Summary Basis of Decision for Tafinlar

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Tafinlar is located below.

Recent Activity for Tafinlar

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Tafinlar

Updated: 2023-04-05

The following table describes post-authorization activity for Tafinlar, a product which contains the medicinal ingredient dabrafenib (as dabrafenib mesylate). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in the PAATs..

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Drug Identification Numbers (DINs):

  • DIN 02409607 - 50 mg dabrafenib, capsule, oral administration
  • DIN 02409615 - 75 mg dabrafenib, capsule, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 256550 2021-09-10 Issued NOC 2022-07-26 Submission filed as a Level I – Supplement to update the PM with data from study COMBI-APlus. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. An NOC was issued.
SNDS # 255279 2021-07-30 Issued NOC 2021-12-08 Submission filed as a Level II – Supplement (Safety) to update the PM to reflect revised pyrexia management guidance. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 245834 2020-10-29 Issued NOC 2021-03-19 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 232721 2019-10-24 Issued NOC 2020-09-11 Submission filed as a Level I – Supplement to update the PM with follow-up data from study MEK115306. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials section of the PM. An NOC was issued.
NC # 231496 2019-09-10 Issued NOL 2019-12-11 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 223526 2019-01-09 Issued NOL 2019-04-12 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 213581 2018-02-09 Issued NOC
2018-09-21		 Submission filed as a Level I - Supplement for a new indication: Taflinar in combination with trametinib is indicated for the adjuvant treatment of patients with Stage III melanoma with a BRAF V600 mutation following resection Regulatory Decision Summary.
NC # 213867 2018-02-21 Issued NOL
2018-06-19		 Submission filed as a Level II (120 day) Notifiable Change to update the PM. As a result of the NC, modifications were made to the Toxicology section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 210753 2017-10-30 Issued NOC
2018-05-18		 Submission filed as a Level I - Supplement for an expanded indication: in combination with trametinib for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600 mutation. Regulatory Decision Summary published.
NC # 207771 2017-07-21 Issued NOL
2017-10-05		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 202556 2017-02-06 Issued NOL
2017-06-09		 Submission filed as a Level II (120 day) Notifiable Change to update the PM. As a result of the NC, modifications were made to the, Warnings and Precautions, and, Drug Interactions, sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 199381 2016-10-18 Issued NOC
2017-05-16		 Submission filed as a Level I - Supplement for a new indication: In combination with trametinib for the treatment of patients with metastic non-small cell lung cancer (NSNLN) with a BRAF V600 mutation whose disease has progressed following systemic therapy. Regulatory Decision Summary published.
NC # 197867 2016-08-23 Issued No Objection Letter
2016-12-07		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Warnings and Precautions, Adverse Reactions, Drug Interactions, Dosage and Administration, and Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DIN 02409607) market notification Not applicable Date of first sale:
2016-09-27		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
PBRER-C # 189304 2015-11-05 Filed
2016-06-20		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C #4 for the period 2015-02-27 to 2015-08-26. No further action was required.
SNDS-C # 185149 2015-06-05 Issued NOC
2016-05-13		 Submission filed as a Level I - Supplement to fulfil commitments made as per the provisions of the NOC/c Guidance. The submission filed the final study reports for three clinical trials in order to confirm the clinical benefit of Tafinlar, used in combination with trametinib, for the treatment of patients with advanced malignant melanoma with a BRAF mutation. Results were submitted from Studies MEK115306, MEK116513, and BRF113220. As a result of the submission, changes were made to the Warnings and Precautions, Adverse Reactions, Dosage and Administration and Clinical Trials sections of the Product Monograph, and corresponding changes were made to Part III: Consumer Information. Overall, the efficacy results reported confirm the clinical benefit of the Tafinlar-trametinib combination in providing a clinically meaningful tumour response and survival benefit. The benefit risk profile of the Tafinlar-trametinib combination for use in patients with unresectable or metastatic BRAFV600 mutant melanoma remains positive. An NOC was issued.
Drug product (DIN 02409615) market notification Not applicable Date of first sale:
2016-05-04		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 190124 2015-12-02 Issued No Objection Letter
2016-03-10		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) based on post-market safety information. As a result of the Notifiable Change, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
PBRER-C # 184534 2015-05-12 Filed
2015-10-06		 Submission filed in response to commitments made as per the provisions of the Notice of Compliance with Conditions (NOC/c) Guidance. The PBRER-C includes the period 2014-08-27 to 2015-02-26. The information was screened and recommended for review together with the next PBRER-C to be filed.
NDS # 185362 2015-06-12 Issued NOC under the NOC/c Guidance
2015-07-31		 Submission filed to transfer ownership of the product [that is (i.e.) drug sponsor name] from GlaxoSmithKline Inc. to Novartis Pharmaceuticals Canada Inc. Notice of Compliance issued under the Notice of Compliance with Conditions (NOC/c) Guidance.
NC # 183907 2015-04-21 Issued No Objection Letter
2015-07-29		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Product Monograph (PM) with new safety information. As a result of the Notifiable Change, revisions were made to the Warnings and Precautions, Adverse Reactions and Dosing and Administration sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
SNDS # 162438 2013-02-11 Issued NOC under the NOC/c
2015-03-06		 Submission filed as a Level I - Supplement to support the use of Tafinlar in combination with trametinib for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. Data from a Phase I/II study were originally included to support the safety and efficacy of the combination therapy. Following a Notice of Non-Compliance, data from a Phase III double-blinded, randomized study were submitted that demonstrated statistically significant improvements in progression-free survival (PFS) and overall response rate for the combination therapy compared to the single agent Tafinlar. The small magnitude in PFS benefit was not considered to provide substantial evidence of efficacy but together with the improvement in overall response rate and a trend for improvement in overall survival was considered promising nonetheless for the combination of Tafinlar and trametinib.

There are additional risks and increased incidences of certain monotherapy related-adverse events associated with the combination therapy, while the incidence of cutaneous squamous cell and hyperkeratosis is decreased, and the labelling changes to the Tafinlar Product Monograph (PM) will help prescribers manage and mitigate the risks. As a result of the review, the indication for Tafinlar was expanded to include the combination therapy stated above, and changes were made to the following sections of the PM: Serious Warnings and Precautions box, Warnings and Precautions, Adverse Reactions, Dosing and Administration, and the Part III: Consumer Information.

Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance based on the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization for the new indication was issued with conditions.
NC # 175143 2014-05-29 Issued No Objection Letter
2014-09-10		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Warnings and Precautions, Adverse Reactions, and Drug Interactions sections of the Product Monograph (PM). Corresponding changes were also made to the PM Part III: Consumer Information. The submission was reviewed and a No Objection Letter was issued.
Drug product (DINs 02409607, 02409615) market notification Not applicable Date of first sale:
2013-08-28		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 157590 2012-07-31 Issued NOC
2013-07-16		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Tafinlar

Date SBD issued: 2013-10-09

The following information relates to the New Drug Submission for Tafinlar.

Dabrafenib (as dabrafenib mesylate), 50 mg and 75 mg, capsules, oral

Drug Identification Number (DIN):

  • 02409607 - 50 mg capsule
  • 02409615 - 75 mg capsule

GlaxoSmithKline Inc.

New Drug Submission Control Number: 157590

 

On July 16, 2013, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the drug product, Tafinlar.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Tafinlar is favourable as a monotherapy for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. A validated test is required to identify BRAF V600 mutation status.

 

1 What was approved?

 

Tafinlar, a BRAF protein kinase inhibitor, was authorized as a monotherapy for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation. A validated test is required to identify BRAF V600 mutation status. Tafinlar should not be used in patients with BRAF wild-type melanoma.

The indication was updated during the review process to contain the following information:

  • Effectiveness of Tafinlar monotherapy was based on overall response rate and progression-free survival results. Prolongation of overall survival and improvement in quality-of-life has not been demonstrated for Tafinlar.
  • Clinical data supporting the effectiveness of Tafinlar in patients with BRAF V600K mutations are limited, and Phase II studies report fewer responses in BRAF V600K patients compared to BRAF V600E patients. There are no clinical data for other less common BRAF V600 mutations.
  • Tafinlar monotherapy has not been studied in patients previously treated with BRAF inhibitors.

The safety and efficacy have not been established in children and adolescents less than 18 years of age.

Tafinlar is contraindicated for patients who are hypersensitive to dabrafenib or to any ingredient in the formulation or component of the container. Tafinlar was approved for use under the conditions stated in the Tafinlar Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Tafinlar (50 mg and 75 mg dabrafenib, as dabrafenib mesylate) is presented as a capsule. In addition to the medicinal ingredient, the contents of the capsule contain colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose. The capsule shell contains hypromellose, red iron oxide, and titanium dioxide. The printing ink contains black iron oxide, shellac, and propylene glycol.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Tafinlar Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Tafinlar approved?

 

Health Canada considers that the benefit/risk profile of Tafinlar is favourable as a single agent (monotherapy) for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Cutaneous melanoma is the most aggressive form of skin cancer. Systematic treatment options for unresectable or metastatic melanoma include cytotoxic chemotherapy, immunotherapy (including interleukin-2 and ipilimumab), and in the case of melanoma with a BRAF V600 mutation, vemurafenib. Tafinlar is the second BRAF inhibitor to be approved for patients with BRAF V600 mutation-postive melanoma. Zelboraf (vemurafenib), another BRAF inhibitor, was issued a Notice of Compliance (NOC) in February of 2012.

The pivotal study supporting market authorization was a Phase III, randomized, open-label study (BRF113683) of 250 treatment-naïve patients with unresectable or metastatic melanoma with the BRAF V600E mutation. Supportive safety and efficacy data were provided from two Phase II studies that also included patients with melanoma with the second most common BRAF mutation, V600K, and patients with BRAF mutation-positive melanoma metastatic to the brain.

In the pivotal Phase III study, BRAF V600E mutation-positive melanoma patients randomized to Tafinlar had clinically meaningful and statistically significant improvements in progression-free survival (PFS), compared to patients randomized to dacarbazine (DTIC). There was a reduction of 70% in the risk of disease progression or death compared with DTIC. Across subgroups (gender, age, high or low lactate dehydrogenase levels, unresectable stage III and M1c stages of melanoma), a consistent PFS benefit of the same magnitude as the overall study population was observed. Prolongation of overall survival and improvement in quality-of-life was not demonstrated.

The most common adverse drug reactions (≥15%) of any grade for Tafinlar in either the integrated monotherapy safety population or Phase III pivotal study included hyperkeratosis, headache, pyrexia, palmar-plantar erythrodysaesthesia (PPE), asthenia, arthralgia, fatigue, nausea, skin papilloma, alopecia, rash, and vomiting.

The most common treatment-related serious adverse events were cutaneous squamous cell carcinoma (cuSCC) and pyrexia (non-infectious febrile events). BRAF inhibitors are known to cause secondary cuSCCs. Other secondary malignancies also reported with Tafinlar include new primary melanomas and non-cutaneous cancers.

Grade 3 or higher hyperglycemia was reported in 5% of patients treated with Tafinlar. In some cases this resulted in treatment interruption, prolongation of hospitalization and initiation or change in the active management of diabetes. Other significant but less frequent adverse events reported included pancreatitis, uveitis, and iritis.

Tafinlar has not been studied in patients with severe renal impairment or in patients with moderate or severe hepatic impairment. Hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, and patients with moderate to severe hepatic impairment may have increased exposure and increased toxicities.

A Serious Warnings and Precautions box in the Tafinlar Product Monograph highlights the risks of second malignancies, serious non-infectious febrile events, teratogenicity and potential for decreased efficacy of oral contraceptives (due to a drug-drug interaction), as well as the lack of data in patients with moderate of severe hepatic impairment. A Serious Drug Interaction Box was also included in the Tafinlar Product Monograph with regard to the risk of teratogenicity and potential for decreased efficacy of oral contraceptives.

The safety profile of Tafinlar is considered acceptable with proper monitoring and with adequate management of the adverse events described in the Tafinlar Product Monograph. Appropriate warnings and precautions are in place in the Tafinlar Product Monograph to address the identified safety concerns. The approved Tafinlar Product Monograph accurately reflects the safety and efficacy of Tafinlar over the duration of exposure (median 7.5 months) studied in patients in the pivotal study.

A Risk Management Plan (RMP) for Tafinlar was submitted by GlaxoSmithKline Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

Overall, the benefit-risk assessment of Tafinlar monotherapy for patients with unresectable or metastatic melanoma harbouring a BRAF V600 mutation is favourable. Proper monitoring of adverse events and dosing considerations together with the recommended labelling changes in the approved Tafinlar Product Monograph will help maintain a favourable benefit-risk profile for Tafinlar in the post-market setting.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Tafinlar?

 

Submission Milestones: Tafinlar

Submission Milestone Date
Pre-submission meeting: 2012-05-17
Submission filed: 2012-07-31
Screening  
Screening Acceptance Letter issued: 2012-09-20
Review  
Biopharmaceutics Evaluation complete: 2013-03-04
Quality Evaluation complete: 2013-06-18
Clinical Evaluation complete: 2013-07-12
Labelling Review complete: 2013-07-15
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2013-07-16

 

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Tafinlar?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Tafinlar is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Dabrafenib, the medicinal ingredient of Tafinlar, is referred to as a BRAF inhibitor although it also inhibits other members (ARAF and CRAF) of the RAF kinase family. Oncogenic mutations in BRAF lead to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and may promote tumour cell growth. BRAF mutations have been identified at a high frequency in specific cancers, including approximately 50% of melanomas. The most common BRAF mutation, V600E, and the next most common, V600K, account for approximately 95% of BRAF mutations found in patients with melanoma.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies of dabrafenib. The clinical pharmacological data support the use of Tafinlar for the specified indication.

Dabrafenib is a moderate to strong inducer of cytochrome P450 (CYP) enzyme 3A4 (CYP3A4) and possibly an inducer of CYP2B6, CYP2C8, CYP2C9, and CYP2C19. Therefore, medicinal products that are substrates for these CYPs, particularly those sensitive to induction, should be avoided if possible, as dabrafenib may increase their metabolism and alter their clinical effectiveness. There is also potential for greater risk of drug-related reactions following co-administration of strong CYP3A4 inhibitors as they may increase the systemic exposure of dabrafenib and its active metabolites. Co-administration with strong inducers of CYP3A4 and CYP2C8 should also be avoided due to the possibility of sub-therapeutic exposure to dabrafenib. A Serious Drug Interaction Box was included in the Tafinlar Product Monograph because of the teratogenicity of dabrafenib in animals and the likelihood for increasing the metabolism of oral contraceptives and reducing their clinical effectiveness.

Dabrafenib has not been studied in patients with moderate and severe hepatic impairment. Hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites. Therefore, patients with moderate to severe hepatic impairment may have increased exposure and increased toxicities. A warning is listed in the Serious Warnings and Precautions box in the Tafinlar Product Monograph.

A high-fat, high-calorie meal significantly reduced the relative bioavailability of dabrafenib when compared to the fasted state, and delayed absorption. Capsules should be taken under fasting conditions, either 1 hour before or 2 hours after a meal, consistent with the drug administration in the Phase II and Phase III studies.

Pharmacodynamic effects of dabrafenib on QTc prolongation and blood pressure were observed. In a Phase I study, there was a mean increase of 7.3 ms and 12.2 ms in the QTc interval on Days 8 and 15, respectively, in patients receiving a 150 mg twice daily dose of Tafinlar. Decreases in blood pressure were also reported in the pivotal Phase III study.

Overall, the clinical pharmacological data support the use of Tafinlar for the specified indication. Appropriate warnings and precautions are in place in the approved Tafinlar Product Monograph to address the identified safety concerns.

For further details, please refer to the Tafinlar Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy and safety of Tafinlar in the treatment of patients with BRAF V600 mutation positive unresectable or metastatic melanoma were evaluated in three multicentre, international, clinical studies:

  • BRF113683: a pivotal Phase III randomized open-label study of 250 treatment-naïve patients with BRAF V600E mutation.
  • BRF113929: a supportive Phase II open-label study of 172 patients with BRAF V600E or BRAF V600K mutation, and melanoma metastatic to the brain. This study included two cohorts; no prior local therapy, and prior local therapy for brain metastases.
  • BRF113710: a supportive Phase II open-label, single-arm study of 92 patients with BRAF V600E or BRAF V600K mutation who were previously untreated or who had failed at least one prior systemic therapy.

Screening for eligibility required central testing for BRAF V600 mutation using a BRAF mutation assay conducted on the most recent tumour sample available from either a primary tumour or a tumour from a metastatic site. The assay used in clinical studies specifically differentiated between the V600E and V600K mutations. Only patients with the BRAF mutation specified in the protocol were eligible for study enrolment.

Phase III Pivotal Study BRF113683

The efficacy and safety of Tafinlar in previously untreated patients with BRAF V600E mutation-positive melanoma were evaluated in Study BRF113683 in which patients were randomized (3:1) to receive either Tafinlar 150 mg twice daily or intravenous dacarbazine (DTIC) 1,000 mg/m2 every 3 weeks. Patients with BRAF V600K mutation-positive melanoma were excluded from this study. The primary objective was to evaluate the efficacy of Tafinlar compared to DTIC with respect to progression-free survival (PFS) per investigator assessment. Secondary efficacy objectives included comparison of overall response rate (ORR), overall survival, duration of response, and health-related quality of life (HRQoL) status.

Treatment with Tafinlar monotherapy was associated with a statistically significant improvement on the primary endpoint, investigator-assessed PFS, compared to treatment with DTIC (Hazard ratio 0.30, 95% Confidence Interval: 0.18, 0.51; p<0.0001). This represents a relative reduction of 70% in the risk of disease progression or death compared with DTIC. Independent reviewer-assessed PFS results were consistent with investigator-assessed results.

The ORR results favoured dabrafenib over DTIC; 53% for the patients treated with Tafinlar compared to 19% in the DTIC arm. The data for overall survival were not mature at the time of analysis. There was no statistically significant difference in HRQoL status as measured by patient reported outcomes between the two treatment arms.

Phase II Study BRF113929

The efficacy and safety of Tafinlar 150 mg twice daily in patients with histologically confirmed BRAF mutation-positive (V600E or V600K) melanoma metastatic to the brain were evaluated in a two-cohort Phase II study (BRF113929). Patients enrolled had no prior local therapy for brain metastases (Cohort A) or had received prior local therapy for brain metastases (Cohort B). Prior treatment for patients in Cohort B included brain surgery, whole-brain radiation therapy, and stereotactic radiosurgery.

Intracranial response rates for BRAF V600E mutation-positive patients were 20% and 18% in Cohorts A and B, respectively, by independent-radiologist assessments. Intracranial response rates for BRAF V600K mutation-positive patients were 0% and 11% in Cohorts A and B, respectively, by independent-radiologist assessments. In both cohorts, patients with BRAF V600E mutation-positive melanoma had better overall intracranial responses than patients with BRAF V600K mutation-positive melanoma.

Phase II Study BRF113710

The efficacy and safety of Tafinlar in patients with BRAF V600E or V600K mutation-positive metastatic melanoma were evaluated in a Phase II study (BRF113710). The majority (80%) had received prior chemotherapy (cytotoxic/non-cytotoxic) in the advanced or metastatic setting, while the remainder were treatment naïve for systemic therapy (20%).

Confirmed overall response rates (ORR) for patients with either a BRAF V600E mutation [number of patients (n) = 76)] or a BRAF V600K mutation (n = 16) were reported by both investigator and independent radiologist assessments. There were greater numbers of overall responses for patients with the BRAF V600E mutation (ORR of 59 % and 41% by investigator and independent-radiologist reviews, respectively) compared to patients with the BRAF V600K mutation (ORR of 13% and 25% by investigator and independent radiologist reviews, respectively). Although response rates were lower in patients with the less common BRAF V600K mutation, they were considered better than what one would expect with DTIC based on historical comparisons to the whole patient population.

Conclusion

The overall efficacy based on one pivotal Phase III study and two supportive Phase II studies demonstrated effectiveness of Tafinlar in patients with BRAF V600E mutation-positive melanoma. The efficacy data for Tafinlar in BRAF V600K mutation-positive melanoma patients were less clear; these patients were excluded from the pivotal study. There was small number of patients with the BRAF V600K mutation enrolled in the Phase II studies, and the available data suggest that the efficacy is lower in patients with the BRAF V600K subtype. There are no efficacy data for Tafinlar in patients with other less BRAF V600 mutations, which comprise only approximately 5% of all mutation-positive patients. The specified indication allows for the broader BRAF V600 mutation-positive melanoma patient population so as not to exclude use in patients harbouring BRAF V600K or other less common V600 mutations. At the same time, the labelling identifies fewer data and limited numbers of responses for BRAF V600K mutation-positive patients compared to BRAF V600E mutation-positive patients. Furthermore, the indication also states that there are no clinical data for other less common BRAF V600 mutations. Also important to consider is the information provided by the sponsor's clinical expert that some Canadian testing sites identify the BRAF V600 mutation without specifying the subtype.

For more information on Tafinlar, refer to the Tafinlar Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Tafinlar as monotherapy was evaluated in an integrated safety population of 586 patients with unresectable or metastatic melanoma, with a median duration of treatment of 5.5 months (range 0 to 23 months). Approximately 46% of patients received treatment with Tafinlar for more than 6 months. The most common adverse drug reactions (³15%) of any grade for Tafinlar in either the integrated monotherapy safety population or the Phase III pivotal study (described in the Clinical Efficacy section) include hyperkeratosis, headache, pyrexia, palmar-plantar erythrodysaesthesia (PPE), asthenia, arthralgia, fatigue, nausea, skin papilloma, alopecia, rash, and vomiting. The most common treatment-related serious adverse events (SAEs) in patients treated with Tafinlar were cutaneous squamous cell carcinoma (cuSCC) and pyrexia. Serious cases of pyrexia occurred in 10 of 187 patients (5%). Reports of CuSCC occurred in 17 of 187 patients (9%), 12 cases of cuSCC (6%) were classified as an SAE. The cases of cuSCC included SCC of the skin, and keratoacanthoma.

Events of Grade 3 hyperglycemia were reported in 5% of patients treated with Tafinlar monotherapy. In some cases this resulted in treatment interruption, prolongation of hospitalization, and initiation or change in the active management of diabetes. Other significant but less frequent adverse events reported in patients receiving Tafinlar monotherapy included pancreatitis (1%), uveitis and iritis (1%).

Non-cutaneous cancers have also been reported in patients receiving Tafinlar. It is thought that in cells containing wild-type BRAF with RAS mutations, BRAF inhibitors may promote or initiate tumour cell growth. The approved labelling discusses this possibility and indicates that Tafinlar should not be used in patients with wild-type BRAF expressing melanomas. An additional warning also recommends against using Tafinlar in patients where the BRAF mutational status is not known. A validated test is required to confirm BRAF V600 mutational status in order to use Tafinlar.

Tafinlar has not been studied in patients with severe renal impairment, or in patients with moderate or severe hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure and increased toxicities. No dosing recommendations have been established for Tafinlar in these patients. Because excretion via the kidneys is a minor pathway, less impact of renal impairment is anticipated although caution should still be exercised in patients with severe renal impairment.

Cardiac signals were identified in the non-clinical studies and cardiovascular-related events have been reported in clinical studies with Tafinlar monotherapy. Patients were excluded from clinical studies if they had abnormal valve morphology ≥Grade 2 based on observations that right side heart valve defects were observed in animals. The heart valve defects was were not consistently observed in animals; and in clinical studies 1 in 586 patients had worsening of baseline valve disease but this did result in permanent discontinuation of Tafinlar. It is not known if excluding patients with valve abnormalities affected this incidence rate. Patients were also excluded from clinical studies if they had a corrected QT (QTc) interval of ≥480 msec. Tafinlar was associated with QTc interval prolongation and care should be taken when using with other medications known to increase the QTc interval. Atrial fibrillation and hypotension also have occurred with Tafinlar monotherapy and the Tafinlar Product Monograph has been updated accordingly to include these events.

Overall, Tafinlar presented an acceptable safety profile given the disease setting. Appropriate warnings and precautions are in place in the approved Tafinlar Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box highlights the risks of second malignancies, serious non-infectious febrile events, teratogenicity, and potential for decreased efficacy of oral contraceptives (due to a drug-drug interaction), as well as the lack of data in patients with moderate of severe hepatic impairment. A Serious Drug Interaction Box was also included because of the teratogenicity of dabrafenib in animals and the likelihood for increasing the metabolism of oral contraceptives and reducing their clinical effectiveness.

For more information, refer to the Tafinlar Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

Primary pharmacology studies support the use of dabrafenib, the medicinal ingredient of Tafinlar, for the treatment of melanoma with a BRAF V600E mutation. Although studies of BRAF V600K are more limited (for example, no in vivo studies), kinase potency, inhibition of signal transduction, and inhibition of proliferation of tumour cell lines support that dabrafenib would be efficacious in patients with BRAF V600K mutations.

The main target organs for toxicity in the non-clinical program for dabrafenib were the skin, heart, vasculature, testes, epithelium, gastrointestinal tract, and lung. Reproductive and developmental toxicity studies suggest that there is risk for effects on female fertility, embryo-fetal toxicity including teratogenicity, at therapeutic doses of dabrafenib in humans. Pyrexia has not been observed preclinically in studies in mice, rats or dogs; the cause and mechanism of this adverse event in humans remain unknown. The definitive juvenile toxicity study findings suggest that dabrafenib may pose a higher risk for tubular injury for human infants <1 years of age and may affect bone growth in pediatric populations. Although dabrafenib absorbs light in the region of concern for photosafety and was phototoxic in vitro in the mouse fibroblast 3T3 Neutral Red Uptake assay, only 3% of patients enrolled in clinical studies experienced a photosensitivity reaction while receiving dabrafenib as a monotherapy. In dogs, coronary arterial degeneration, valvular hypertrophy with increased myxomatous ground substance, and atrial fibrovascular proliferation were observed. Patients with abnormal valve morphology of Grade 2 or greater were excluded from clinical studies.

Dabrafenib was an inducer of CYP2B6 and CYP3A4 in human hepatocytes in vitro, and dabrafenib and its metabolites inhibited human organic anion-transporting polypeptides OATP1B1 and OATP1B3. In humans, dabrafenib was both a substrate for and a strong to moderate inducer of CYP3A4 (and possibly other CYPs). The potential for drug interactions, particularly drug-drug interactions, is significant and can lead to increased toxicities or altered clinical effectiveness of dabrafenib or concomitant medications.

Despite the fact that there was no evidence of brain penetration of dabrafenib or circulating metabolites in a positron emission tomography study in the pig, intracranial responses were observed in clinical studies in patients with melanoma metastatic to the brain.

Dabrafenib was not genotoxic in the bacterial mutagenicity study, in the mouse lymphoma assay, and the rat micronucleus assay. Long-term animal studies have not been conducted to evaluate the carcinogenic potential of dabrafenib. Carcinogenicity studies are generally not required for therapeutics intended for the treatment of patients with advanced cancer.

Overall, the non-clinical toxicology program conducted with dabrafenib supports the specified indication of unresectable or metastatic melanoma with a BRAF V600 mutation, and no further non-clinical studies are recommended in support of approval for this indication.

For more information on the results of non-clinical studies, as well as the potential risks to humans, refer to the Tafinlar Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Tafinlar has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf-life is considered acceptable.

Proposed limits of drug-related impurities are considered adequately qualified (that is within International Conference on Harmonisation (ICH) limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipients used in the product formulation are not of animal or human origin. The shellac used in the black ink is derived from insects; however, insects are not implicated in bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE). The magnesium stearate is of vegetable grade.

The Tafinlar capsule strength of 75 mg is proportional to the 50 mg capsule strength (common blend).

The drug product standard is claimed as 'professed" with specifications that conform to the current Health Canada requirements.

 

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