For:
BRAF+ Advanced Melanoma or BRAF+ Melanoma Involving Lymph Nodes After Surgery
Important Safety Information

New Primary Malignancies. Cutaneous Malignancies: In the COMBI-d study in patients with unresectable or metastatic melanoma, the incidence of basal cell carcinoma in patients receiving TAFINLAR wit...

See More

Indications TAFINLAR, in combination with MEKINIST, 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.

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

Limitation of Use: TAFINLAR is not indicated for the treatment of patients with wild-type BRAF melanoma.

Efficacy—Adjuvant

Study Design

In the adjuvant treatment of patients with stage III melanoma with BRAF V600E/K mutations

THE ONLY ORAL THERAPY APPROVED IN THE ADJUVANT SETTING1-6

TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) adjuvant treatment efficacy TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) adjuvant treatment efficacy

DMFS, distant metastasis-free survival; FFR, freedom from relapse; OS, overall survival; RFS, relapse-free survival.

aRadiological tumor assessment was conducted every 3 months for the first 2 years and every 6 months thereafter, until first relapse was observed.7 The median duration of follow-up (time from randomization to last contact or death) was 2.8 years for primary analysis. bEnrollment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomization. All patients had no prior systemic anticancer treatment, including radiotherapy. Patients with a history of prior malignancy, if disease-free for at least 5 years, were eligible.7,8 cDefined as the time from randomization to disease recurrence, new primary melanoma, or death from any cause.1,2

KEY ELIGIBILITY CRITERIA7

  • Completely resected, high-risk stage IIIA (lymph-node metastasis >1 mm), IIIB, or IIIC cutaneous melanoma
  • BRAF V600E/K mutations
  • Surgically free of disease ≤12 weeks before randomization
  • Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1
  • No prior radiotherapy or anticancer systemic therapy

COMBI-AD included patients with all substages of stage III disease prior to resection1,2

  • 19% of these patients had lymph-node involvement only identifiable by microscope and no primary tumor ulceration (n=165/870 with no ulceration and micrometastasis; 4-year update)

Follow-up until end of study9

  • Patients were followed for disease recurrence until the first recurrence and thereafter for survival
  • The study will be considered complete and final OS analysis will occur when ≈70% of randomized patients have died or are lost to follow-up

 

Relapse-Free Survival (4-Year)

ROBUST EFFICACY AND SUSTAINED RELAPSE-FREE SURVIVAL AT 4 YEARS

TAFINLAR + MEKINIST demonstrated an estimated 51% reduction in risk of relapse or death (primary end point)10

RFSa in the COMBI-AD study as of April 30, 2018 data cutoff10

An estimated 51% reduction in risk of relapse or death vs. placebo An estimated 51% reduction in risk of relapse or death vs. placebo

HR, hazard ratio; RFS, relapse-free survival.

  • Median duration of follow-up for updated analysis in the treatment arm was 44 months10
  • First tumor assessment was performed at 3 months11
  • Median RFS was not reached for TAFINLAR + MEKINIST (95% CI, 46.9-not reached) and was 16.6 months (95% CI, 12.7-22.1) for placebo (hazard ratio [HR], 0.49; 95% CI, 0.40-0.59)10

Primary analysis positive for RFS, with HR of 0.47 (0.39-0.58), P=.0000000000000153 (median follow-up: 2.8 years)10,11

  • Results at 12, 24, 36, and 48 months were not prespecified and are observational in nature; as such there was no prespecified statistical procedure controlling for type 1 error

Overall Survival (3-Year)

In the adjuvant treatment of patients with stage III melanoma with BRAF V600E/K mutations

THE ONLY ORAL ADJUVANT THERAPY WITH 3-YEAR OS DATA1,2,7

TAFINLAR + MEKINIST demonstrated an estimated 86% rate of OS vs 77% with placeboa

  • These results did not meet the prespecified boundary to claim statistical significance at this first OS interim analysis (P=.000019)

OS in the COMBI-AD study7

Overall survival (3-year) in the adjuvant treatment of patients with stage III melanoma with BRAF V600E/K mutations with TAFINLAR® (dabrafenib) + MEKINIST® (trametinib) Overall survival (3-year) in the adjuvant treatment of patients with stage III melanoma with BRAF V600E/K mutations with TAFINLAR® (dabrafenib) + MEKINIST® (trametinib)

From The New England Journal of Medicine, Long GV, Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma, Volume No. 377, Page No. 1818. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

HR, hazard ratio; OS, overall survival.
a First interim analysis of OS was taken at the same time as the primary analysis for relapse-free survival, with a median followup of 2.8 years.

  • Based on 153 events (60 [14%] in the combination arm and 93 [22%] in the placebo arm)7
  • Results at 12, 24, and 36 months were not prespecified and are observational in nature; as such there was no prespecified statistical procedure controlling for type 1 error
Median duration of treatment with TAFINLAR + MEKINIST was 11 months Median duration of treatment with TAFINLAR + MEKINIST was 11 months

*Recommended treatment duration of up to 12 months or until disease recurrence or unacceptable toxicity.1,2

Consistent RFS regardless of patient type (updated 4-year analysis)

HRs for RFS, according to subgroup10

Hazard ratios for RFS according to subgroup Hazard ratios for RFS according to subgroup

Adapted with permission. © 2018 American Society of Clinical Oncology. All rights reserved.
AJCC, American Joint Committee on Cancer. 2017.

  • Small patient numbers can be a limitation of subgroup analysis. These analyses are not intended to demonstrate efficacy in particular subgroups

The only oral therapy approved

References: 1. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 2. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 3. Zelboraf [prescribing information]. South San Francisco, CA: Genentech Inc; 2017. 4. Cotellic [prescribing information]. South San Francisco, CA: Genentech Inc; 2018. 5. Braftovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2018. 6. Mektovi [prescribing information]. Boulder, CO: Array BioPharma Inc; 2018. 7. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF mutated melanoma. N Engl J Med. 2017;377(19):1813-1823. 8. Supplement to: Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813-1823. 9. Hauschild A, Santinami M, Long GV, et al. COMBI-AD: Adjuvant dabrafenib plus trametinib for resected stage III BRAF V600-mutant melanoma. Presented at: 2017 European Society for Medical Oncology Congress; September 2017; Madrid, Spain. 10. Hauschild A, Dummer R, Schadendorf D, et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600–mutant stage III melanoma. J Clin Oncol. 2018. doi:10.1200/JCO.18.01219. 11. Data on file. Clinical study report. BRF115532/DRB436F2301. Novartis Pharmaceuticals Corp; October 12, 2017.

Indications

TAFINLAR® (dabrafenib) capsules, in combination with MEKINIST® (trametinib) tablets, 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.

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

Limitation of Use: TAFINLAR is not indicated for the treatment of patients with wild-type BRAF melanoma.

Important Safety Information

New Primary Malignancies.

Cutaneous Malignancies: In the COMBI-d study in patients with unresectable or metastatic melanoma, the incidence of basal cell carcinoma in patients receiving TAFINLAR with MEKINIST was 3.3% compared with 6% of patients receiving single-agent TAFINLAR. Among the 7 patients receiving TAFINLAR with MEKINIST who developed basal cell carcinoma, 2 experienced more than 1 occurrence (range: 1 to 3). Cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma, and new primary melanoma occurred in 3% and 0.5% of patients receiving TAFINLAR with MEKINIST, respectively.

In the COMBI-AD study, cuSCC and new primary melanoma occurred in 1% and <1% of patients receiving TAFINLAR with MEKINIST, respectively.

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

Noncutaneous Malignancies: In the COMBI-d study, noncutaneous malignancies occurred in 1.4% of patients receiving TAFINLAR with MEKINIST. In the COMBI-AD study, noncutaneous malignancies occurred in 1% of patients receiving TAFINLAR with MEKINIST. Monitor patients closely for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for monomeric G protein (RAS)-mutation–positive noncutaneous malignancies. No dose modification of MEKINIST is required for patients who develop noncutaneous malignancies.

Tumor Promotion in BRAF Wild-type Tumors. In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase (MAPK) signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of therapy.

Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur. In the COMBI-d study, the incidence of hemorrhagic events in patients treated with the combination was 19% compared with 15% of patients receiving single-agent TAFINLAR. Gastrointestinal hemorrhage occurred in 6% of patients treated with the combination compared with 3% of patients receiving single-agent TAFINLAR. In the COMBI-d study, intracranial hemorrhage was fatal in 1.4% of patients receiving the combination. No fatal hemorrhagic events were observed in the COMBI-AD study.

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

Colitis and Gastrointestinal Perforation. Colitis and gastrointestinal perforation, including fatal outcomes, can occur. Across clinical trials with MEKINIST, colitis occurred in 0.6% of patients and gastrointestinal perforation occurred in 0.3% of patients, respectively. Monitor patients closely for colitis and gastrointestinal perforations.

Venous Thromboembolism. In the COMBI-d study, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 2.8% of patients treated with the combination. In the COMBI-AD study, DVT and PE occurred in 2% of patients receiving TAFINLAR with MEKINIST.

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 MEKINIST for life-threatening PE. Withhold MEKINIST for uncomplicated DVT or PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose.

Cardiomyopathy. Cardiomyopathy, including cardiac failure, can occur. In the COMBI-d study, cardiomyopathy (defined as a decrease in left ventricular ejection fraction [LVEF] ≥10% from baseline and below the institutional lower limit of normal [LLN]) occurred in 6% of patients treated with the combination and 2.9% of patients receiving single-agent TAFINLAR, and resulted in dose interruption (4.4%), dose reduction (2.4%), and permanent discontinuation (1.5%) of MEKINIST. Development of cardiomyopathy resulted in dose interruption of TAFINLAR (4.4%) or discontinuation of TAFINLAR (1.0%) in patients receiving the combination. In patients receiving single-agent TAFINLAR, development of cardiomyopathy resulted in dose interruption, reduction, or discontinuation in 2.4%, 0.5%, and 1.0% of patients, respectively. Cardiomyopathy resolved in 10 of 12 patients receiving the combination and in 3 of 6 patients receiving single-agent TAFINLAR.

In the COMBI-AD study, cardiomyopathy, defined as a decrease in LVEF below the institutional LLN with an absolute decrease in LVEF >10% below screening, occurred in 3% of patients receiving TAFINLAR with MEKINIST and resulted in discontinuation, dose reduction, and dose interruption of drug in 0.2%, 1.6%, and 2.1% of patients, respectively. Cardiomyopathy resolved in 12 of 14 patients receiving TAFINLAR with MEKINIST.

Assess LVEF by an echocardiogram or a multigated acquisition (MUGA) scan before initiation of therapy, 1 month after initiation then at 2- to 3-month intervals while on treatment. Withhold TAFINLAR for symptomatic cardiomyopathy or asymptomatic left ventricular dysfunction of >20% from baseline that is below institutional LLN. Resume TAFINLAR at the same dose level upon recovery of cardiac function to at least the institutional LLN for LVEF and absolute decrease ≤10% compared with baseline. For an asymptomatic absolute decrease in LVEF of ≥10% from baseline that is below the LLN, withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume at a lower dose. If no improvement to normal LVEF value within 4 weeks, permanently discontinue MEKINIST. For symptomatic cardiomyopathy or an absolute decrease in LVEF of >20% from baseline that is below LLN, permanently discontinue MEKINIST.

Ocular Toxicities.

Retinal Vein Occlusion (RVO): Across all clinical trials including MEKINIST, the incidence of RVO was 0.2%. RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmologic evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO.

Retinal Pigment Epithelial Detachment (RPED): RPED can occur. Retinal detachments may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina. In clinical trials, routine monitoring of patients to detect asymptomatic RPED was not conducted; therefore, the true incidence of this finding is unknown.

Perform ophthalmologic evaluation periodically, and at any time a patient reports visual disturbances. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmologic evaluation within 3 weeks, resume MEKINIST at the same or a reduced dose. If no improvement after 3 weeks, resume at a reduced dose or permanently discontinue MEKINIST.

Uveitis: Uveitis occurred in 2% of patients treated with the combination across metastatic melanoma trials. Treatment employed in clinical trials included steroid and mydriatic ophthalmic drops.

Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, and eye pain). If iritis is diagnosed, administer ocular therapy and continue TAFINLAR without dose modification. If severe uveitis (ie, iridocyclitis) or if mild or moderate uveitis does not respond to ocular therapy, withhold TAFINLAR and treat as clinically indicated. Resume TAFINLAR at the same or lower dose if uveitis improves to grade 0 or 1. Permanently discontinue TAFINLAR for persistent grade 2 or greater uveitis of >6 weeks.

Interstitial Lung Disease (ILD). In clinical trials of MEKINIST as a single agent, ILD or pneumonitis occurred in 2% of patients. In the COMBI-d study, 1.0% of patients treated with the combination developed pneumonitis. In the COMBI-AD study, <1% of patients treated with the combination developed pneumonitis.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.

Serious Febrile Reactions. The incidence and severity of pyrexia are increased when the combination is used compared with TAFINLAR as a single agent.

In patients treated with the combination in the metastatic melanoma studies, the incidence of fever was 54% and serious febrile reactions or fever of any severity complicated by severe rigors or chills, hypotension, dehydration, renal failure, or syncope occurred in 17%. About half of the patients taking combination therapy who experienced pyrexia had 3 or more discrete episodes. Fever was complicated by severe chills or rigors in 0.4%, dehydration in 1.8%, renal failure in 0.5%, and syncope in 0.7% in patients receiving the combination.

Withhold TAFINLAR for temperature of ≥101.3ºF or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Withhold MEKINIST for a temperature of >104ºF or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Upon resolution, resume at same or lower dose. Administer antipyretics as secondary prophylaxis when resuming TAFINLAR and/or MEKINIST if the patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (eg, prednisone 10 mg daily) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia, or for pyrexia associated with complications such as hypotension, severe rigors or chills, dehydration, or renal failure, and there is no evidence of active infection.

Serious Skin Toxicity. Across clinical trials of the combination in unresectable metastatic melanoma, serious skin toxicity occurred in 0.7% of patients.

In the COMBI-d study, the overall incidence of any skin toxicity was 55% for patients receiving the combination. No serious or severe cases of skin toxicity occurred in patients treated with the combination. Reductions in the dose of MEKINIST were required in 5% of patients receiving the combination, and no patient required permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Withhold TAFINLAR and MEKINIST for intolerable or severe skin toxicity. Resume TAFINLAR and MEKINIST at a lower dose level in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue TAFINLAR and MEKINIST if skin toxicity has not improved within 3 weeks.

Hyperglycemia. In the COMBI-d study, 27% of patients with a history of diabetes receiving the combination and 13% of patients receiving single-agent TAFINLAR required more intensive hypoglycemic therapy. The incidence of grade 3 and grade 4 hyperglycemia based on laboratory values was 5% and 0.5% of patients treated with the combination, respectively. For patients receiving single-agent TAFINLAR, 4.3% of patients had grade 3 hyperglycemia based on laboratory values and no patients had grade 4 hyperglycemia.

Monitor serum glucose levels upon initiation, and as clinically appropriate in patients with preexisting diabetes or hyperglycemia. Initiate or optimize antihyperglycemic medications as clinically indicated.

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.

Embryo-fetal Toxicity. TAFINLAR and MEKINIST can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use effective nonhormonal contraception during treatment, and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective.

Most Common Adverse Reactions. In the COMBI-d and COMBI-v studies, the most common adverse reactions (≥20%) for the combination were pyrexia (54%), nausea (35%), rash (32%), chills (31%), diarrhea (31%), headache (30%), vomiting (27%), hypertension (26%), arthralgia (25%), peripheral edema (21%), and cough (20%). In the COMBI-d and COMBI-v studies, the most common grade 3 or 4 adverse reactions (≥2%) for the combination were hypertension (11%), pyrexia (5%), and hemorrhage (2%). In the COMBI-AD study, the most common adverse reactions (≥20%) for the combination were pyrexia (63%), fatigue (59%), nausea (40%), headache (39%), rash (37%), chills (37%), diarrhea (33%), vomiting (28%), arthralgia (28%), and myalgia (20%). The most common grade 3 or 4 adverse reactions (≥2%) for the combination were pyrexia (5%) and fatigue (5%).

Other Clinically Important Adverse Reactions. In the COMBI-d and COMBI-v studies, other clinically important adverse reactions observed in <10% of patients receiving the combination were pancreatitis, panniculitis, bradycardia, and rhabdomyolysis. In the COMBI-AD study, other clinically important adverse reactions observed in <20% of patients receiving the combination were blurred vision (6%), decreased ejection fraction (5%), and rhabdomyolysis (<1%).

Laboratory Abnormalities. In the COMBI-d and COMBI-v studies, treatment-emergent laboratory abnormalities occurring in ≥10% of patients receiving the combination were hyperglycemia (60%), increased aspartate aminotransferase (AST) (59%), increased blood alkaline phosphatase (49%), increased alanine aminotransferase (ALT) (48%), hypoalbuminemia (48%), neutropenia (46%), anemia (43%), hypophosphatemia (38%), lymphopenia (32%), hyponatremia (25%), and thrombocytopenia (21%). In the COMBI-AD study, treatment-emergent laboratory abnormalities occurring in ≥20% of patients receiving the combination were hyperglycemia (63%), increased AST (57%), increased ALT (48%), neutropenia (47%), hypophosphatemia (42%), increased blood alkaline phosphatase (38%), lymphopenia (26%), anemia (25%), and hypoalbuminemia (25%).

Please see full Prescribing Information for TAFINLAR and full Prescribing Information for MEKINIST.