TAFINLAR SIDE EFFECTS

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• New Primary Malignancies.
• Tumor Promotion in BRAF Wild-Type Tumors.
• Hemorrhage.
• Cardiomyopathy.
• Uveitis.
• Serious Febrile Reactions.
• Serious Skin Toxicities.
• Hyperglycemia.
• Glucose-6-Phosphate Dehydrogenase Deficiency.

There are additional adverse reactions associated with trametinib. Refer to the trametinib prescribing information for additional information.

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 pooled safety populations described in the WARNINGS AND PRECAUTIONS reflect exposure to TAFINLAR as a single agent in 586 patients with various solid tumors, including BRAF V600 mutationpositive unresectable or metastatic melanoma, enrolled in BREAK-2, BREAK-3, BREAK-MB, BRF113220, and BRF112680 and that to TAFINLAR administered with trametinib in 1087 patients enrolled in METRIC, MEK113583, MEK111504, COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma or NSCLC. Among these 586 patients who received TAFINLAR as a single agent, 46% were exposed for 6 months or longer and 15% were exposed for greater than one year. Among the 1087 patients who received TAFINLAR administered with trametinib, 70% were exposed for 6 months or longer and 21% were exposed for greater than one year.

Metastatic Or Unresectable BRAF V600E Or V600K Mutation-Positive Melanoma

TAFINLAR As A Single Agent

The safety of TAFINLAR was evaluated in BREAK-3, 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 1000 mg/m² intravenously every 3 weeks (n = 63). The trial excluded patients with abnormal LVEF or cardiac valve morphology (≥ Grade 2), corrected QT interval ≥ 480 milliseconds on electrocardiogram, or a known history of G6PD deficiency. The median duration on treatment was 4.9 months for patients treated with TAFINLAR and 2.8 months for dacarbazine-treated patients. The population exposed to TAFINLAR was 60% male, 99% white, and had a median age of 53 years.

The most common adverse reactions (≥ 20%) in patients treated with TAFINLAR were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES).

The incidence of adverse events resulting in permanent discontinuation of study medication in the BREAK-3 study was 3% for patients treated with TAFINLAR and 3% for patients treated with dacarbazine. The most frequent (≥ 2%) adverse reactions leading to dose reduction of TAFINLAR were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%). Table 1 and Table 2 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR as a single agent in the BREAK-3 study.

Table 1: Select Adverse Reactions Occurring in ≥ 10% (All Grades) or ≥ 2% (Grades 3 or 4) of Patients Treated with TAFINLAR in the BREAK-3 Study^a

Adverse Reactions	TAFINLAR N = 187		Dacarbazine N = 59
	All Grades (%)	Grades 3 and 4b (%)	All Grades (%)	Grades 3 and 4 (%)
Skin and subcutaneous tissue
Hyperkeratosis	37	1	0	0
Alopecia	22	NA	2	NA
Palmar-plantar erythrodysesthesia syndrome	20	2	2	0
Rash	17	0	0	0
Nervous system
Headache	32	0	8	0
General
Pyrexia	28	3	10	0
Musculoskeletal
Arthralgia	27	1	2	0
Back pain	12	3	7	0
Myalgia	11	0	0	0
Neoplasms
Papillomac	27	0	2	0
cuSCCd	7	4	0	0
Respiratory
Cough	12	0	5	0
Gastrointestinal
Constipation	11	2	14	0
Infections
Nasopharyngitis	10	0	3	0
Abbreviations: cuSCC, cutaneous squamous cell carcinoma, includes squamous cell carcinoma of the skin and keratoacanthoma; NA, not applicable. a Adverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1). c Includes skin papilloma and papilloma. d Cases of cuSCC were required to be reported as Grade 3 per protocol.

 

Table 2: Laboratory Abnormalities Worsening from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in the BREAK-3 Study [Between-Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3 or 4)]^a

Laboratory Abnormality	TAFINLAR N = 187		Dacarbazine N = 59
	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
Hyperglycemia	50	6	43	0
Hypophosphatemia	37	6b	14	2
Increased alkaline phosphatase	19	0	14	2
Hyponatremia	8	2	3	0
a Adverse reactions, reported using MedDRA and graded using NCI CTCAE version 4.0 for assessment of toxicity. b Grade 4 laboratory abnormality limited to hypophosphatemia (n = 1).

 

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

Gastrointestinal: Pancreatitis

Immune System: Hypersensitivity manifesting as bullous rash

Renal and Urinary: Interstitial nephritis

TAFINLAR With Trametinib

The safety of TAFINLAR when administered with trametinib was evaluated in 559 patients with previously untreated, unresectable or metastatic, BRAF V600E or V600K mutation-positive melanoma who received TAFINLAR in two trials, the COMBI-d study (n = 209) a multicenter, double-blind, randomized (1:1), active controlled trial and the COMBI-v study (n = 350) a multicenter, open-label, randomized (1:1), active controlled trial. In the COMBI-d and COMBI-v studies, patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. Both trials excluded patients with abnormal LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), history of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED), QTcB interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, or a known history of G6PD deficiency.

Among these 559 patients, 199 (36%) were exposed to TAFINLAR for > 6 months to 12 months while 185 (33%) were exposed to TAFINLAR for ≥ 1 year. The median age was 55 years (range: 18 to 91), 57% were male, 98% were white, 72% had baseline ECOG performance status 0 and 28% had ECOG performance status 1, 64% had M1c stage disease, 35% had elevated lactate dehydrogenase (LDH) at baseline and 0.5% had a history of brain metastases.

The most common adverse reactions (≥ 20%) for TAFINLAR in patients who received TAFINLAR plus trametinib in the COMBI-d and COMBI-v studies were: pyrexia, rash, chills, headache, arthralgia, and cough. The demographics and baseline tumor characteristics of patients enrolled in the COMBI-d study are summarized in Clinical Studies. Patients who received TAFINLAR plus trametinib had a median duration of exposure of 11 months (range: 3 days to 30 months) to TAFINLAR. Among the 209 patients who received TAFINLAR plus trametinib, 26% were exposed to TAFINLAR for > 6 months to 12 months while 46% were exposed to TAFINLAR for > 1 year.

In the COMBI-d study, adverse reactions resulting in discontinuation of TAFINLAR occurred in 11% of patients who received TAFINLAR plus trametinib; the most frequent was pyrexia (1.9%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 26% of patients who received TAFINLAR plus trametinib; the most frequent were pyrexia (14%), neutropenia (1.9%), rash (1.9%), and chills (1.9%). Adverse reactions leading to dose interruptions of TAFINLAR occurred in 56% of patients who received TAFINLAR plus trametinib; the most frequent were pyrexia (35%), chills (11%), vomiting (7%), nausea (5%), and decreased ejection fraction (5%).

Table 3 and Table 4 present adverse reactions and laboratory abnormalities, respectively, observed in the COMBI-d study.

Table 3: Select Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Treated with TAFINLAR Administered with Trametinib in the COMBI-d Study^a

Adverse Reactions	Pooled TAFINLAR plus		COMBI-d Study
	Trametinib N = 559		TAFINLAR plus Trametinib N = 209		TAFINLAR N =211
	All Grades(%)	Grades 3 and 4b (%)	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
General
Pyrexia	54	5	57	7	33	1.9
Chills	31	0.5	31	0	17	0.5
Skin
Rashc	32	1.1	42	0	27	1.4
Dry skin	10	0	12	0	16	0
Nervous system
Headache	30	0.9	33	0.5	30	1.4
Dizziness	11	0.2	14	0	7	0
Musculoskeletal
Arthralgia	25	0.9	26	0.9	31	0
Myalgia	15	0.2	13	0.5	13	0
Respiratory
Cough	20	0	21	0	21	0
Gastrointestinal
Constipation	13	0.2	13	0.5	10	0
Infections
Nasopharyngitis	12	0	12	0	10	0
a NCI CTCAE version 4.0. b Grade 4 adverse reactions limited to headache (n = 1). c Includes rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, rash maculo-papular, and rash folliculitis.

 

Other clinically important adverse reactions for TAFINLAR across the COMBI-d and COMBI-v studies (N = 559) observed in less than 10% of patients who received TAFINLAR administered with trametinib were:

Gastrointestinal: Colitis, Gastrointestinal perforation, Pancreatitis

Immunologic: Sarcoidosis

Subcutaneous Tissue: Panniculitis

Table 4: Select Laboratory Abnormalities Worsening from Baseline Occurring at ≥ 10% (All Grades) of Patients Who Received TAFINLAR with Trametinib in the COMBI-d Study

Laboratory Abnormality	Pooled TAFINLAR plus Trametinib N = 559a		COMBI-d Study
			TAFINLAR plus Trametinib N = 209b		TAFINLAR N = 211b
	All Grades (%)	Grades 3 and 4c (%)	All Grades (%)	Grades 3 and 4c (%)	All Grades (%)	Grades 3 and 4c (%)
Chemistry
Hyperglycemia	60	4.7	65	6	57	4.3
Hypophosphatemia	38	6	38	3.8	35	7
Hyponatremia	25	8	24	6	14	2.9
Hepatic
Increased blood alkaline phosphatase	49	2.7	50	1.0	25	0.5
a For these laboratory tests the denominator is 556. b For these laboratory tests the denominator is 208 for the combination arm, 208-209 for the TAFINLAR arm. c Grade 4 adverse reactions limited to hyperglycemia (n = 4), hyponatremia and hypophosphatemia (each n = 1), in the pooled combination arm; hyperglycemia (n = 1) in the COMBI-d study combination arm; hypophosphatemia (n = 1) in the TAFINLAR arm.

 

Adjuvant Treatment Of BRAF V600E Or V600K Mutation-Positive Melanoma

The safety of TAFINLAR when administered with trametinib was evaluated in 435 patients with Stage III melanoma with BRAF V600E or V600K mutations following complete resection who received at least one dose of study therapy in the COMBI-AD study. Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily for 12 months. The trial excluded patients with abnormal left ventricular ejection fraction; history of acute coronary syndromes, coronary angioplasty, or stenting within 6 months; Class II or greater congestive heart failure (New York Heart Association); QTc interval ≥ 480 msec; treatment-refractory hypertension; uncontrolled arrhythmias; or history of RVO. The median age of patients who received TAFINLAR administered with trametinib was 50 years (range: 18 to 89), 56% were male, 99% were white, 92% had baseline ECOG performance status 0, and 8% had baseline ECOG performance status of 1. Patients who received TAFINLAR in combination with trametinib had a median duration of exposure of 11 months (range: 0 to 12) to TAFINLAR. Among the 435 patients receiving TAFINLAR in combination with trametinib, 71% were exposed to TAFINLAR for > 6 months.

The most common adverse reactions (≥ 20%) in patients who received TAFINLAR administered with trametinib were: pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.

Adverse reactions resulting in discontinuation, dose reduction, or dose interruption of TAFINLAR occurred in 25%, 35%, and 66% of patients, respectively; the most frequent for each were pyrexia and chills.

Table 5 summarizes adverse reactions that occurred in at least 20% of patients who received TAFINLAR administered with trametinib.

Table 5: Adverse Reactions Occurring in ≥ 20% of Patients in the COMBI-AD Study^a

Adverse Reactions	TAFINLAR plus Trametinib N = 435		Placebo N = 432
	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
General
Pyrexiab	63	5	11	< 1
Fatiguec	59	5	37	< 1
Chills	37	1	4	0
Gastrointestinal
Nausea	40	< 1	20	0
Diarrhea	33	< 1	15	< 1
Vomiting	28	< 1	10	0
Nervous system
Headached	39	1	24	0
Skin
Rashe	37	< 1	16	< 1
Musculoskeletal
Arthralgia	28	< 1	14	0
Myalgiaf	20	< 1	14	0
a NCI CTCAE version 4.0. b Includes pyrexia and hyperpyrexia. c Includes fatigue, asthenia, and malaise. d Includes headache and tension headache. e Includes rash, rash maculo-papular, rash macular, rash generalized, rash erythematous, rash papular, rash pruritic, nodular rash, rash vesicular, and rash pustular. f Includes myalgia, musculoskeletal pain, and musculoskeletal chest pain.

 

Other clinically important adverse reactions observed in less than 20% of patients in the COMBI-AD study who received TAFINLAR administered with trametinib were blurred vision (6%), ejection fraction decreased (5%), rhabdomyolysis (< 1%), and sarcoidosis (< 1%).

The laboratory abnormalities are summarized in Table 6.

Table 6: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the COMBI-AD Study

Laboratory Abnormality	TAFINLAR plus Trametiniba N = 435		Placeboa N = 432
	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
Chemistry
Hyperglycemia	63	3	47	2
Hypophosphatemia	42	7	10	< 1
Hypoalbuminemia	25	< 1	< 1	0
Hepatic
Increased AST	57	6	11	< 1
Increased ALT	48	5	18	< 1
Increased blood alkaline phosphatase	38	1	6	< 1
Hematology
Neutropenia	47	6	12	< 1
Lymphopenia	26	5	6	< 1
Anemia	25	< 1	6	< 1
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement: TAFINLAR plus Trametinib (range: 429 to 431) and placebo arm (range: 426 to 428).

 

Trial COMBI-APlus (Pyrexia Management Study)

COMBI-APlus evaluated the impact of pyrexia related outcomes of a revised pyrexia management algorithm in patients who received dabrafenib administered with trametinib in the adjuvant treatment of BRAF V600 mutation-positive melanoma after complete resection. The pyrexia management algorithm interrupted both dabrafenib and trametinib when patient’s temperature is ≥ 100.4°F.

Grade 3-4 pyrexia occurred in 4.3% of patients, hospitalizations due to pyrexia occurred in 5.1% of patients, pyrexia with complications (dehydration, hypotension, renal dysfunction, syncope, severe chills) occurred in 2.2% of patients, and treatment discontinuation due to pyrexia occurred in 2.5% of patients.

Metastatic, BRAF V600E -Mutation Positive Non-Small Cell Lung Cancer

The safety of TAFINLAR when administered with trametinib was evaluated in 93 patients with previously untreated (n = 36) and previously treated (n = 57) metastatic BRAF V600E mutation-positive NSCLC in a multicenter, multi-cohort, non-randomized, open-label trial (Study BRF113928). Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. The trial excluded patients with abnormal LVEF, history of acute coronary syndrome within 6 months, history of Class II or greater congestive heart failure (New York Heart Association), QTc interval ≥ 480 msec, treatment refractory hypertension, uncontrolled arrhythmias, active brain metastases, history of interstitial lung disease or pneumonitis, or history or current RVO.

Among these 93 patients, 53 (57%) were exposed to TAFINLAR and trametinib for > 6 months and 27 (29%) were exposed to TAFINLAR and trametinib for ≥ 1 year. The median age was 65 years (range: 41 to 91); 46% were male; 85% were white; 32% had baseline ECOG performance status 0 and 61% had ECOG performance status 1; 98% had non-squamous histology; and 12% were current smokers, 60% were former smokers, and 28% had never smoked.

The most common adverse reactions (≥ 20%) in these 93 patients were: pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.

Adverse reactions resulting in discontinuation of TAFINLAR occurred in 18% of patients; the most frequent were pyrexia (2.2%), decreased ejection fraction (2.2%), and respiratory distress (2.2%). Adverse reactions leading to dose reductions of TAFINLAR occurred in 35% of patients; the most frequent were pyrexia (10%), diarrhea (4.3%), nausea (4.3%), vomiting (4.3%), and neutropenia (3.2%). Adverse reactions leading to dose interruptions of TAFINLAR occurred in 62% of patients; the most frequent were pyrexia (27%), vomiting (11%), neutropenia (8%), and chills (6%).

Table 7 and Table 8 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR administered with trametinib in Study BRF113928.

Table 7: Adverse Reactions Occurring in ≥ 20% (All Grades) of Patients Treated with TAFINLAR Administered with Trametinib in Study BRF113928^a

Adverse Reactions	TAFINLAR plus Trametinib N = 93
	All Grades (%)	Grades 3 and 4b (%)
General
Pyrexia	55	5
Fatigueb	51	5
Edemac	28	0
Chills	23	1.1
Gastrointestinal
Nausea	45	0
Vomiting	33	3.2
Diarrhea	32	2.2
Decreased appetite	29	0
Skin
Dry skin	31	1.1
Rashd	28	3.2
Vascular
Hemorrhagee	23	3.2
Respiratory system
Cough	22	0
Dyspnea	20	5
a NCI CTCAE version 4.0. b Includes fatigue, malaise, and asthenia. c Includes peripheral edema, edema, and generalized edema. d Includes rash, rash generalized, rash papular, rash macular, rash maculo-papular, and rash pustular. e Includes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.

 

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

Gastrointestinal: Pancreatitis

Renal and Urinary: Tubulointerstitial nephritis

Table 8: Treatment-Emergent Laboratory Abnormalities Occurring in ≥ 20% (All Grades) of Patients Who Received TAFINLAR with Trametinib in Study BRF113928

Laboratory Abnormality	TAFINLAR plus Trametinib N = 93
	All Grades (%)	Grades 3 and 4 (%)
Chemistrya
Hyperglycemia	71	9
Hyponatremia	57	17
Hypophosphatemia	36	7
Increased creatinine	21	1.1
Hepatica
Increased blood alkaline phosphatase	64	0
Increased AST	61	4.4
Increased ALT	32	6
Hematologyb
Leukopenia	48	8
Anemia	46	10
Neutropenia	44	8
Lymphopenia	42	14
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a For these laboratory tests the denominator is 90. b For these laboratory tests the denominator is 91.

 

Locally Advanced Or Metastatic, BRAF V600E-Mutation Positive Anaplastic Thyroid Cancer

The safety of TAFINLAR when administered with trametinib was evaluated in a nine-cohort, multicenter, nonrandomized, open-label study in patients with rare cancers with the BRAF V600E mutation, including locally advanced or metastatic ATC (Study BRF117019). At the time of the safety analysis, a total of 100 patients were enrolled in the trial, 16 of whom were enrolled in the ATC cohort. The primary safety population included all patients who received at least one dose of TAFINLAR or trametinib. Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity.

Among these 100 patients, 46 (46%) were exposed to TAFINLAR and trametinib for > 6 months and 23 (23%) were exposed to TAFINLAR and trametinib for ≥ 1 year. The median age was 59.5 years (range: 18 to 85); 62% were male; 85% were white; and 31% had baseline ECOG performance status 0 and 59% had ECOG performance status 1.

The adverse reaction profile among all patients and among patients in the ATC cohort was similar to that observed in other approved indications.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of TAFINLAR in combination with trametinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatologic: SCAR (including DRESS and SJS)