For:

BRAF+ Advanced Melanoma or BRAF+ Melanoma Involving Lymph Nodes After Surgery

IMPORTANT SAFETY INFORMATION AND INDICATIONS

Important Safety Information

New Primary Malignancies

Cutaneous Malignancies

Across clinical trials of TAFINLAR administered with MEKINIST (“the combination”), the incidence of cutaneous squamous cell carcinomas (cuSCCs), including keratoacanthomas, occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and <1% of patients, respectively.

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

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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

For the adjuvant treatment of patients with BRAF V600E/K melanoma and involvement of lymph node(s), following complete resection

COMBI-AD STUDY DESIGN^1-4

12 months of treatment^a

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. 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. ^cDefined as the time from randomization to disease recurrence, new primary melanoma, or death from any cause.

KEY ELIGIBILITY CRITERIA

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 0 or 1
No prior radiotherapy or anticancer systemic therapy

COMBI-AD included patients with substages A-C of stage III disease prior to resection⁵

19% of these patients had micrometastasis and no primary tumor ulceration (n=165/870 with no ulceration and micrometastasis; 5-year update)

Follow-up until end of study⁶

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

5-Year Relapse-Free Survival

In COMBI-AD–For the adjuvant treatment of patients with BRAF V600E/K melanoma and involvement of lymph node(s), following complete resection

52% OF PATIENTS WERE RELAPSE FREE AND ALIVE AT 5 YEARS⁵

RFS in COMBI-AD study (as of November 8, 2019, data cutoff)^5,7,a

HR, hazard ratio; RFS, relapse-free survival.
^aFirst tumor assessment was performed at 3 months.⁸

49% reduction in risk of relapse or death vs placebo at 5 years⁵

Median duration of follow-up for updated analysis was 60 months in the TAFINLAR + MEKINIST treatment arm and 58 months for the placebo arm⁵
At the 5-year follow-up, median relapse-free survival (RFS) was still not reached (NR) (95% CI, 47.9-NR) vs 16.6 months (95% CI, 12.7-22.1) for placebo in COMBI-AD (hazard ratio [HR], 0.51; 95% CI, 0.42-0.61)⁵
Results at 12, 24, 36, 48, and 60 months were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error
In the primary analysis, the median RFS was not reached in the TAFINLAR + MEKINIST group (95% CI, 44.5-not estimable) and 16.6 months in the placebo group (95% CI, 12.7-22.1); (HR, 0.47; 95% CI, 0.39-0.58; P<.0001)^3,4

HRs for RFS, according to subgroup⁵

Adapted with permission. © 2018 American Society of Clinical Oncology. All rights reserved.
AJCC, American Joint Committee on Cancer 2017; HR, hazard ratio; RFS, relapse-free survival.

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

5-Year Distant Metastasis-Free Survival

5-year DMFS with TAFINLAR + MEKINIST vs placebo (as of November 8, 2019, data cutoff)^5,a

DMFS, distant metastasis-free survival.
^aDMFS was defined as the time from randomization to the date of first distant metastasis or date of death, whichever occurred first.¹

Distant metastasis-free survival (DMFS) favored the treatment arm vs placebo with extended follow-up, though median DMFS was NR in either arm (HR, 0.55; 95% CI, 0.44-0.70)⁵
- TAFINLAR + MEKINIST: median DMFS NR (95% CI, NR-NR)
- Placebo: median DMFS NR (95% CI, 49.8-NR)

Discontinuation due to disease recurrence with TAFINLAR + MEKINIST (as of June 30, 2017, data cutoff)²

5% of patients taking TAFINLAR + MEKINIST discontinued treatment prematurely due to disease recurrence vs 41% with placebo (median follow-up 2.8 years; June 2017 cutoff)²

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

3-Year Overall Survival

In COMBI-AD–For the adjuvant treatment of patients with BRAF V600E/K melanoma and involvement of lymph node(s), following complete resection

86% OF PATIENTS WERE ALIVE AT 3 YEARS VS 77% WITH PLACEBO^1,3,4,a

OS in COMBI-AD (as of June 30, 2017, data cutoff)^1,3,4,a

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, RFS, relapse-free survival.
^aFirst interim analysis of OS was taken at the same time as the primary analysis for RFS, with a median follow-up of 2.8 years.¹

These results did not meet the prespecified boundary to claim statistical significance at this first OS interim analysis (P=.000019); median OS had not been reached in either treatment group as of the data cutoff at a median of 2.8 years of follow-up¹
Based on 153 events (60 [14%] in the TAFINLAR + MEKINIST arm and 93 [22%] in the placebo arm)¹
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

NEXT: Efficacy—Metastatic

References: 1. 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. 2. 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. 3. Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp. 4. Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp. 5. Dummer R, Hauschild A, Santinami M, et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage III melanoma. N Engl J Med. 2020;383(12):1139-1148. 6. Data on file. COMBI-AD: adjuvant dabrafenib plus trametinib for resected Stage III BRAF V600–mutant melanoma. Novartis Pharmaceuticals Corp; September 2017. 7. Data on file. FIR Documentation. BRF115532/CDRB436F2301. Novartis Pharmaceuticals Corp; February 19, 2019. 8. Data on file. Clinical study report. BRF115532/DRB436F2301. Novartis Pharmaceuticals Corp; October 21, 2017. 9. Braftovi [prescribing information]. Boulder, CO: Array BioPharma Inc. 10. Mektovi [prescribing information]. Boulder, CO: Array BioPharma Inc. 11. Zelboraf [prescribing information]. South San Francisco, CA: Genentech Inc. 12. Cotellic [prescribing information]. South San Francisco, CA: Genentech Inc.

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.

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

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

Noncutaneous Malignancies

Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of monomeric G protein (RAS) through mutation or other mechanisms. Across clinical trials of TAFINLAR monotherapy and the combination, noncutaneous malignancies occurred in 1% of patients.

Monitor patients receiving the combination for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for RAS-mutation–positive noncutaneous malignancies. No dose modification is required for MEKINIST in 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. Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with the combination. Fatal cases have been reported.

Across clinical trials of the combination, hemorrhagic events occurred in 17% of patients. Gastrointestinal hemorrhage occurred in 3% of patients who received the combination. Intracranial hemorrhage occurred in 0.6% of patients who received the combination. Fatal hemorrhage occurred in 0.5% of patients who received the combination. The fatal events were cerebral hemorrhage and brainstem hemorrhage.

Permanently discontinue TAFINLAR for all grade 4 hemorrhagic events and for any grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for grade 3 hemorrhagic events; if improved, resume at the next lower dose level. Permanently discontinue MEKINIST for all grade 4 hemorrhagic events and for any grade 3 hemorrhagic events that do not improve. Withhold 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 of the combination, colitis occurred in <1% of patients and gastrointestinal perforation occurred in <1% of patients. Monitor patients closely for colitis and gastrointestinal perforations.

Venous Thromboembolic Events. Across clinical trials of the combination, deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients.

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

Cardiomyopathy. Cardiomyopathy, including cardiac failure, can occur. Across clinical trials of the combination, cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥10% from baseline and below the institutional lower limit of normal (LLN), occurred in 6% of patients. Development of cardiomyopathy resulted in dose interruption or discontinuation of TAFINLAR in 3% and <1% of patients, respectively, and in 3% and <1% of patients receiving MEKINIST, respectively. Cardiomyopathy resolved in 45 of 50 patients who received the combination.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of the combination, 1 month after initiation, and 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 to baseline. For an asymptomatic absolute decrease in LVEF of 10% or greater 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): There were no cases of RVO across clinical trials of the combination. 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 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)/Pneumonitis. Across clinical trials of the combination, interstitial lung disease or pneumonitis occurred in 1% of patients.

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. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur. The incidence and severity of pyrexia are increased when TAFINLAR is administered with MEKINIST.

Across clinical trials of the combination, fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure occurred in 5% of patients. Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in <1% of patients.

Withhold TAFINLAR and MEKINIST for temperature of ≥100.4ºF. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia. Fever may be complicated by hypotension, rigors or chills, dehydration, or renal failure. Evaluate for signs and symptoms of infection and monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Upon 24 hours after resolution, if appropriate, resume both TAFINLAR and MEKINIST at the same or a 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 Toxicities. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with the combination. Across clinical trials of the combination, other serious skin toxicity occurred in <1% of patients.

Monitor for new or worsening serious skin reactions. Permanently discontinue the combination for SCARs. For other skin toxicities, withhold TAFINLAR and/or MEKINIST for intolerable or severe skin toxicity. Resume TAFINLAR and/or MEKINIST at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue TAFINLAR and/or MEKINIST if skin toxicity has not improved within 3 weeks.

Hyperglycemia. Across clinical trials of the combination, 15% of patients with a history of diabetes required more intensive hypoglycemic therapy. Grade 3 and grade 4 hyperglycemia occurred in 2% of patients.

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. Monitor patients with G6PD deficiency for signs of hemolytic anemia while taking TAFINLAR.

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.

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%), rhabdomyolysis (<1%), and sarcoidosis (<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.