the safety with single-agent TAFINLAR in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with trametinib 2 mg orally once daily (n = 54), TAFINLAR 150 mg orally twice daily with trametinib 1 mg orally twice daily (n = 54), or TAFINLAR 150 mg orally twice daily (n = 54). Treatment continued until disease progression or unacceptable toxicity. Patients randomized to TAFINLAR as a single agent were offered TAFINLAR 150 mg orally twice daily with trametinib 2 mg orally once daily at the time of investigator-assessed disease progression. The major efficacy outcome measure was investigator-assessed overall response rate (ORR). Additional efficacy outcome measures were investigator-assessed duration of response, independent radiology review committee (IRRC)-assessed ORR, and IRRC-assessed duration of response.

The median age of patients was 53 years, 57% were male, >99% were white, 66% of patients had a pre-treatment ECOG performance status of 0, 67% had Mlc disease, 54% had a normal LDH at baseline, and 8% had history of brain metastases. Most patients (81%) had not received prior anti- cancer therapy for unresectable or metastatic disease. Based on local laboratory or centralized testing, 85% of patients' tumors had BRAF V600E mutations and 15% had BRAF V600K mutations.

The median duration of follow-up was 14 months. Efficacy outcomes for the arm receiving TAFINLAR in combination with trametinib 2 mg orally once daily and single-agent TAFINLAR, are summarized in Table 9.

Table 9. Investigator-Assessed and Independent Review Committee-Assessed Response Rates and Response Duration in Trial 2

CI, Confidence interval; ORR, Confirmed overall response rate; NR, Not reported. The ORR results were similar in subgroups defined by BRAF mutation subtype, i.e., in the 85% of patients with V600E mutation-positive melanoma and in the 15% of patients with V600K mutation-positive melanoma. In exploratory subgroup analyses of the patients with retrospectively confirmed BRAF V600E or V600K mutation-positive melanoma using the THxID™-BRAF assay, the ORR results were also similar to the intent-to-treat analysis. 16 HOW SUPPLIED/STORAGE AND HANDLING

50 mg Capsules: Dark red capsule imprinted with 'GS TEW' and '50 mg' available in bottles of 120 (NDC 0173-0846-08). Each bottle contains a silica gel desiccant. 75 mg Capsules: Dark pink capsule imprinted with 'GS LHF' and '75 mg' available in bottles of 120 (NDC 0173-0847-08). Each bottle contains a silica gel desiccant.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Inform patients of the following:

• Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with trametinib is indicated [see Dosage and Administration (2.1)].

• TAFINLAR increases the risk of developing new primary cutaneous and non-cutaneous

malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies [see Warnings and Precautions (5.1)] .

• TAFINLAR administered in combination with trametinib increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions [see Warnings and Precautions (5.3)].

• TAFINLAR administered in combination with trametinib increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)].

• TAFINLAR administered in combination with trametinib can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)].

• TAFINLAR can cause visual disturbances. Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions [see Warnings and Precautions (5.6)]. • TAFINLAR can cause pyrexia including serious febrile reactions. The incidence and severity of pyrexia are increased when TAFINLAR is given in combination with trametinib. Instruct patients to contact their doctor if they experience a fever while taking TAFINLAR [see Warnings and Precautions (5.7)].

· TAFINLAR can cause serious skin toxicity. Advise patients to contact their healthcare

provider for progressive or intolerable rash [see Warnings and Precautions (5.8)].

• TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. · TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)].

• TAFINLAR can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 weeks after treatment. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11) and Use in Specific

Populations (8.1)].

• Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR [see Use in Specific Populations (8.3)].

• Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific

Populations (8.6)].

• TAFINLAR should be taken either at least 1 hour before or at least 2 hours after a meal [see Dosage and Administration (2.1)].

TAFINLAR is a registered trademark of the Glaxo SmithKline group of companies.

THxID is a trademark of bioMerieux.

TAFINLAR^® (TAFF-in-lar), (dabrafenib), Capsules

If your healthcare provider prescribes TAFINLAR for you in combination with trametinib, also read the Patient Information Leaflet that comes with trametinib. What is the most important information I should know about TAFINLAR?

TAFINLAR used by itself or in combination with trametinib may cause serious side effects, including:

Risk of new cancers. TAFINLAR may cause new cancers, including cutaneous squamous cell carcinoma (cuSCC) that can spread to other parts of the body. Talk with your healthcare provider about your risk for developing skin cancers or other cancers.

Check your skin and tell your healthcare provider right away about any skin changes including a:

• new wart

• skin sore or reddish bump that bleeds or does not heal · change in size or color of a mole

Your healthcare provider should check your skin before you start taking TAFINLAR, and every two months while taking TAFINLAR to look for any new skin cancers. Your healthcare provider may continue to check your skin for up to six months after you stop taking TAFINLAR, or until you start another therapy for your cancer.

Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider about any new symptoms that have developed while taking TAFINLAR.

See "What are the possible side effects of TAFINLAR?" for more information about side effects.

What is TAFINLAR?

TAFINLAR is a prescription medicine which is used by itself or in combination with trametinib to treat a type of skin cancer called melanoma:

• that has spread to other parts of the body or cannot be removed by surgery, and

• that has a certain type of abnormal "BRAF" gene.

Your healthcare provider will perform a test to make sure that TAFINLAR is right for you.

TAFINLAR is not used to treat people with a type of skin cancer called wild-type BRAF melanoma.

It is not known if TAFINLAR is safe and effective in children.

What should I tell my healthcare provider before taking TAFINLAR?

Before you start taking TAFINLAR, tell your healthcare provider if you: have liver, kidney, or heart problems, have eye problems, have lung or breathing problems, have diabetes, plan to have surgery, dental, or other medical procedures, have a deficiency of the glucose-6-phosphate dehydrogenase (G6PD) enzyme, have any other medical conditions, are pregnant or plan to become pregnant. TAFINLAR can harm your unborn baby.

• Females who are able to become pregnant should use birth control during treatment and for 4 weeks after stopping TAFINLAR or for 4 months after treatment with TAFINLAR in combination with trametinib.

• Birth control using hormones (such as birth control pills, injections, or patches) may not work as well while you are taking TAFINLAR. You should use another effective method of birth control while taking TAFINLAR. Talk to your healthcare provider about birth control methods that may be right for you.

· Tell your healthcare provider right away if you become pregnant during treatment with

TAFINLAR.

• are breastfeeding or plan to breastfeed. It is not known if TAFINLAR passes into your breast milk. You and your healthcare provider should decide if you will take TAFINLAR or breastfeed. You should not do both.

TAFINLAR may cause lower sperm counts in men. This could affect the ability to father a child. Talk to your healthcare provider if this is a concern for you. Talk to your healthcare provider about family planning options that might be right for you.

Tell your healthcare provider about all the medicines you take including prescription and over- the-counter medicines, vitamins, and herbal supplements. TAFINLAR and certain other medicines can affect each other, causing side effects. TAFINLAR may affect the way other medicines work, and other medicines may affect how TAFINLAR works. You can ask your pharmacist for a list of medicines that may interact with TAFINLAR.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I take TAFINLAR?

• Take TAFINLAR exactly as your healthcare provider tells you. Do not change your dose or stop TAFINLAR unless your healthcare provider tells you.

• Take TAFINLAR 2 times a day, about 12 hours apart.

• When taking TAFINLAR in combination with trametinib, take the first dose of TAFINLAR in the morning, and take the second dose of TAFINLAR in the evening about 12 hours later.

Take trametinib only once a day at the same each day, either in the morning or in the evening at the same time as TAFINLAR. See trametinib patient information leaflet on how to take trametinib. • Take TAFINLAR at least 1 hour before or 2 hours after a meal.

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

• If you miss a dose, take it as soon as you remember. If it is within 6 hours of your next

scheduled dose, just take your next dose at your regular time. Do not make up for the missed dose. If you take too much TAFINLAR, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of TAFINLAR?

TAFINLAR may cause serious side effects, including:

• See "What is the most important information I should know about TAFINLAR?" · Bleeding. TAFINLAR in combination with trametinib can cause bleeding. Tell your

healthcare provider right away if you develop any bleeding while taking TAFINLAR.

• Deep venous thrombosis (DVT) and pulmonary embolism (PE). TAFINLAR in

combination with trametinib can cause DVT and PE. Tell your healthcare provider right away if you develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling while taking TAFINLAR.

• Heart problems including heart failure. TAFINLAR in combination with trametinib can cause heart problems including heart failure. Tell your healthcare provider right away if you develop following signs and symptoms of a heart problem:

• feeling like your heart is pounding or racing

· shortness of breath

• swelling of your ankles and feet

• feeling lightheaded.

Fever. TAFINLAR can cause fever, including severe fever. In some cases, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Tell your healthcare provider right away if you get a fever while taking TAFINLAR. More severe cases of fever may occur when TAFINLAR is used in combination with trametinib.

• Eye problems. You should have your eyes examined before and while you are taking

TAFINLAR. Tell your healthcare provider right away if you get these symptoms during treatment with TAFINLAR:

· eye pain, swelling, or redness

• blurred vision or other vision changes during treatment with TAFINLAR • Blood sugar problems. Some people may develop high blood sugar or worsening diabetes during treatment with TAFINLAR. If you are diabetic, your healthcare provider will check your blood sugar levels before and during treatment with TAFINLAR. Tell your healthcare provider if you have any of the following symptoms of high blood sugar:

• increased thirst

• urinating more often than normal

• your breath smells like fruit

The most common side effects of TAFINLAR when used by itself include: thickening of the outer layers of the skin, headache, joint aches, warts, hair loss, redness, swelling, peeling, or tenderness of hands or feet.

In addition to the side effects above, other common side effects of TAFINLAR when used in combination with trametinib include: tiredness, feeling sick to your stomach (nausea) or vomiting, diarrhea, swelling of the face, arms, or legs, cough, skin rash, loss of appetite, night sweats, constipation, muscle pain

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of TAFINLAR. For more information about side effects, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1- 800-FDA-1088. You may also report side effects to GSK at 1-888-825-5249.

How should I store TAFINLAR?

• Store TAFINLAR at room temperature, between 68°F to 77°F (20°C to 25°C).

• Ask your healthcare provider or pharmacist how to safely throw away TAFINLAR that is out of date or no longer needed.

Keep TAFINLAR and all medicine out of the reach of children.

General information about TAFINLAR

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TAFINLAR for a condition for which it was not prescribed. Do not give TAFINLAR to other people, even if they have the same symptoms that you have. It may harm them.

If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about TAFINLAR that is written for health professionals. For more information, call Glaxo SmithKline at 1-888-825-5249 or go to www.TAFINLAR.com. What are the ingredients in TAFINLAR?

Active ingredient: dabrafenib

Inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose Capsule shells contain: hypromellose, red iron oxide (El 72), titanium dioxide (El 71).

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples, therefore, are to be construed as merely illustrative and not a limitation of the scope of the present invention.

All the excipients utilized herein are standard pharmaceutical grade excipients available from numerous manufacturers well known to those in the art.

Examples

Examples 1 to 3~Tablet preparation

Dry direct compression, tablets comprising Compound A and the ingredients in Table 10 were prepared.

Table 10

Opadry White OY-S-28876 NP 4.65 NP

Purified Water² - - -

Total Tablet Weight 149.35 159.65 169.95

Note:

1. The amount of Compound A required to achieve the label claim of Compound B (the free or un-solvated compound) is calculated utilizing the molecular conversion factor of 0.8873 for the ratio of Compound B (un-solvated) to compound A (the DMSO solvate), and based on the purity value from the certificate of analysis. The amount of Mannitol is adjusted accordingly.

2. Water is removed during processing.

NP = not present in formulation.

Blending

The micronized drug substance, sodium lauryl sulfate, silicon dioxide, croscarmellose sodium, microcrystalline cellulose and hypromellose are screened, if required, and transferred into a suitable bin blender and blended. The magnesium stearate is screened, if required, transferred to the bin blender and blended for an additional time.

Compression

The lubricated blend is compressed on a rotary tablet press to the target weight for each strength (145 mg, 155 mg and 165 mg corresponding to 0.5 mg, 1 mg and 2 mg, respectively). The compressed tablets are sampled for in-process monitoring of individual weight variation, appearance, hardness, thickness, friability and disintegration time.

Coating

Tablet cores are sprayed with an aqueous suspension of Opadry® Pink YS- 1-14762- A) (for 2 mg strength), Opadry® Yellow YS-1- 12525-A (for 0.5 mg strength) or Opadry® White OY- S-28876 (for 1 mg strength). Coating continues until a target weight gain of approximately 3% is attained. The tablets are then dried and bulk packed into HDPE containers with plastic liners and desiccant bags, and stored until packaged.

TAFINLAR is a well known marketed product. Pharmaceutical dosages of Tafinlar are made by methods well known to those of skill in the art.

While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:

1. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

N- {3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido[4,3-d]pyrimidin- 1 -yljphenyl} acetamide,

or a pharmaceutically acceptable salt of solvate thereof, and

N- {3-[5-(2-Amino-4-pyrimidinyl)-2-(l , 1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl} -2,6- difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof,

to such human.

2. A method of treating a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

N- {3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido[4,3-d]pyrimidin-l-yl]phenyl} acetamide dimethyl sulfoxide solvate, and N- {3-[5-(2-Amino-4-pyrimidinyl)-2-(l , 1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl} -2,6- difluorobenzenesulfonamide methanesulfonate,

to such human.

3. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

N- {3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido [4,3 -d]pyrimidin- 1 -yljphenyl} acetamide dimethyl sulfoxide solvate, and N- {3-[5-(2-Amino-4-pyrimidinyl)-2-(l , 1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl} -2,6- difluorobenzenesulfonamide methanesulfonate,

to such human,

which method takes into account adverse reactions of the combination.

4. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

to such human, which method takes into account Drug Interactions of the combination.

5. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

N- {3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido[4,3-d]pyrimidin-l-yl]phenyl}acetamide dimethyl sulfoxide solvate, and N- {3-[5-(2-Amino-4-pyrimidinyl)-2-(l , 1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl} -2,6- difluorobenzenesulfonamide methanesulfonate,

to such human,

which method takes into account the risk for Retinal Pigment Epithelial Detachment caused by the combination.

6. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

to such human,

which method takes into account Cardiomyopathy caused by the combination.

7. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

to such human,

which method takes into account Interstitial Lung Disease and/or pneumonitis caused by the combination.

8. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

to such human,

which method takes into account the clinical pharmacology of the combination.

9. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

to such human,

which method takes into account the toxicology of the combination.

10. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

to such human,

which method takes into account the risk for Retinal Vein Occlusion caused by the combination.

1 1. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

to such human,

which method takes into account Skin Toxicity caused by the combination.

12. A method of treating cancer in a human in need thereof which comprises the administration of a therapeutically effective amount of a combination of: N- {3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido[4,3-d]pyrimidin-l-yl]phenyl}acetamide dimethyl sulfoxide solvate, and N- {3-[5-(2-Amino-4-pyrimidinyl)-2-(l , 1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl} -2,6- difluorobenzenesulfonamide methanesulfonate,

to such human,

which method takes into account febrile reactions caused by the combination.

13. A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of:

to such human,

which method takes into account thromboembolic events caused by the combination.

14. A method according to any one of claims 1 to 13 where the amount of N- {3-[3- cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H- pyrido[4,3-d]pyrimidin- l-yl]phenyl}acetamide dimethyl sulfoxide solvate is selected from 0.5 to 5mg and that amount is administered once a day, the amount of N- {3-[5-(2-Amino-4-pyrimidinyl)- 2-( 1 , 1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl} -2,6-difluorobenzenesulfonamide methanesulfonate is selected from 50 to lOOmg and that amount is administered twice a day, and the compounds are adimnistered for at least 7 consecutive days as some point during therapy.