Tafinlar Drug Information
Generic name: DABRAFENIB
Uses of Tafinlar
BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma TAFINLAR ® is indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.
BRAF V600E Mutation-Positive Metastatic NSCLC TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test.
BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation, as detected by an FDA-approved test, and with no satisfactory locoregional treatment options.
BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors TAFINLAR is indicated, in combination with trametinib, 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 (ORR) and duration of response (DoR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
BRAF V600E Mutation-Positive Low-Grade Glioma TAFINLAR is indicated, in combination with trametinib, for the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.
Limitations of Use TAFINLAR is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition. TAFINLAR is not indicated for treatment of patients with wild-type BRAF solid tumors.
Dosage & Administration of Tafinlar
Patient Selection Melanoma Confirm the presence of BRAF
V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR as a single agent. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with TAFINLAR and trametinib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.
An FDA-approved test for the detection of BRAF V600E mutation in solid tumors other than melanoma and NSCLC is not currently available.
Recommended Dosage TAFINLAR Capsules Adult Patients
The recommended dosage for TAFINLAR capsules in adult patients is 150 mg taken orally twice daily. Pediatric Patients The recommended dosage for TAFINLAR capsules in pediatric patients who weigh at least 26 kg is based on body weight (Table 1). A recommended dosage of TAFINLAR capsules has not been established in patients who weigh less than 26 kg.
Table 1. Recommended Dosage for TAFINLAR Capsules in Pediatric Patients (Weight-based) TAFINLAR Tablets for Oral Suspension Adult and Pediatric Patients The recommended dosage for TAFINLAR tablets for oral suspension for adult and pediatric patients is based on body weight (Table 2). Table 2.
Recommended Dosage for TAFINLAR Tablets for Oral Suspension in Adult and Pediatric Patients (Weight-based) Duration of Treatment The recommended duration of treatment for patients with unresectable or metastatic melanoma or solid tumors, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity. The recommended duration of treatment in the adjuvant melanoma setting is until disease recurrence or unacceptable toxicity for up to 1 year. Combination Therapy with Trametinib Refer to the trametinib prescribing information for recommended trametinib dosing information.
Administration Take TAFINLAR at the same time each day, approximately 12 hours apart. Do not take a missed dose of TAFINLAR within 6 hours of the next dose of TAFINLAR. If vomiting occurs after TAFINLAR administration, do not take an additional dose.
Take the next dose at its scheduled time. TAFINLAR Capsules Take TAFINLAR capsules on an empty stomach (at least 1 hour before or 2 hours after a meal). Do not open, crush, or break TAFINLAR capsules.
TAFINLAR Tablets for Oral Suspension Prior to use of the oral suspension, instruct caregivers (and if appropriate, patients) on proper dosing and administration of TAFINLAR tablets for oral suspension. Take the oral suspension on an empty stomach (at least 1 hour before or 2 hours after a meal). Breastfeeding and/or baby formula may be given on demand if a pediatric patient is unable to tolerate the fasting conditions.
Do not swallow whole, chew or crush TAFINLAR tablets for oral suspension. Gently stir the water and prescribed number of tablets with the handle of a teaspoon until the tablets are fully dissolved. It may take at least 3 minutes to fully dissolve the tablets.
Once the tablets are dissolved, the oral suspension will be cloudy white. Table 3. Recommended Dosage Reductions for TAFINLAR Capsules for Adverse Reactions Reductions for TAFINLAR Tablets for Oral Suspension for Adverse Reactions Dosage modifications for adverse reactions associated with TAFINLAR are presented in Table 5.
Table 5. Recommended Dosage Modifications for TAFINLAR for Adverse Reactions Other Adverse Reactions c, including Hemorrhage Refer to the trametinib prescribing information for dose modifications for adverse reactions associated with trametinib.
| Body Weight | Recommended Dosage |
|---|---|
| 26 to 37 kg | 75 mg orally twice daily |
| 38 to 50 kg | 100 mg orally twice daily |
| 51 kg or greater | 150 mg orally twice daily |
| Body Weight | Recommended Dosage |
|---|---|
| 8 to 9 kg | 20 mg twice daily |
| 10 to 13 kg | 30 mg twice daily |
| 14 to 17 kg | 40 mg twice daily |
| 18 to 21 kg | 50 mg twice daily |
| 22 to 25 kg | 60 mg twice daily |
| 26 to 29 kg | 70 mg twice daily |
| 30 to 33 kg | 80 mg twice daily |
| 34 to 37 kg | 90 mg twice daily |
| 38 to 41 kg | 100 mg twice daily |
| 42 to 45 kg | 110 mg twice daily |
| 46 to 50 kg | 130 mg twice daily |
| ≥ 51 kg | 150 mg twice daily |
| Recommended Dosage | 75 mg orally twice daily | 100 mg orally twice daily | 150 mg orally twice daily |
|---|---|---|---|
| First dose reduction | 50 mg orally twice daily | 75 mg orally twice daily | 100 mg orally twice daily |
| Second dose reduction | N/A | 50 mg orally twice daily | 75 mg orally twice daily |
| Third dose reduction | N/A | N/A | 50 mg orally twice daily |
| Subsequent modification | Permanently discontinue if unable to tolerate TAFINLAR capsules 50 mg orally twice daily. | ||
| Body Weight (Recommended dosage) | First Dose Reduction | Second Dose Reduction | Third Dose Reduction |
|---|---|---|---|
| Tablets for oral suspension twice daily | |||
| 8 to 9 kg (20 mg twice daily) | 10 mg twice daily | N/A | N/A |
| 10 to 13 kg (30 mg twice daily) | 20 mg twice daily | 10 mg twice daily | N/A |
| 14 to 17 kg (40 mg twice daily) | 30 mg twice daily | 20 mg twice daily | 10 mg twice daily |
| 18 to 21 kg (50 mg twice daily) | 30 mg twice daily | 20 mg twice daily | 10 mg twice daily |
| 22 to 25 kg (60 mg twice daily) | 40 mg twice daily | 30 mg twice daily | 20 mg twice daily |
| 26 to 29 kg (70 mg twice daily) | 50 mg twice daily | 40 mg twice daily | 20 mg twice daily |
| 30 to 33 kg (80 mg twice daily) | 50 mg twice daily | 40 mg twice daily | 30 mg twice daily |
| 34 to 37 kg (90 mg twice daily) | 60 mg twice daily | 50 mg twice daily | 30 mg twice daily |
| 38 to 41 kg (100 mg twice daily) | 70 mg twice daily | 50 mg twice daily | 30 mg twice daily |
| 42 to 45 kg (110 mg twice daily) | 70 mg twice daily | 60 mg twice daily | 40 mg twice daily |
| 46 to 50 kg (130 mg twice daily) | 90 mg twice daily | 70 mg twice daily | 40 mg twice daily |
| ≥ 51 kg (150 mg twice daily) | 100 mg twice daily | 80 mg twice daily | 50 mg twice daily |
| a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. b See Tables 3 and 4 for recommended dose reductions of TAFINLAR. c Dose modifications are not recommended for TAFINLAR when administered with trametinib for the following adverse reactions of trametinib: retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED), interstitial lung disease/pneumonitis, and uncomplicated venous thromboembolism. Dose modification of TAFINLAR is not required for new primary cutaneous malignancies. | |
| Severity of Adverse Reaction a | Dosage Modification for TAFINLAR b |
| New Primary Malignancies [see Warnings and Precautions (5.1)] | |
| Non-Cutaneous RAS Mutation-positive Malignancies | Permanently discontinue TAFINLAR. |
| Cardiomyopathy [see Warnings and Precautions (5.4)] | |
| Symptomatic cardiomyopathy Absolute decrease in left ventricular ejection fraction (LVEF) of greater than 20% from baseline that is below the institutional lower limit of normal (LLN) | Withhold TAFINLAR until LVEF improves to at least the institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, then resume TAFINLAR at same dose. |
| Uveitis [see Warnings and Precautions (5.5)] | |
| Uveitis, including iritis and iridocyclitis | For mild or moderate uveitis that does not respond to ocular therapy, or for severe uveitis, withhold TAFINLAR for up to 6 weeks. If improved to Grade 0-1, then resume TAFINLAR at same or lower dose. If not improved, permanently discontinue TAFINLAR. |
| Febrile Reactions [see Warnings and Precautions (5.6)] | |
| Fever of 100.4°F to 104°F (or first symptoms in case of recurrence) | Withhold TAFINLAR until fever resolves, then resume TAFINLAR at same or lower dose. |
| Fever higher than 104°F Fever complicated by rigors, hypotension, dehydration, or renal failure | Withhold TAFINLAR until febrile reactions resolve for at least 24 hours, then resume TAFINLAR at lower dose. Or Permanently discontinue TAFINLAR. |
| Skin Toxicities [see Warnings and Precautions (5.7)] | |
| Intolerable Grade 2 Grade 3 or 4 | Withhold TAFINLAR for up to 3 weeks. If improved, resume TAFINLAR at lower dose. If not improved, permanently discontinue TAFINLAR. |
| Severe cutaneous adverse reactions (SCARs) | Permanently discontinue TAFINLAR. |
| Other Adverse Reactions c, including Hemorrhage [see Warnings and Precautions (5.3)] | |
| Intolerable Grade 2 Any Grade 3 | Withhold TAFINLAR. If improved to Grade 0-1, resume TAFINLAR at lower dose. If not improved, permanently discontinue TAFINLAR. |
| First occurrence of any Grade 4 | Withhold TAFINLAR until improves to Grade 0-1, then resume TAFINLAR at lower dose. Or Permanently discontinue TAFINLAR. |
| Recurrent Grade 4 | Permanently discontinue TAFINLAR. |
Side Effects of Tafinlar
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. Adult Safety Pools The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to TAFINLAR 150 mg orally, twice daily 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. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to TAFINLAR 150 mg orally, twice daily, administered in combination with trametinib 2 mg orally, once daily, in 1087 patients enrolled in COMBI-d, COMBI-v, COMBI-AD, and BRF113928 with unresectable or metastatic melanoma, adjuvant melanoma, or NSCLC.
Pediatric Safety Pool The pediatric pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to weight-based TAFINLAR orally, twice daily administered in combination with trametinib in 166 pediatric patients across two trials: a multi-center, open-label, multi-cohort study in pediatric patients with BRAF V600E mutation-positive glioma requiring systemic therapy (Study G2201; n = 123) and a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors with MAPK pathway activation (Study X2101; n = 43). 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.
Table 6 and Table 7 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR as a single agent in the BREAK-3 study. Table 6. 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 Worsening from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in the BREAK-3 Study a Other clinically important adverse reactions for TAFINLAR in a pool of TAFINLAR monotherapy clinical studies observed in less than 10% of patients who received TAFINLAR were: Gastrointestinal: Pancreatitis Immune System: Hypersensitivity manifesting as bullous rash Nervous System: Peripheral neuropathy Renal and Urinary: Interstitial nephritis Skin and Subcutaneous Tissue: Photosensitivity 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 multi-center, double-blind, randomized (1:1), active-controlled trial and the COMBI-v study (n = 350), a multi-center, open-label, randomized (1:1), active-controlled trial.
In both trials, 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 known history of G6PD deficiency. 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. In the COMBI-d study, adverse reactions leading to discontinuation of TAFINLAR occurred in 11% of patients who received TAFINLAR plus trametinib; the most frequent was pyrexia (1.9%).
Table 8 and Table 9 present adverse reactions and laboratory abnormalities, respectively, observed in the COMBI-d study. Table 8. Select Adverse Reactions Occurring in ≥ 10% (All Grades) of Patients Treated with TAFINLAR Administered with Trametinib in the 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: Cardiac: Atrioventricular block, bundle branch block Gastrointestinal: Colitis, gastrointestinal perforation, pancreatitis Immune System: Sarcoidosis Nervous System: Peripheral neuropathy, Guillain-Barré syndrome Skin and Subcutaneous Tissue: Panniculitis, photosensitivity Table 9.
Select Laboratory Abnormalities Worsening from Baseline Occurring at ≥ 10% (All Grades) of Patients Who Received TAFINLAR with Trametinib in the 0K 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 LVEF; 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.
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 10 summarizes the adverse reactions that occurred in at least 20% of patients who received TAFINLAR administered with trametinib. The laboratory abnormalities are summarized in Table 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 multi-center, multi-cohort, non-randomized, open-label trial (Study BRF113928).
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. Table 12 and Table 13 present adverse reactions and laboratory abnormalities, respectively, of TAFINLAR administered with trametinib in Study BRF113928. Table 12.
Adverse Reactions Occurring in ≥ 20% (All Grades) of Patients Treated with TAFINLAR Administered with Trametinib in Study BRF 5 Other clinically important adverse reactions for TAFINLAR in Study BRF113928 observed in less than 20% of patients who received TAFINLAR administered with trametinib were: Cardiac: Atrioventricular block Gastrointestinal: Pancreatitis Nervous System: Peripheral neuropathy Renal and Urinary: Tubulointerstitial nephritis Table 13. Treatment-Emergent Laboratory Abnormalities Occurring in ≥ 20% (All Grades) of Patients Who Received TAFINLAR with Trametinib in Study BRF The safety of TAFINLAR when administered with trametinib was evaluated in a multi-cohort, multi-center, non-randomized, open-label study in adult patients with cancers with the BRAF V600E mutation (Study BRF117019). Serious adverse reactions occurred in 45% of patients who received TAFINLAR in combination with trametinib.
Serious adverse reactions in > 5% of patients included pyrexia (11%) and pneumonia (6%). Fatal adverse reactions occurred in 3.9% of patients who received TAFINLAR in combination with trametinib. Fatal adverse reactions that occurred in > 1% of patients included sepsis (1.9%).
Permanent treatment discontinuation due to an adverse reaction occurred in 13% of patients. Adverse reactions which resulted in permanent treatment discontinuation in > 1% of patients included nausea (1.5%). Dosage interruptions due to an adverse reaction occurred in 55% of patients.
Dose reductions due to an adverse reaction occurred in 44% of patients. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, are listed in Table 14 and Table 15. Table 14 summarizes the adverse reactions in Study BRF117019.
Table 14. Adverse Reactions (≥ 20%) in Adult Patients Treated with TAFINLAR Plus Trametinib in Study BRF Clinically relevant adverse reactions for TAFINLAR in Study BRF117019 observed in less than 20% of patients who received TAFINLAR in combination with trametinib were: peripheral neuropathy (9%), decreased ejection fraction (8%), atrioventricular block summarizes the laboratory abnormalities in Study BRF117019. Table 15.
Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Adult Patients Treated with TAFINLAR Plus Trametinib in Study BRF 0E Mutation-Positive Solid Tumors in Pediatric Patients Study CTMT212X2101 (X2101) The safety of TAFINLAR when administered with trametinib was evaluated in Study X2101, a multi-center, open-label, multi-cohort study in pediatric patients (n = 48) with refractory or recurrent solid tumors. The median duration of exposure to TAFINLAR in Parts C (dose escalation) and D (cohort expansion) was 20.8 and 24.9 months, respectively. The median duration of exposure to trametinib in Parts C and D was 20.8 and 24.4 months, respectively.
The median age of pediatric patients who received TAFINLAR with trametinib was 9 years (range: 1 to 17). Serious adverse reactions in > 5% of patients included pyrexia (25%) and decreased ejection fraction (6%). Adverse reactions which required dose reductions in > 5% of patients included pyrexia (13%).
The most common (≥ 20%) adverse reactions, including laboratory abnormalities, are listed in Table 16 and Table 17. Table 16 summarizes the adverse reactions in Study X2101. Table 16.
Adverse Reactions (≥ 20%) in Pediatric Patients Treated with TAFINLAR Plus Trametinib in Study X 0 Clinically relevant adverse reactions for TAFINLAR in Study X2101 observed in less than 20% of patients (N=48) who received TAFINLAR in combination with trametinib were: atrioventricular block (2.1%). Table 17 summarizes the laboratory abnormalities in Study X2101. Table 17.
Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Pediatric Patients Treated with TAFINLAR Plus Trametinib in Study X 0E Mutation-Positive Low-Grade Glioma in Pediatric Patients Study CDRB436G2201 (G2201) The safety of TAFINLAR in combination with trametinib was evaluated in pediatric patients 1 to < 18 years of age in Study G2201. Patients with low-grade glioma (LGG) who required first systemic therapy were randomized (2:1) to TAFINLAR plus trametinib (n = 73) or carboplatin plus vincristine (n = 33). Nine patients crossed over from the carboplatin plus vincristine arm to the TAFINLAR and trametinib arm.
Pediatric patients received weight-based TAFINLAR orally twice daily administered in combination with trametinib until disease progression or intolerable toxicity. Patients in the control arm received carboplatin and vincristine at doses of, respectively in 10-week induction course followed by eight 6-week cycles of maintenance therapy or until disease progression or intolerable toxicity. Serious adverse reactions occurred in 40% of these patients.
Serious adverse reactions in > 3% of patients included pyrexia (14%) and vomiting (4%). Permanent discontinuation of TAFINLAR due to an adverse reaction occurred in 4% of patients. Adverse reactions which resulted in permanent discontinuation of TAFINLAR included chills, fatigue, pyrexia, weight increased, and headache.
Adverse reactions which required dosage interruption in > 5% of patients included pyrexia (53%). Adverse reactions which required dose reductions in > 2% of patients included rash ( %) laboratory abnormalities that worsened from baseline were leukopenia summarizes the adverse reactions in Study G2201. Table 18.
Adverse Reactions (≥ 15%) in Pediatric LGG Patients Who Received TAFINLAR in Combination with Trametinib in Study G summarizes the laboratory abnormalities in Study G2201. Table 19. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Pediatric LGG Patients Who Received TAFINLAR in Combination with Trametinib in Study G 6
Postmarketing Experience
The following adverse reactions have been identified during post approval 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. Cardiac: Atrioventricular block complete Immune System: Hemophagocytic lymphohistiocytosis (HLH) Skin and Subcutaneous Tissue: SCAR (including DRESS and SJS)
| 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 and connective tissue | ||||
| Arthralgia | 27 | 1 | 2 | 0 |
| Back pain | 12 | 3 | 7 | 0 |
| Myalgia | 11 | 0 | 0 | 0 |
| Neoplasms | ||||
| Papilloma c | 27 | 0 | 2 | 0 |
| cuSCC d | 7 | 4 | 0 | 0 |
| Respiratory system | ||||
| Cough | 12 | 0 | 5 | 0 |
| Gastrointestinal | ||||
| Constipation | 11 | 2 | 14 | 0 |
| Infections and infestations | ||||
| Nasopharyngitis | 10 | 0 | 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). | ||||
| 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 | 6 b | 14 | 2 |
| Increased alkaline phosphatase | 19 | 0 | 14 | 2 |
| Hyponatremia | 8 | 2 | 3 | 0 |
| 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 Abnormalities | 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 |
| 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 | ||||
| Pyrexia b | 63 | 5 | 11 | < 1 |
| Fatigue c | 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 | ||||
| Headache d | 39 | 1 | 24 | 0 |
| Skin and subcutaneous tissue | ||||
| Rash e | 37 | < 1 | 16 | < 1 |
| Musculoskeletal and connective tissue | ||||
| Arthralgia | 28 | < 1 | 14 | 0 |
| Myalgia f | 20 | < 1 | 14 | 0 |
| 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 Trametinib a N = 435 | Placebo a 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 |
| 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 (%) | |
| General | ||
| Pyrexia | 55 | 5 |
| Fatigue b | 51 | 5 |
| Edema c | 28 | 0 |
| Chills | 23 | 1.1 |
| Gastrointestinal | ||
| Nausea | 45 | 0 |
| Vomiting | 33 | 3.2 |
| Diarrhea | 32 | 2.2 |
| Decreased appetite | 29 | 0 |
| Skin and subcutaneous tissue | ||
| Dry skin | 31 | 1.1 |
| Rash d | 28 | 3.2 |
| Vascular | ||
| Hemorrhage e | 23 | 3.2 |
| Respiratory system | ||
| Cough | 22 | 0 |
| Dyspnea | 20 | 5 |
| 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 |
| a NCI CTCAE version 4.0. b Includes fatigue, asthenia, and malaise. c Includes peripheral edema and peripheral swelling. d Includes rash, rash maculo-papular, rash erythematous, rash pustular, and rash papular. e Includes epistaxis, hematuria, contusion, hematoma, hemoptysis, conjunctival hemorrhage, hematochezia, rectal hemorrhage, hemorrhoidal hemorrhage, melena, purpura, eye contusion, eye hemorrhage, gastric hemorrhage, gingival bleeding, hematemesis, hemorrhage intracranial, hemorrhagic stroke, hemothorax, increased tendency to bruise, large intestinal hemorrhage, mouth hemorrhage, petechiae, pharyngeal hemorrhage, prothrombin time prolonged, pulmonary hematoma, retinal hemorrhage, vaginal hemorrhage, and vitreous hemorrhage. f Includes cough and productive cough. g Includes myalgia, musculoskeletal chest pain, and musculoskeletal pain. | ||
| Adverse Reactions | TAFINLAR plus Trametinib a (N = 206) | |
| All Grades (%) | Grade 3 or 4 (%) | |
| General | ||
| Pyrexia | 55 | 4.9 |
| Fatigue b | 50 | 5 |
| Chills | 30 | 0.5 |
| Peripheral edema c | 22 | 0 |
| Gastrointestinal | ||
| Nausea | 40 | 1.5 |
| Constipation | 27 | 0 |
| Vomiting | 27 | 1.5 |
| Diarrhea | 26 | 2.9 |
| Skin and subcutaneous tissue | ||
| Rash d | 40 | 2.4 |
| Nervous system | ||
| Headache | 30 | 1.5 |
| Vascular | ||
| Hemorrhage e | 29 | 4.4 |
| Respiratory system | ||
| Cough f | 29 | 0 |
| Musculoskeletal and connective tissue | ||
| Myalgia g | 24 | 0.5 |
| Arthralgia | 23 | 0.5 |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 199 to 202 based on the number of patients with a baseline value and at least one post-treatment value. | ||
| Laboratory Abnormality | TAFINLAR plus Trametinib a | |
| All Grades (%) | Grade 3 or 4 (%) | |
| Chemistry | ||
| Hyperglycemia | 61 | 8 |
| Decreased sodium | 35 | 10 |
| Decreased magnesium | 24 | 0 |
| Increased creatinine | 21 | 1.5 |
| Hepatic | ||
| Increased alkaline phosphatase | 51 | 5 |
| Increased AST | 51 | 4.6 |
| Increased ALT | 39 | 3 |
| Hematology | ||
| Decreased hemoglobin | 44 | 9 |
| a NCI CTCAE version 4.0. b Includes fatigue, asthenia, and malaise. c Includes rash, rash maculo-papular, rash erythematous, rash papular, rash pustular, and rash macular. d Includes dermatitis acneiform and acne. e Includes abdominal pain and abdominal pain upper. f Includes epistaxis, hematuria, contusion, hematoma, petechiae, rectal hemorrhage, and red blood cell count decreased. | ||
| Adverse Reactions | TAFINLAR plus Trametinib a (N = 48) | |
| All Grades (%) | Grade 3 or 4 (%) | |
| General | ||
| Pyrexia | 75 | 17 |
| Fatigue b | 48 | 0 |
| Skin and subcutaneous tissue | ||
| Rash c | 73 | 2.1 |
| Dry skin | 48 | 0 |
| Dermatitis acneiform d | 40 | 0 |
| Gastrointestinal | ||
| Vomiting | 52 | 4.2 |
| Diarrhea | 42 | 2.1 |
| Abdominal pain e | 33 | 4.2 |
| Nausea | 33 | 2.1 |
| Constipation | 23 | 0 |
| Respiratory system | ||
| Cough | 44 | 0 |
| Nervous system | ||
| Headache | 35 | 0 |
| Vascular | ||
| Hemorrhage f | 33 | 0 |
| Infections and infestations | ||
| Paronychia | 23 | 0 |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 39 to 48 based on the number of patients with a baseline value and at least one post-treatment value. | ||
| Laboratory Abnormality | TAFINLAR plus Trametinib a | |
| All Grades (%) | Grade 3 or 4 (%) | |
| Chemistry | ||
| Hyperglycemia | 65 | 2.2 |
| Hypoalbuminemia | 48 | 2.1 |
| Hypocalcemia | 40 | 2.1 |
| Decreased phosphate | 38 | 0 |
| Decreased magnesium | 33 | 2.1 |
| Hypernatremia | 27 | 0 |
| Hypokalemia | 21 | 2.1 |
| Hepatic | ||
| Increased AST | 55 | 4.2 |
| Increased ALT | 40 | 6 |
| Increased alkaline phosphatase | 28 | 6 |
| Increased total bilirubin | 21 | 2.1 |
| Hematology | ||
| Decreased hemoglobin | 60 | 6 |
| Decreased neutrophils | 49 | 28 |
| a NCI CTCAE version 4.03. b Includes diarrhea, colitis, enterocolitis, and enteritis. c Includes abdominal pain and upper abdominal pain. d Includes stomatitis, cheilitis, mouth ulceration, aphthous ulcer, and glossitis. e Includes pyrexia and body temperature increased. f Includes fatigue and asthenia. g Includes headache and migraine with aura. h Includes dizziness and vertigo. i Includes peripheral neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia, neuralgia, hypoaesthesia, and peripheral sensory neuropathy. j Includes epistaxis, post-procedural hemorrhage, hematuria, upper gastrointestinal hemorrhage, and hemorrhage intracranial. k Includes rash, rash macular, rash maculo-papular, rash pustular, rash papular, rash erythematous, eczema, erythema multiforme, dermatitis, dermatitis exfoliative, skin exfoliation, palmar-plantar erythrodysaesthesia syndrome, and dermatitis bullous. l Includes dermatitis acneiform, acne, and acne pustular. m Includes back pain, myalgia, pain in extremity, arthralgia, bone pain, non-cardiac chest pain, neck pain, and musculoskeletal stiffness. | ||||
| Adverse Reactions | TAFINLAR plus Trametinib N = 73 | Carboplatin plus Vincristine N = 33 | ||
| All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | |
| Gastrointestinal | ||||
| Vomiting | 34 | 1 | 48 | 3 |
| Diarrhea b | 29 | 0 | 18 | 6 |
| Nausea | 25 | 0 | 45 | 0 |
| Abdominal pain c | 25 | 0 | 24 | 0 |
| Constipation | 12 | 0 | 36 | 0 |
| Stomatitis d | 10 | 0 | 18 | 0 |
| General | ||||
| Pyrexia e | 68 | 8 | 18 | 3 |
| Fatigue f | 33 | 0 | 39 | 0 |
| Nervous system | ||||
| Headache g | 47 | 1 | 33 | 3 |
| Dizziness h | 15 | 0 | 9 | 3 |
| Peripheral neuropathy i | 7 | 0 | 45 | 6 |
| Vascular | ||||
| Hemorrhage j | 25 | 0 | 12 | 0 |
| Skin and subcutaneous tissue | ||||
| Rash k | 51 | 2.7 | 18 | 3 |
| Dry skin | 26 | 0 | 3 | 0 |
| Dermatitis acneiform l | 22 | 0 | 0 | 0 |
| Alopecia | 3 | 0 | 24 | 0 |
| Musculoskeletal and connective tissue | ||||
| Musculoskeletal pain m | 34 | 0 | 30 | 0 |
| Pain in jaw | 1.4 | 0 | 18 | 0 |
| Metabolism and nutrition | ||||
| Decreased appetite | 5 | 0 | 24 | 0 |
| Respiratory, thoracic and mediastinal | ||||
| Oropharyngeal pain | 11 | 0 | 18 | 0 |
| Psychiatric | ||||
| Anxiety | 1.4 | 0 | 15 | 3 |
| Immune system | ||||
| Hypersensitivity | 0 | 0 | 15 | 3 |
| Infections and infestations | ||||
| Upper respiratory tract infection | 15 | 0 | 6 | 0 |
| Injury, poisoning and procedural complications | ||||
| Infusion-related reaction | 0 | 0 | 15 | 3 |
| Investigations | ||||
| Weight increased | 15 | 7 | 0 | 0 |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. a The denominator used to calculate the rate varied from 70 to 73 in D + T arm and 9 to 33 in C + V arm based on the number of patients with a baseline value and at least one post-treatment value. | ||||
| Laboratory Abnormality | TAFINLAR plus Trametinib N = 73 | Carboplatin plus Vincristine N = 33 | ||
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Hepatic | ||||
| Increased alkaline phosphatase | 55 | 0 | 13 | 0 |
| Increased AST | 37 | 1.4 | 55 | 0 |
| Increased ALT | 29 | 3 | 61 | 9 |
| Chemistry | ||||
| Decreased magnesium | 34 | 4.1 | 76 | 6 |
| Increased magnesium | 32 | 0 | 24 | 3 |
| Increased potassium | 15 | 4.2 | 21 | 6 |
| Decreased calcium | 14 | 4.1 | 22 | 9 |
| Decreased potassium | 8 | 1.4 | 70 | 0 |
| Decreased phosphate | 7 | 2.7 | 33 | 3 |
| Decreased sodium | 5 | 1.4 | 27 | 6 |
| Increased serum fasting glucose | 0 | 0 | 44 | 0 |
| Hematology | ||||
| Decreased leukocytes | 59 | 0 | 91 | 18 |
| Decreased hemoglobin | 46 | 0 | 94 | 36 |
| Decreased neutrophils | 44 | 17 | 84 | 75 |
| Decreased platelets | 30 | 0 | 73 | 18 |
| Increased lymphocytes | 24 | 0 | 13 | 3.1 |
| Decreased lymphocytes | 16 | 1.4 | 56 | 6 |
Warnings & Cautions for Tafinlar
- New Primary Malignancies Cutaneous Malignancies TAFINLAR Monotherapy (Adult): In the pooled safety population, cutaneous squamous cell carcinomas (cuSCC), and keratoacanthomas occurred in 11% and 4% of patients, respectively. Basal cell carcinoma and new primary melanoma occurred in 4% and 1% of patients, respectively.
- TAFINLAR Administered with Trametinib (Adult): In the pooled safety population, the incidence of cuSCC (including keratoacanthomas) occurred in 2% of patients.
- TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, new primary melanoma occurred in < 1% of patients. Perform dermatologic evaluations prior to initiation of TAFINLAR, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. Non-Cutaneous Malignancies Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms. In the pooled adult safety populations of TAFINLAR monotherapy and TAFINLAR administered with trametinib, non-cutaneous malignancies occurred in 1% of patients. Monitor patients receiving TAFINLAR for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies.
Tumor Promotion in BRAF Wild-Type Tumors
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR as a single agent or in combination with trametinib.
Hemorrhage
Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is administered with trametinib. Fatal cases have been reported. TAFINLAR Administered with Trametinib (Adult): In the pooled safety population, 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. TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, hemorrhagic events occurred in 25% of patients; the most common type of bleeding was epistaxis (16%). 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 TAFINLAR at the next lower dose level.
Cardiomyopathy TAFINLAR Administered with Trametinib (Adult): In the pooled safety population, 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. Cardiomyopathy resolved in 45 of 50 patients who received TAFINLAR administered with trametinib.
Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with trametinib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold TAFINLAR for symptomatic cardiomyopathy or an absolute decrease in LVEF of greater than 20% from baseline that is below the 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 to less than or equal to 10% compared to baseline.
- Uveitis TAFINLAR Monotherapy (Adult): In the pooled safety population, uveitis occurred in 1% of patients. Cases of biocular panuveitis or biocular iridocyclitis have been reported in the post-marketing setting.
- TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, 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 (e.g., change in vision, photophobia, eye pain). If iritis is diagnosed, administer ocular therapy and continue TAFINLAR without dose modification. If severe uveitis (i.e., 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 improves to Grade 0 or 1. Permanently discontinue TAFINLAR for persistent Grade 2 or greater uveitis of > 6 weeks.
Serious Febrile Reactions
Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur with TAFINLAR. The incidence and severity of pyrexia are increased when TAFINLAR is administered with trametinib compared with TAFINLAR as a single agent. TAFINLAR Monotherapy (Adult): In the pooled safety population, fever (serious and non-serious) occurred in 30% of patients.
Approximately 13% of these patients experienced 3 or more discrete episodes. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 6% of patients. TAFINLAR Administered with Trametinib (Adult): In the pooled safety population, fever occurred in 58% of patients.
TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, pyrexia occurred in 66% of patients. Withhold TAFINLAR when used as monotherapy, and both TAFINLAR and trametinib when used in combination, if the patient’s temperature is ≥ 100.4°F. 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. If appropriate, TAFINLAR, or both TAFINLAR and trametinib when used in combination, may be restarted if the patient has recovered from the febrile reaction for at least 24 hours, either at the same or lower dose.
Administer antipyretics as secondary prophylaxis when resuming TAFINLAR if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., 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 dehydration, hypotension, renal failure, or severe chills/rigors, 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 TAFINLAR administered with trametinib. TAFINLAR Administered with Trametinib (Adult): In the pooled safety population, other serious skin toxicity occurred in < 1% of patients. TAFINLAR Administered with Trametinib (Pediatric): In the pooled safety population, 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 TAFINLAR for SCARs. For other skin toxicities, withhold TAFINLAR for intolerable or severe skin toxicity.
Resume TAFINLAR at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue TAFINLAR if skin toxicity has not improved within 3 weeks.
- Hyperglycemia TAFINLAR Monotherapy (Adult): In the pooled safety population, 14% of patients with a history of diabetes that received TAFINLAR required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia occurred in 3% of patients.
- TAFINLAR Administered with Trametinib (Adult): In the pooled safety population, 15% of patients with a history of diabetes who had received TAFINLAR with trametinib required more intensive hypoglycemic therapy. Monitor serum glucose levels upon initiation and as clinically appropriate when TAFINLAR is administered in patients with preexisting diabetes or hyperglycemia. Initiate or optimize anti-hyperglycemic 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.
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.
Hemophagocytic Lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) has been observed in the post-marketing setting when TAFINLAR was administered with trametinib. If HLH is suspected, interrupt treatment. If HLH is confirmed, discontinue treatment and initiate appropriate management of HLH.
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 adult 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.
Drug Interactions with Tafinlar
Effects of Other Drugs on TAFINLAR
Strong inhibitors of CYP3A4 or CYP2C8 may increase the concentration of dabrafenib. Substitution of strong inhibitors of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors.
Effects of TAFINLAR on Other Drugs
Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy.
Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.
Pregnancy Safety for Tafinlar
Pregnancy Risk Summary Based on findings from animal reproduction studies and its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. There is insufficient data in pregnant women exposed to TAFINLAR to assess the risks. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended adult clinical dose of 150 mg twice daily (see Data).
Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data In a combined female fertility and embryo-fetal development study in rats conducted during the period of organogenesis, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day.
At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended adult dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.
Pediatric Use of Tafinlar
Pediatric Use BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors and LGG The safety and effectiveness of TAFINLAR in combination with trametinib have been established in 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; or with LGG with BRAF V600E mutation who require systemic therapy. The safety and effectiveness of TAFINLAR in combination with trametinib have not been established for these indications in pediatric patients less than 1 year old. The safety and effectiveness of TAFINLAR as a single agent in pediatric patients have not been established.
Juvenile Animal Toxicity Data In a repeat-dose toxicity study in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC.
Overdosage Information for Tafinlar
There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR.
Clinical Studies of Tafinlar
BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma – TAFINLAR as a Single Agent BREAK-3 Study The safety and efficacy of TAFINLAR as a single agent were evaluated in an international, multi-center, randomized (3:1), open-label, active-controlled trial (the BREAK-3 study; NCT01227889) conducted in 250 patients with previously untreated BRAF V600E mutation-positive, unresectable or metastatic melanoma. Patients with any prior use of BRAF inhibitors or MEK inhibitors were excluded. Randomization was stratified by disease stage at baseline.
The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. In addition, an independent radiology review committee (IRRC) assessed the following efficacy outcome measures in pre-specified supportive analyses: PFS, confirmed overall response rate (ORR), and duration of response (DoR). The median age of patients in the BREAK-3 study was 52 years.
All patients had tumor tissue with mutations in BRAF V600E as determined by a clinical trial assay at a centralized testing site. Tumor samples from 243 patients (97%) were tested retrospectively using an FDA-approved companion diagnostic test, tHxID™-BRAF assay. The median durations of follow-up prior to initiation of alternative treatment in patients randomized to receive TAFINLAR was 5.1 months and in the dacarbazine arm was 3.5 months.
Twenty-eight (44%) patients crossed over from the dacarbazine arm at the time of disease progression to receive TAFINLAR. The BREAK-3 study demonstrated a statistically significant increase in PFS in the patients treated with TAFINLAR. Table 20 and Figure 1 summarize the PFS results.
Table 20. Investigator-Assessed Progression-Free Survival and Confirmed Overall Response Results in the BREAK-3 Study Figure 1. Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival in the BREAK-3 Study In supportive analyses based on IRRC assessment and in an exploratory subgroup analysis of patients with retrospectively confirmed V600E mutation-positive melanoma with the tHxID™-BRAF assay, the PFS results were consistent with those of the primary efficacy analysis.
BREAK-MB Study The activity of TAFINLAR for the treatment of BRAF V600E mutation-positive melanoma, metastatic to the brain was evaluated in a single-arm, open-label, two-cohort multi-center trial (the BREAK-MB study; NCT01266967). All patients received TAFINLAR 150 mg twice daily. Patients in Cohort A (n = 74) had received no prior local therapy for brain metastases, while patients in Cohort B (n = 65) had received at least one local therapy for brain metastases, including, but not limited to, surgical resection, whole brain radiotherapy, or stereotactic radiosurgery, such as gamma knife, linear-accelerated-based radiosurgery, or charged particles.
In addition, patients in Cohort B were required to have evidence of disease progression in a previously treated lesion or an untreated lesion. Additional eligibility criteria were at least one measurable lesion of 0.5 cm or greater in largest diameter on contrast-enhanced MRI, stable or decreasing corticosteroid dose, and no more than two prior systemic regimens for treatment of metastatic disease. The major efficacy outcome measure was estimation of the overall intracranial response rate (OIRR) in each cohort.
The intracranial response rate as determined by an independent radiology review committee, masked to investigator response assessments, was in Cohort A and in Cohort B. The median duration of intracranial response was 4.6 months in both cohorts.
BRAF V600E or V600K Unresectable or Metastatic Melanoma – TAFINLAR With Trametinib COMBI-d Study and COMBI-v Study The safety and efficacy of TAFINLAR administered with trametinib were evaluated in two international, randomized, active-controlled trials: one double-blind trial (the COMBI-d study; NCT01584648) and one open-label trial (the COMBI-v study; NCT01597908). The COMBI-d study compared TAFINLAR plus trametinib to TAFINLAR plus placebo as first-line therapy for patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma. Randomization was stratified by LDH level (> ULN vs. ≤ ULN) and BRAF mutation subtype V600E vs.
V600K. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR). V600K.
The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and ORR as assessed by investigator per RECIST v1.1. All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing with the FDA-approved companion diagnostic test; 85% with BRAF V600E mutation positive melanoma and 15% with BRAF V600K mutation positive melanoma.
In the COMBI-v study, 704 patients were randomized to TAFINLAR plus trametinib (n = 352) or single-agent vemurafenib (n = 352). The COMBI-d and COMBI-v studies demonstrated statistically significant improvements in OS and PFS. Table 21 and Figures 2 and 3 summarize the efficacy results.
Table 21. Efficacy Results in Patients with BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma a with trametinib for the treatment of BRAF V600E or V600K mutation-positive melanoma, metastatic to the brain, was evaluated in a non-randomized, open-label, multi-center, multi-cohort trial (the COMBI-MB study; NCT02039947). Eligible patients were required to have at least one measurable intracranial lesion and to have no leptomeningeal disease, parenchymal brain metastasis greater than 4 cm in diameter, ocular melanoma, or primary mucosal melanoma.
Patients received TAFINLAR 150 mg orally twice daily and trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was intracranial response rate, defined as the percentage of patients with a confirmed intracranial response per RECIST v1.1, modified to allow up to five intracranial target lesions at least 5 mm in diameter, as assessed by independent review. The COMBI-MB study enrolled 121 patients with a BRAF V600E (85%) or V600K (15%) mutation.
The intracranial response rate was with a complete response rate of 4.1% and a partial response rate of 46%. The median duration of intracranial response was 6.4 months (range: 1 to 31). Of the patients with an intracranial response, 9% had stable or progressive disease as their best overall response.
Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma The efficacy of TAFINLAR administered with trametinib was evaluated in an international, multi-center, randomized, double-blind, placebo-controlled trial (COMBI AD; NCT01682083) that enrolled patients with Stage III melanoma with BRAF V600E or V600K mutations as detected by the tHxID ™ -BRAF assay and pathologic involvement of regional lymph node(s). Enrollment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomization. The trial excluded patients with mucosal or ocular melanoma, unresectable in-transit metastases, distant metastatic disease, or prior systemic anti-cancer treatment, including radiotherapy.
Randomization was stratified by BRAF mutation status (V600E or V600K) and American Joint Committee on Cancer (AJCC; 7 th Edition) Stage (IIIA, IIIB, or IIIC). The major efficacy outcome measure was relapse-free survival (RFS), defined as the time from randomization to disease recurrence (local, regional, or distant metastasis), new primary melanoma, or death from any cause, whichever occurred first as assessed by the investigator. Patients underwent imaging for tumor recurrence every 3 months for the first two years and every 6 months thereafter.
In COMBI-AD, a total of 870 patients were randomized: 438 to TAFINLAR in combination with trametinib and 432 to placebo. The median duration of follow-up at the time of the primary analysis was 2.8 years. COMBI-AD showed a statistically significant improvement in RFS in patients randomized to TAFINLAR in combination with trametinib compared to those randomized to placebo.
Efficacy results are presented in Table 22 and Figure 4. Table 22. Efficacy Results in COMBI-AD in the Adjuvant Figure 4.
Kaplan-Meier Curves for Investigator-Assessed Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma The median duration of follow-up at the time of the final overall survival analysis was 8.0 years. Median overall survival was not estimable in both arms.
BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer The safety and efficacy of TAFINLAR alone or administered with trametinib were evaluated in a multi-center, three-cohort, non-randomized, activity-estimating, open-label trial (Study BRF113928, NCT01336634). Key eligibility criteria were locally confirmed BRAF V600E mutation-positive metastatic NSCLC, no prior exposure to BRAF or MEK-inhibitor, and absence of EGFR mutation or ALK rearrangement (unless patients had progression on prior tyrosine kinase inhibitor therapy). Patients enrolled in Cohorts A and B were required to have received at least one previous platinum-based chemotherapy regimen for NSCLC with demonstrated disease progression but no more than three prior systemic regimens.
Patients enrolled in Cohort C could not have received prior systemic therapy for metastatic NSCLC. Patients in Cohort A received TAFINLAR 150 mg twice daily. Patients in Cohorts B and C received TAFINLAR 150 mg twice daily and trametinib 2 mg once daily.
The major efficacy outcome measure was overall response rate (ORR) per RECIST v1.1 as assessed by independent review committee (IRC) and duration of response (DoR). Efficacy results are summarized in Table 23. Table 23.
Efficacy Results Based on Independent Review in Study BRF113928.2 In a subgroup analysis of patients with retrospectively, centrally confirmed BRAF V600E mutation-positive NSCLC with the Oncomine ™ Dx Target Test, the ORR results were similar to those presented in Table 22.
BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer The safety and efficacy of TAFINLAR administered with trametinib was evaluated in an activity-estimating, nine-cohort, multi-center, non-randomized, open-label trial (Study BRF117019; NCT02034110) in patients with rare cancers with the BRAF V600E mutation, including locally advanced, unresectable, or metastatic ATC with no standard locoregional treatment options. Trial BRF117019 excluded patients who could not swallow or retain the medication; who received prior treatment with BRAF or MEK inhibitors; with symptomatic or untreated CNS metastases; or who had airway obstruction. Thirty-six patients were enrolled and were evaluable for response in the ATC cohort.
Prior anti-cancer treatments included surgery and external beam radiotherapy (83% each), and systemic therapy (67%). Efficacy results are summarized in Table 24. Table 24.
Efficacy Results in the ATC Cohort Based on Independent Review of Study BRF117019.6 BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors The safety and efficacy of TAFINLAR in combination with trametinib for the treatment of BRAF V600E mutation-positive unresectable or metastatic solid tumors were evaluated in Trials BRF117019, NCI-MATCH, and CTMT212X2101, and supported by results in COMBI-d, COMBI-v, and BRF113928. In adult studies, patients received TAFINLAR 150 mg twice daily and trametinib 2 mg once daily. The major efficacy outcome measures were ORR per RECIST v1.1, RANO or modified RANO criteria and duration of response (DoR).
BRF117019 Study and NCI-MATCH Study Study BRF117019 (NCT02034110) is a multi-cohort, multi-center, non-randomized, open-label trial in adult patients with selected tumors with the BRAF V600E mutation, including high-grade glioma (HGG) (n = 45), biliary tract cancer (BTC) (n = 43), low-grade glioma (LGG) (n = 13), adenocarcinoma of small intestine (ASI) (n = 3), gastrointestinal stromal tumor (GIST) (n = 1), and anaplastic thyroid cancer. Patients were enrolled based on local assessments of BRAF V600E mutation status; a central laboratory confirmed the BRAF V600E mutation in 93 of 105 patients. Arm H (EAY131-H) of the NCI-MATCH study (NCT02465060) is a single-arm, open-label study that enrolled patients with a BRAF V600E mutation.
Patients with melanoma, thyroid cancer, or CRC were excluded. BRAF V600E mutation status for enrollment was determined either by central or local laboratory test. Of the 131 patients, 90% received prior systemic therapy.
Efficacy results in patients with solid tumors are summarized in Table 25. Table 25. Efficacy Results Based on Independent Review in Studies BRF117019 and NCI-MATCH Arm H CTMT212X2101 (X2101) Study Study X2101 (NCT02124772) was a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors.
Part C was a dose escalation of TAFINLAR in combination with trametinib in patients with a BRAF V600E mutation. Part D was a cohort expansion phase of TAFINLAR in combination with trametinib in patients with LGG with a BRAF V600E mutation. The major efficacy outcome measure was ORR as assessed by independent review committee per RANO criteria.
The efficacy of TAFINLAR in combination with trametinib was evaluated in 48 pediatric patients, including 34 patients with LGG and 2 patients with HGG. Prior anti-cancer treatments included surgery (83%), external beam radiotherapy (2.8%), and systemic therapy (92%). The ORR was CDRB436G2201 (G2201) Study – High-Grade Glioma Cohort Study G2201 (NCT02684058) was a multi-center, randomized, open-label, Phase II study of dabrafenib and trametinib in chemotherapy-naïve pediatric patients with BRAF V600E mutant low-grade glioma (LGG) and patients with relapsed or progressive BRAF V600E mutant HGG.
Patients with HGG were enrolled in a single-arm cohort. The efficacy of TAFINLAR in combination with trametinib was evaluated in 41 pediatric patients with relapsed or progressive HGG. Prior anti-cancer treatments included surgery (98%), radiotherapy (90%), and chemotherapy (81%).
The ORR was The median DoR was not reached (95% CI: 9.2, NE). For the 23 patients who responded in the HGG cohort, DoR was ≥ 6 months for 78% of patients, ≥ 12 months for 48% of patients, and ≥ 24 months for 22% of patients.
BRAF V600E Mutation-Positive Low-Grade Glioma CDRB436G2201 (G2201) Study – Low-Grade Glioma Cohort The safety and efficacy of TAFINLAR in combination with trametinib for the treatment of BRAF V600E mutation-positive low-grade glioma (LGG) in pediatric patients aged 1 to < 18 years of age were evaluated in the multi-center, open-label trial (Study CDRB436G2201; NCT02684058). Patients with LGG (WHO grades 1 and 2) who required first systemic therapy were randomized in a 2:1 ratio to dabrafenib plus trametinib (D + T) or carboplatin plus vincristine (C + V). BRAF mutation status was identified prospectively via a local assessment or a central laboratory test.
In addition, retrospective testing of available tumor samples by the central laboratory was performed to evaluate BRAF V600E mutation status. Patients received age- and weight-based dosing of TAFINLAR and trametinib until loss of clinical benefit or until unacceptable toxicity. Carboplatin and vincristine were dosed based on body surface area at doses mg/kg for patients < 12 kg, respectively, as one 10-week induction course followed by eight 6-week cycles of maintenance therapy.
The major efficacy outcome measure was overall response rate (ORR) by independent review based on RANO LGG criteria. The primary analysis was performed when all patients had completed at least 32 weeks of therapy. In the LGG cohort, 110 patients were randomized to D + T (n = 73) or C + V (n = 37).
Study G2201 showed a statistically significant improvement in ORR and PFS in LGG patients randomized to D + T compared to those randomized to C + V. Efficacy results are shown in Table 26. Table 26.
Efficacy Results Based on Independent Review in Study G2 1 (LGG Cohort) At the time of the interim analysis of overall survival (OS), conducted when all patients had completed at least 32 weeks of treatment or had discontinued earlier, there was one death on the C + V arm. The OS results at interim analysis did not reach statistical significance.
| Abbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached. a Pike estimator, stratified by disease state. b Stratified log-rank test. | ||
| Investigator-Assessed Endpoints | TAFINLAR N = 187 | Dacarbazine N = 63 |
| Progression- F ree Survival | ||
| Number of events (%) | 78 (42%) | 41 (65%) |
| Progressive disease | 76 | 41 |
| Death | 2 | 0 |
| Median, months (95% CI) | 5.1 (4.9, 6.9) | 2.7 (1.5, 3.2) |
| HR a (95% CI) | 0.33 (0.20, 0.54) | |
| P value b | < 0.0001 | |
| Confirmed Tumor Responses | ||
| Overall response rate (95% CI) | 52% (44%, 59%) | 17% (9%, 29%) |
| Complete response, n (%) | 6 (3%) | 0 |
| Partial response, n (%) | 91 (48%) | 11 (17%) |
| Duration of response | ||
| Median DoR, months (95% CI) | 5.6 (5.4, NR) | NR (5.0, NR) |
| Abbreviations: ATC, anaplastic thyroid cancer; CI, confidence interval; DoR, duration of response; NE, not estimable; ORR, overall response rate. | |
| ATC Cohort Population | N = 36 |
| Overall Response Rate | |
| ORR (95% CI) | 53% (35.5%, 69.6%) |
| Complete response | 6% |
| Partial response | 47% |
| Duration of Response | n = 19 |
| Median DoR, months (95% CI) | 13.6 (3.8, NE) |
| % with DoR ≥ 6 months | 68% |
| % with DoR ≥ 12 months | 53% |
| Abbreviations: NA, not applicable; PR, partial response. a Excludes NSCLC (n = 6) and ATC (n = 36) (previously approved tumor types for TAFINLAR in combination with trametinib). b Median DoR 9.8 months (95% CI: 5.3, 20.4). c Median DoR 13.6 months (95% CI: 5.5, 26.7). d Denotes a right-censored DoR. | ||||
| Tumor Type a | N | Objective Response Rate | Duration of Response | |
| % | 95% CI | Range (months) | ||
| Biliary tract cancer b | 48 | 46 | (31, 61) | 1.8 d, 40 d |
| High-grade glioma c | 48 | 33 | (20, 48) | 3.9, 44 |
| Glioblastoma | 32 | 25 | (12, 43) | 3.9, 27 |
| Anaplastic pleomorphic xanthoastrocytoma | 6 | 67 | (22, 96) | 6, 43 |
| Anaplastic astrocytoma | 5 | 20 | (0.5, 72) | 15 |
| Astroblastoma | 2 | 100 | (16, 100) | 15, 23 d |
| Undifferentiated | 1 | PR | (2.5, 100) | 6 |
| Anaplastic ganglioglioma | 1 | 0 | NA | NA |
| Anaplastic oligodendroglioma | 1 | 0 | NA | NA |
| Low-grade glioma | 14 | 50 | (23, 77) | 6, 29 d |
| Astrocytoma | 4 | 50 | (7, 93) | 7, 23 |
| Ganglioglioma | 4 | 50 | (7, 93) | 6, 13 |
| Pleomorphic xanthoastrocytoma | 2 | 50 | (1.3, 99) | 6 |
| Pilocytic astrocytoma | 2 | 0 | NA | NA |
| Choroid plexus papilloma | 1 | PR | (2.5, 100) | 29 d |
| Gangliocytoma/ganglioglioma | 1 | PR | (2.5, 100) | 18 d |
| Low-grade serous ovarian carcinoma | 5 | 80 | (28, 100) | 12, 42 d |
| Adenocarcinoma small intestine | 4 | 50 | (7, 93) | 7, 8 |
| Adenocarcinoma pancreas | 3 | 0 | NA | NA |
| Mixed ductal/adenoneuroendocrine carcinoma | 2 | 0 | NA | NA |
| Neuroendocrine carcinoma of colon | 2 | 0 | NA | NA |
| Ameloblastoma of mandible | 1 | PR | (2.5, 100) | 30 |
| Combined small cell-squamous carcinoma of lung | 1 | PR | (2.5, 100) | 5 |
| Mucinous-papillary serous adenocarcinoma of peritoneum | 1 | PR | (2.5, 100) | 8 |
| Adenocarcinoma of anus | 1 | 0 | NA | NA |
| Gastrointestinal stromal tumor | 1 | 0 | NA | NA |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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