New Primary Malignancies

Cutaneous Malignancies
In the pooled adult safety population of TAFINLAR administered with MEKINIST (“the combination”), the incidence of cutaneous squamous cell carcinoma (cuSCC, including keratoacanthomas) occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and <1% of patients, respectively.

In the pooled pediatric safety population of the combination, new primary melanoma occurred in <1% of patients.

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. In the pooled adult safety population 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.

In the pooled adult safety population of the combination, hemorrhagic events occurred in 17% of patients; gastrointestinal hemorrhage occurred in 3% of patients; intracranial hemorrhage occurred in 0.6% of patients; fatal hemorrhage occurred in 0.5% of patients. The fatal events were cerebral hemorrhage and brainstem hemorrhage.

In the pooled pediatric safety population of the combination, hemorrhagic events occurred in 25% of patients; the most common type of bleeding was epistaxis (16%). Serious events of bleeding occurred in 3.6% of patients and included gastrointestinal hemorrhage (1.2%), cerebral hemorrhage (0.6%), uterine hemorrhage (0.6%), postprocedural hemorrhage (0.6%), and epistaxis (0.6%).

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

Venous Thromboembolic Events. In the pooled adult safety population of MEKINIST administered with TAFINLAR, deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients. In the pooled pediatric safety population of MEKINIST administered with TAFINLAR, embolism events occurred in <1% 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. In the pooled adult safety population 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. In the pooled pediatric safety population of the combination, cardiomyopathy, defined as a decrease in LVEF ≥10% from baseline and below the institutional LLN, occurred in 9% of patients.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of 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. In the pooled pediatric safety population of MEKINIST administered with TAFINLAR, RPED events occurred in <1% of patients.

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: In the pooled adult safety population of the combination, uveitis occurred in 2% of patients. In the pooled pediatric safety population of the combination, uveitis occurred in 1.2% of patients.

Treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (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. In the pooled safety population of MEKINIST administered with TAFINLAR, ILD 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.

In the pooled adult safety population 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.

In the pooled pediatric safety population of the combination, pyrexia occurred in 66% of patients.

Withhold TAFINLAR and MEKINIST for temperature of ≥100.4 ºF. 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.

In the pooled adult safety population of the combination, other serious skin toxicity occurred in <1% of patients. In the pooled pediatric safety population of the combination, serious adverse events of skin and subcutaneous tissue disorders occurred in 1.8% of patients.

Monitor for new or worsening serious skin reactions. Permanently discontinue 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. In the pooled adult safety population 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. In the pooled pediatric safety population of the combination, grade 3 and grade 4 hyperglycemia events occurred in <1% 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.

Hemophagocytic Lymphohistiocytosis (HLH). HLH has been observed in the postmarketing setting when TAFINLAR was administered with MEKINIST. If HLH is suspected, interrupt treatment. If HLH is confirmed, discontinue treatment and initiate appropriate management of HLH.

Most Common Adverse Reactions. In Study BRF117019, the most commonly occurring adverse reactions (≥20%) in patients receiving the combination were pyrexia (55%), fatigue (50%), chills (30%), peripheral edema (22%), nausea (40%), constipation (27%), vomiting (27%), diarrhea (26%), rash (40%), headache (30%), hemorrhage (29%), cough (29%), myalgia (24%), and arthralgia (23%).

In Study X2101, the most commonly occurring adverse reactions (≥20%) in patients receiving the combination were pyrexia (75%), fatigue (48%), rash (73%), dry skin (48%), dermatitis acneiform (40%), vomiting (52%), diarrhea (42%), abdominal pain (33%), nausea (33%), constipation (23%), cough (44%), headache (35%), hemorrhage (33%), and paronychia (23%).

In the pediatric pooled safety population of Studies G2201 and X2101, the most common adverse reactions (>20%) in patients receiving the combination were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%) and dermatitis acneiform (23%). The most common (>2%) grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and aspartate aminotransferase increased (3.1%).

Other Clinically Important Adverse Reactions. In Study BRF117019, other clinically important adverse reactions observed in <20% of adult patients receiving the combination were peripheral neuropathy (9%), decreased ejection fraction (8%), atrioventricular block (2.9%), uveitis (1.9%), and hypersensitivity (1.9%). In Study X2101, other clinically important adverse reactions observed in <20% of patients receiving the combination were atrioventricular block (2.1%).

Laboratory Abnormalities. In Study BRF117019, the most common treatment-emergent laboratory abnormalities occurring at ≥20% of patients receiving the combination were hyperglycemia (61%), decreased sodium (35%), decreased magnesium (24%), increased creatinine (21%), increased alkaline phosphatase (51%), increased aspartate aminotransferase (AST) (51%), increased alanine aminotransferase (ALT) (39%), and decreased hemoglobin (44%).

In Study X2101, the most common treatment-emergent laboratory abnormalities occurring at ≥20% of patients receiving the combination were hyperglycemia (65%), hypoalbuminemia (48%), hypocalcemia (40%), decreased phosphate (38%), decreased magnesium (33%), hypernatremia (27%), hypokalemia (21%), increased AST (55%), increased ALT (40%), increased alkaline phosphatase (28%), increased total bilirubin (21%), decreased hemoglobin (60%), and decreased neutrophils (49%).

In Study G2201, the most common treatment-emergent laboratory abnormalities occurring at ≥20% of patients receiving the combination were decreased leukocytes (59%), increased alkaline phosphatase (55%), decreased hemoglobin (46%), decreased neutrophils (44%), increased AST (37%), decreased magnesium (34%), increased magnesium (32%), decreased platelets (30%), increased ALT (29%), and increased lymphocytes (24%).

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

TAFINLAR, in combination with MEKINIST, is indicated for the treatment of adult and pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Limitation of Use: TAFINLAR, in combination with MEKINIST, is not indicated for the treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition. TAFINLAR is not indicated for the treatment of patients with wild-type BRAF solid tumors.