Tafinlar (Page 3 of 10)

5.10 Risks Associated With Combination Treatment

TAFINLAR is indicated for use in combination with trametinib. Review the prescribing information for trametinib for information on the serious risks of trametinib prior to initiation of TAFINLAR with trametinib.

5.11 Embryo-Fetal Toxicity

Based on findings from animal studies and 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. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective non-hormonal contraception, since TAFINLAR can render hormonal contraceptives ineffective, during treatment with TAFINLAR and for 2 weeks after the last dose [see Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

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

  • New Primary 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)]
  • Cardiomyopathy [see Warnings and Precautions (5. 4 )]
  • Uveitis [see Warnings and Precautions (5. 5 )]
  • Serious Febrile Reactions [see Warnings and Precautions (5. 6 )]
  • Serious Skin Toxicities [see Warnings and Precautions (5. 7 )]
  • Hyperglycemia [see Warnings and Precautions (5. 8 )]
  • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5. 9 )]

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

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 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 mutation-positive 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) [see Clinical Studies (14.1)]. The trial excluded patients with abnormal left ventricular ejection fraction (LVEF) 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 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 3 and Table 4 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR as a single agent in the BREAK-3 study.

Table 3. Select Adverse Reactions Occurring in ≥ 10% (All Grades) or ≥ 2% (Grades 3 or 4) of Patients Treated With TAFINLAR in the BREAK-3 Studya
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.
TAFINLAR N = 187 Dacarbazine N = 59
Adverse Reactions All Grades (%) Grades 3 and 4 b (%) 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
Table 4. 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
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).
TAFINLAR N = 187 Dacarbazine N = 59
Laboratory Abnormality 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

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 [see Clinical Studies (14.2)].

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 [see Clinical Studies (14.2)]. 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 5 and Table 6 present adverse reactions and laboratory abnormalities, respectively, observed in the COMBI-d study.

Table 5. Select Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Treated With TAFINLAR Administered With Trametinib in the COMBI-d Studya
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.
Pooled TAFINLAR plus Trametinib N = 559 COMBI-d Study
TAFINLAR plus Trametinib N = 209 TAFINLAR N = 211
Adverse Reactions All Grades (%) Grades 3 and 4 b (%) 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

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 6. Select Laboratory Abnormalities Worsening from Baseline Occurring at ≥ 10% (All Grades) of Patients Who Received TAFINLAR With Trametinib in the COMBI-d Study
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.
Laboratory Abnormality Pooled TAFINLAR plus T rametinib N = 559 a COMBI-d Study
TAFINLAR plus Trametinib N = 209 b TAFINLAR N = 211 b
All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%) All Grades (%) Grades 3 and 4 c (%)
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

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 [see Clinical Studies (14.3)]. 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 retinal vein occlusion. 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 7 summarizes adverse reactions that occurred in at least 20% of patients who received TAFINLAR administered with trametinib.

Table 7. Adverse Reactions Occurring in ≥ 20% of Patients in the COMBI-AD Studya
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.
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

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 8.

Table 8. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the COMBI-AD Study
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).
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

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 left ventricular ejection fraction, 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 retinal vein occlusion [see Clinical Studies (14.4)].

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 9 and Table 10 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR administered with trametinib in Study BRF113928.

Table 9. Adverse Reactions Occurring in ≥ 20% (All Grades) of Patients Treated With TAFINLAR Administered with Trametinib in Study BRF113928a
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.
Adverse Reactions TAFINLAR plus T rametinib N = 93
All Grades (%) Grades 3 and 4 b (%)
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

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 10. Treatment-Emergent Laboratory Abnormalities Occurring in ≥ 20% (All Grades) of Patients Who Received TAFINLAR With Trametinib in Study BRF113928
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.
Laboratory Abnormality TAFINLAR plus Trametinib N = 93
All Grades (%) Grades 3 and 4 (%)
Chemistry a
Hyperglycemia 71 9
Hyponatremia 57 17
Hypophosphatemia 36 7
Increased creatinine 21 1.1
Hepatic a
Increased blood alkaline phosphatase 64 0
Increased AST 61 4.4
Increased ALT 32 6
Hematology b
Leukopenia 48 8
Anemia 46 10
Neutropenia 44 8
Lymphopenia 42 14

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, non-randomized, 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.

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