Summary Basis of Decision for Braftovi
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Braftovi is located below.
Recent Activity for Braftovi
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.
Summary Basis of Decision (SBD) for Braftovi
Date SBD issued: 2021-06-08
The following information relates to the new drug submission for Braftovi.
Encorafenib
Drug Identification Number (DIN):
- DIN 02513099 - 75 mg encorafenib, capsule, oral administration
Pfizer Canada ULC
New Drug Submission Control Number: 237413
On March 2, 2021, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for the drug product Braftovi.
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-harm-uncertainty profile of Braftovi, in combination with binimetinib, is favourable for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation, as detected by a validated test.
1 What was approved?
Braftovi (encorafenib) is a protein kinase inhibitor. It was authorized for use in combination with another protein kinase inhibitor, binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation, as detected by a validated test.
Clinical data supporting the use of Braftovi in the treatment of patients with BRAF V600 mutations are limited to patients with V600E or V600K mutations.
The safety and effectiveness of Braftovi have not been established in pediatric (younger than 18 years of age) patients. Therefore, Health Canada has not authorized an indication for pediatric use.
No overall differences in the safety or effectiveness of Braftovi used in combination with binimetinib were observed in patients over 65 years of age compared to younger patients.
Braftovi is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Braftovi was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Braftovi (75 mg encorafenib) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains colloidal silicon dioxide, copovidone, crospovidone, ferrosoferric oxide, gelatin, iron oxide red, iron oxide yellow, magnesium stearate of vegetable origin, microcrystalline cellulose, pharmaceutical glaze, poloxamer 188, propylene glycol, succinic acid, and titanium dioxide.
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 Braftovi Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Braftovi approved?
Health Canada considers that the benefit-harm-uncertainty profile of Braftovi, in combination with binimetinib, is favourable for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation, as detected by a validated test.
Clinical data supporting the use of Braftovi in the treatment of patients with BRAF V600 mutations are limited to patients with V600E or V600K mutations.
Melanoma is the most lethal form of skin cancer due to its propensity to metastasize to vital organs, including the brain, lungs, liver, and other visceral organs. Exposure to ultraviolet light, including history of severe sunburns and exposure to indoor tanning are among risk factors for melanoma. Caucasians are at a higher risk of developing melanoma than other populations. According to the Canadian Cancer Society, approximately 8,200 Canadians will be diagnosed with melanoma in 2021. It is estimated that more than 1,000 Canadians die from melanoma each year.
Approximately 50% of patients with metastatic melanoma have mutations in the BRAF gene (B-Raf proto-oncogene, serine/threonine kinase). Over 95% of these mutations are in BRAF exon 15 at V600 (the amino acid valine at position 600). The most common V600 mutations are V600E and V600K accounting for 66-91% and 7-30% of all BRAF V600 mutations, respectively. These mutations lead to constitutive activation of the BRAF protein and downstream signal transduction in the mitogen-activated protein kinase (MAPK) intracellular signalling pathway (also referred to as RAS/RAF/MEK/ERK signalling pathway), promoting the proliferation and survival of cancer cells. In a prospective study of 197 patients with metastatic melanoma, BRAF mutations were associated with features of high-risk melanoma including truncal location of the primary tumour, earlier age of onset, lack of chronic skin damage, and shortened survival. Current treatment options for patients with BRAF V600-mutant advanced melanoma include immune checkpoint inhibitors and combinations of BRAF and MEK inhibitors.
Encorafenib, the medicinal ingredient in Braftovi, is a kinase inhibitor that targets several mutated forms of BRAF kinase (V600E, V600D, and V600K) in in vitro cell assays.
The clinical efficacy and safety of Braftovi in combination with binimetinib (a MEK inhibitor) were supported by data derived from a pivotal Phase III, randomized, active-controlled, open-label study (COLUMBUS), conducted in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Patients were randomized in a ratio of 1:1:1 to receive Braftovi 450 mg once daily in combination with binimetinib 45 mg twice daily (Combo 450 treatment arm), Braftovi 300 mg once daily (encorafenib treatment arm), or vemurafenib 960 mg twice daily (vemurafenib treatment arm). Treatment continued until disease progression or unacceptable toxicity occurred.
The primary efficacy endpoint was progression-free survival, as assessed by a blinded independent central review, for patients treated with Braftovi in combination with binimetinib compared to patients treated with vemurafenib. A statistically and clinically significant improvement in progression-free survival was observed in patients treated with Combo 450 as compared to patients treated with vemurafenib. The median progression-free survival times were 14.9 months (95% confidence interval [CI]: 11.0, 18.5) in patients treated with Combo 450 and 7.3 months (95% CI: 5.6, 8.2) in patients treated with vemurafenib, which corresponded to a hazard ratio of 0.54 (95% CI: 0.41, 0.71; one-sided stratified log-rank p<0.001).
Secondary efficacy endpoints, including objective response rate, duration of response, and overall survival, while not tested in the protocol-specified hierarchical testing strategy, were supportive of a clinical benefit of the Combo 450 treatment compared to the vemurafenib treatment.
The reported safety data from the Columbus study, based on a median duration of treatment of 51.2 weeks in the Combo 450 arm and 27.1 weeks in the vemurafenib arm, were consistent with data previously reported for patients treated with other combinations of MEK and BRAF inhibitors.
In patients who received Braftovi in combination with binimetinib, the most common adverse reactions (observed in at least 20% of patients) were fatigue, nausea, diarrhea, vomiting, constipation, abdominal pain, headache, rash, hyperkeratosis, increased blood creatinine kinase, arthralgia, myopathy, and visual impairment.
A Serious Warnings and Precautions box has been included in the Braftovi Product Monograph to highlight the following significant drug reactions identified as driven by Braftovi: new primary cutaneous malignancies, major hemorrhagic events, uveitis, venous thromboembolism, and QT prolongation.
A Risk Management Plan (RMP) for Braftovi was submitted by Pfizer Canada ULC 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.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Braftovi Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Braftovi was accepted.
Overall, the safety profile of Braftovi in combination with binimetinib is considered acceptable for the target patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Braftovi Product Monograph to address the identified safety concerns.
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 Braftovi?
Submission Milestones: Braftovi
| Submission Milestone | Date |
|---|---|
| Submission filed | 2020-03-20 |
| Screening | |
| Screening Acceptance Letter issued | 2020-05-07 |
| Review | |
| Review of Risk Management Plan complete | 2021-01-06 |
| Biopharmaceutics Evaluation complete | 2021-01-19 |
| Labelling Review complete | 2021-02-08 |
| Quality Evaluation complete | 2021-02-18 |
| Non-Clinical Evaluation complete | 2021-02-24 |
| Clinical/Medical Evaluation complete | 2021-03-01 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate | 2021-03-02 |
The Canadian regulatory decision on the review of Braftovi was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications 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.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
The pharmacokinetics of encorafenib, the medicinal ingredient in Braftovi, was studied in healthy subjects and patients with solid tumours.
Following a single dose of encorafenib, systemic exposure of encorafenib (as measured by the area under the plasma concentration-time curve [AUC] and the maximum observed plasma concentration [Cmax]) was dose proportional over the dose range of 50 mg to 700 mg.
After once-daily dosing of encorafenib in combination with binimetinib 45 mg twice daily, systemic exposure of encorafenib was less than dose proportional over the dose range of 50 mg to 800 mg. Steady state was reached within 15 days, with a 50% lower exposure compared to day 1. The inter-subject variability (percent coefficient of variation [CV%]) of the AUC ranged from 12% to 69%. Concomitant food intake had no clinically relevant effect on the encorafenib exposure.
Encorafenib is eliminated primarily by cytochrome P450 (CYP) 3A4-mediated metabolism. A dedicated clinical study indicates a 25% higher total encorafenib exposure in patients with mild hepatic impairment compared to subjects with normal liver function. This translates to a 55% increase of the unbound encorafenib exposure. Accordingly, a reduction of the starting dose of Braftovi to 300 mg once daily is recommended in patients with mild hepatic impairment. The pharmacokinetic properties of encorafenib have not been studied in patients with moderate or severe hepatic impairment.
Based on population pharmacokinetic analyses, age (range 19 to 94 years), sex, body weight (range 42 to 168 kg), and mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to 90 mL/min/1.73 m2) have no clinically meaningful effects on the pharmacokinetics of encorafenib. The effect of severe renal impairment (eGFR <30 mL/min/1.73 m2) on the pharmacokinetic properties of encorafenib has not been studied.
Encorafenib prolongs the corrected QT (QTc) interval in a dose-dependent manner. Based on a central tendency analysis of QTc in a study of adult patients with melanoma, the largest mean (90% confidence interval [CI]) change from baseline in the Fridericia-corrected QT interval (ΔQTcF) is 18 ms (14 to 22 ms) after administration of the recommended dose of 450 mg encorafenib once daily in combination with 45 mg binimetinib twice daily.
In patients with advanced melanoma, the maximum tolerated dose for encorafenib when used alone is 300 mg once daily. When encorafenib is used in combination with binimetinib 45 mg twice daily, the maximum tolerated dose is 450 mg once daily. No apparent pharmacokinetic interaction was observed between encorafenib and binimetinib. The addition of binimetinib may reduce encorafenib toxicities by blocking the paradoxical activation of mitogen-activated protein kinase (MAPK) signalling pathway induced by encorafenib.
The sponsor proposed a dose reduction schema for Braftovi in the event of adverse reactions (450 mg to 300 mg or 300 mg to 225 mg) that could be achieved with a single dose strength of 75 mg, which eliminated the need for a 50 mg dose strength (the latter has been discontinued). The lowest dose in the proposed schema (225 mg) is higher than the 200 mg dose that was allowed in the pivotal clinical study. Population pharmacokinetic analyses indicate that the anticipated mean difference in exposures of encorafenib (approximately 12.5%) between the reduced dose levels of 225 mg and 200 mg is within the observed intra-patient and inter-patient variability. Exposure-response modelling further suggests no substantial differences in efficacy and safety predictions between the two doses, with broad overlap of the predicted 95% CI values.
Overall, the clinical pharmacology data support the intended use of encorafenib in combination with binimetinib for the specified indication.
For further details, please refer to the Braftovi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Braftovi in combination with binimetinib was evaluated in a pivotal Phase III, randomized, active-controlled, open-label study (COLUMBUS), conducted in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Patients enrolled were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was not allowed. Patients were randomized (1:1:1) to receive Braftovi 450 mg once daily in combination with binimetinib 45 mg twice daily (Combo 450 treatment arm), Braftovi 300 mg once daily (encorafenib treatment arm), or vemurafenib 960 mg twice daily (vemurafenib treatment arm). Treatment continued until disease progression or unacceptable toxicity occurred.
The primary efficacy endpoint was progression-free survival, as assessed by a blinded independent central review, for patients treated with Braftovi in combination with binimetinib compared to patients treated with vemurafenib. Additional efficacy measures included overall survival, objective response rate, and duration of response, which were also assessed by a blinded independent central review.
The study demonstrated a statistically and clinically significant improvement in progression-free survival in patients treated with Combo 450 as compared to patients treated with vemurafenib. The median progression-free survival times were 14.9 months (95% confidence interval [CI]: 11.0, 18.5) in patients treated with Combo 450 and 7.3 months (95% CI: 5.6, 8.2) in patients treated with vemurafenib, which corresponded to a hazard ratio (HR) of 0.54 (95% CI: 0.41, 0.71; one-sided stratified log-rank p<0.001).
The confirmed objective response rate per central review was 63.0% (95% CI: 55.8%, 69.9%) in the Combo 450 treatment arm compared to 40.3% (95% CI: 33.3%, 47.6%) in the vemurafenib treatment arm.
Responses were durable, with a median duration of response for confirmed responses per central review of 16.6 months (95% CI: 12.2, 20.4) in patients treated with Combo 450 and 12.3 months (95% CI: 6.9, 16.9) in patients treated with vemurafenib.
In an interim analysis of the endpoint of overall survival, performed as per study protocol when 232 events had been observed in the Combo 450 and vemurafenib arms combined, the overall survival data were analyzed descriptively without formal statistical significance testing, due to the protocol-specified hierarchical testing rules. An estimated 39% reduction in the risk of death was observed for patients randomized to the Combo 450 arm compared to those randomized to the vemurafenib arm (HR = 0.61; 95% CI: 0.47, 0.79), with median (95% CI) overall survival of 33.6 months (24.4, 39.2) and 16.9 months (14.0, 24.5), respectively.
Indication
The New Drug Submission for Braftovi was filed by the sponsor with the following indication:
Braftovi (encorafenib) is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation.
Upon review of the submitted data, Health Canada revised the proposed indication to: i) refer to a validated test for detection of the BRAF V600 mutations and ii) include a caveat statement reflecting the patient population studied. Accordingly, Health Canada approved the following indication:
Braftovi is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation, as detected by a validated test.
Clinical data supporting the use of Braftovi in the treatment of patients with BRAF V600 mutations are limited to patients with V600E or V600K mutations.
For more information, refer to the Braftovi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety evaluation of Braftovi in combination with binimetinib is based primarily on data from 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who were treated with Braftovi (450 mg once daily) in combination with binimetinib (45 mg twice daily) in the randomized, open-label, active-controlled COLUMBUS study (described in the Clinical Efficacy section). Based on a median duration of treatment of 51.2 weeks, the safety data were consistent with data previously reported for patients treated with other combinations of BRAF and MEK inhibitors.
In patients who received Braftovi in combination with binimetinib, the most common adverse reactions (observed in at least 20% of patients) were fatigue, nausea, diarrhea, vomiting, constipation, abdominal pain, headache, rash, hyperkeratosis, increased blood creatinine kinase, arthralgia, myopathy, and visual impairment.
Important identified toxicities associated with Braftovi include new primary cutaneous malignancies, major hemorrhagic events, uveitis, venous thromboembolism, and QT prolongation.
Fewer patients receiving Braftovi in combination with binimetinib (57.8%) experienced grade 3/4 adverse events compared to patients receiving vemurafenib (63.4%).
A slightly higher proportion of patients in the vemurafenib arm (37.1%) experienced at least one serious adverse event compared to the Braftovi in combination with binimetinib arm (34.4%). The most commonly reported serious adverse events in the Braftovi in combination with binimetinib arm were pyrexia, abdominal pain, anemia, acute kidney injury, cerebral hemorrhage, general physical health deterioration, pneumonia, pulmonary embolism, and vomiting.
Adverse reactions leading to dose interruptions of Braftovi occurred in 30% of patients receiving Braftovi in combination with binimetinib. The dose interruptions were most commonly due to nausea (7%), vomiting (7%), and pyrexia (4%).
Adverse reactions requiring dose reductions of Braftovi occurred in 14% of patients receiving Braftovi in combination with binimetinib. The most common adverse reactions that resulted in dose reductions were arthralgia (2%), fatigue (2%), and nausea (2%).
Adverse reactions led to permanent discontinuation of Braftovi in 5% of patients receiving Braftovi in combination with binimetinib. Hemorrhage (2%) and headache (1%) were the most common adverse reactions that resulted in permanent discontinuation of Braftovi.
Appropriate warnings and precautionary measures, including recommendations for dose modifications, are in place in the Braftovi Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box highlights the following significant adverse reactions identified as driven by Braftovi: new primary cutaneous malignancies, major hemorrhagic events, uveitis, venous thromboembolism, and QT prolongation.
For more information, refer to the Braftovi Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF proteins in in vitro cell-free assays with 50% inhibition concentration (IC50) values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumour cell growth.
Encorafenib inhibited in vitro growth of tumour cell lines expressing BRAF V600E, V600D, and V600K mutations.
In vivo, in mice implanted with tumour cells expressing the BRAF V600E mutation, encorafenib induced tumour regressions associated with mitogen-activated protein kinase (MAPK) intracellular signalling pathway (also referred to as RAS/RAF/MEK/ERK signalling pathway) suppression.
Encorafenib (a BRAF inhibitor) and binimetinib (a MEK inhibitor) target two different kinases in the RAS/RAF/MEK/ERK signalling pathway. In comparison to either drug when administered alone, the combination of encorafenib and binimetinib resulted in greater antiproliferative activity in vitro in BRAF mutation-positive cell lines and greater antitumour activity in vivo in BRAF V600E-mutant human melanoma xenograft models. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E-mutant human melanoma xenografts in nude mice.
In non-clinical toxicity studies in rats, the toxicity findings included hyperplasia and hyperkeratosis in the skin and the non-glandular stomach, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides. In monkeys, a notable toxicity finding was central serous retinopathy.
Carcinogenicity studies with encorafenib have not been conducted. In standard genotoxicity studies, encorafenib did not exhibit genotoxicity.
Dedicated fertility studies with encorafenib have not been conducted. However, given the toxicity findings in the male reproductive organs observed in repeat-dose toxicology studies in rats, encorafenib may affect male fertility.
In reproductive toxicity studies, administration of encorafenib to pregnant rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights, and increased incidence of total skeletal variations at a dose of 20 mg/kg/day (approximately 26 times the human exposure achieved at the recommended clinical dose of 450 mg once daily). In pregnant rabbits, administration of encorafenib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, increased incidence of total skeletal variations and increased post-implantation loss, including total loss of pregnancy at a dose of 75 mg/kg/day (approximately 178 times the human exposure achieved at the recommended clinical dose of 450 mg once daily). Encorafenib exposure in the fetal plasma of both rats and rabbits was up to 1.7% and 0.8%, respectively, of maternal exposure.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Braftovi Product Monograph. In view of the intended use of Braftovi, in combination with binimetinib, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Braftovi 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 Braftovi 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 of 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).
Proposed limits of drug-related impurities are considered adequately qualified (i.e., within the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits).
The sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (i.e., excipients, described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The gelatin used in the capsule shells is of animal origin. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| BRAFTOVI | 02513099 | PFIZER CANADA ULC | ENCORAFENIB 75 MG |