Summary Basis of Decision for Alunbrig

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 Alunbrig is located below.

Recent Activity for Alunbrig

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 Alunbrig

Updated: 2023-09-13

The following table describes post-authorization activity for Alunbrig, a product which contains the medicinal ingredient brigatinib. 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 PAATs.

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

Drug Identification Number (DIN):

  • DIN 02479206 - 30 mg brigatinib, tablets, oral administration
  • DIN 02479214 - 90 mg brigatinib, tablets, oral administration
  • DIN 02479222 - 180 mg brigatinib, tablets, oral administration
  • DIN 02479230 - 90 mg and 180 mg brigatinib, tablets (initiation pack), oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
PBRER-C # 266977 2022-08-15 Filed 2023-01-27 Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C #5 for the period 2021-04-28 to 2022-04-27. The information was reviewed and found acceptable. No further action was required.
PBRER-C # 260049 2022-01-04 Filed 2023-01-09 Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C #4 for the period 2021-04-28 to 2021-10-27. The information was reviewed and found acceptable. No further action was required.
PBRER-C # 254053 2021-06-22 Filed 2023-01-09 Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C #3 for the period 2020-10-28 to 2021-04-27. The information was reviewed and found acceptable. No further action was required.
PBRER-C # 248116 2021-01-07 Filed 2023-01-09 Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C #2 for the period 2020-04-28 to 2020-10-27. The information was reviewed and found acceptable. No further action was required.
PBRER-C 241346 2020-07-02 Filed 2023-01-09 Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER‑C #1 for the period 2019-10-28 to 2020-04-27. The information was reviewed and found acceptable. No further action was required.
SNDS-C # 257113 2021-09-29 Issued NOC 2022-07-20 Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The submission filed to remove the conditions from the NOC for the indication of Alunbrig in the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or who were intolerant to an ALK inhibitor (crizotinib). The submission provided confirmatory data from the Phase III confirmatory ALTA1 study. The data were reviewed and considered acceptable and the conditions were removed from the NOC.
SNDS # 237680 2020-03-31 Issued NOC 2021-03-03 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: as a monotherapy for the first line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
Drug product (DINs 02479206, 02479214, 02479222, 02479230) market notification Not applicable Date of first sale:
2018-08-31
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 210369 2017-10-17 Issued NOC under NOC/c Guidance
2018-07-26
Notice of Compliance issued under the NOC/c Guidance for New Drug Submission.
Summary Basis of Decision (SBD) for Alunbrig

Date SBD issued: 2019-01-28

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

Brigatinib
30 mg, 90 mg, and 180 mg tablets, oral

Drug Identification Number (DIN):

  • DIN 02479206 - 30 mg tablets
  • DIN 02479214 - 90 mg tablets
  • DIN 02479222 - 180 mg tablets
  • DIN 02479230 - 90 mg and 180 mg tablets (initiation pack)

Takeda Canada Inc.orporated

New Drug Submission Control Number: 210369

 

On July 26, 2018, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Takeda Canada Incorporated for the drug product Alunbrig. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

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 Alunbrig is favourable as a monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or who were intolerant to an ALK inhibitor (crizotinib).

 

1 What was approved?

 

Alunbrig, a protein kinase inhibitor, was authorized as a monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or who were intolerant to an ALK inhibitor (crizotinib).

Safety and efficacy data in geriatric patients (≥65 years of age) are limited, and there is no information available on patients over 85 years of age. Geriatric patients accounted for 23% of patients in the pivotal trial population, and increased age was associated with greater risk of early pulmonary adverse reactions. Dose adjustment is not required.

Alunbrig is not approved for pediatric use, as its safety and efficacy have not been studied in patients under 18 years of age.

Alunbrig 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.

Alunbrig 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.

Alunbrig (30 mg, 90 mg, or 180 mg brigatinib) is presented as tablets. In addition to the medicinal ingredient, the tablets contain lactose monohydrate, magnesium stearate, microcrystalline cellulose, silica colloidal hydrophobic, and sodium starch glycolate (type A). The tablet coating contains polyethylene glycol, polyvinyl alcohol, talc, 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 Alunbrig Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Alunbrig approved?

 

Health Canada considers that the benefit-harm-uncertainty profile of Alunbrig is favourable as a monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or who were intolerant to an ALK inhibitor (crizotinib). Alunbrig was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

The World Health Organization divides lung cancer into two major classes: NSCLC and small cell lung cancer (SCLC). More than 80% of all lung cancers are NSCLC, which includes two major types: non-squamous cell carcinoma (which includes adenocarcinoma) and squamous cell carcinoma. Eighty-four percent (84%) of cases are diagnosed in advanced stages, and for patients with distant metastases, the five-year survival rate is 4%.

Molecular diagnostic studies can identify the presence of oncogenic alterations, such as the ALK or epidermal growth factor receptor (EGFR) gene mutations, which help determine the use of targeted therapies in the treatment regimen. The disease targeted by Alunbrig is NSCLC with ALK rearrangements (ALK-positive NSCLC).

Brigatinib, the medicinal ingredient in Alunbrig, is a new ALK inhibitor. In the first and second line settings for ALK-positive NSCLC, treatment with the first-generation ALK inhibitor, crizotinib, has shown an improvement in progression-free survival relative to chemotherapy. The National Comprehensive Cancer Network (NCCN) guidelines recommend therapy with crizotinib in this patient population, and reports very high response rates (>60%) when used in patients with advanced diseases. However, acquired resistance is nearly universal in ALK-positive NSCLC, and most patients develop crizotinib resistance within one year of treatment. In nearly a third of patients, tumours acquire secondary mutations in the ALK tyrosine kinase domain. The central nervous system (CNS) is the first site of progression in approximately 50% of patients, suggesting inadequate penetration of crizotinib into the brain (i.e., pharmacologic failure) as the primary cause of resistance in these patients.

Recently, two second-generation ALK inhibitors, ceritinib and alectinib, have become available in Canada for patients with ALK-positive NSCLC who have progressed on or who are intolerant to crizotinib. Both agents were also granted conditional approval by Health Canada. Although the second-generation ALK inhibitors are reported to be very active in patients with locally advanced or metastatic NSCLC disease, the majority progress within a year. Anaplastic lymphoma kinase secondary mutations associated with clinical resistance to ALK-positive inhibitors have also been identified with ceritinib and alectinib.

Alunbrig has been shown to be efficacious in patients with ALK-positive NSCLC who have progressed on or who were intolerant to an ALK inhibitor (crizotinib). The market authorization with conditions was based on promising data from ALTA, an ongoing pivotal Phase II trial.

The main objective of ALTA was to assess the efficacy of Alunbrig in treating ALK-positive locally advanced or metastatic NSCLC in patients who had previously progressed when treated with crizotinib. All 222 patients enrolled in this study were adults with metastatic ALK-positive NSCLC, and had progressed on crizotinib. Patients were randomized to one of two treatment groups to receive Alunbrig either 90 mg daily (hereafter referred to as the 90 mg regimen), or 180 mg daily with a seven-day lead-in at 90 mg daily (hereafter referred to as the 180 mg regimen). The dosage regimens selected for ALTA were determined in Study 101, a Phase I/II open-label study with a dose escalation phase. It was conducted in individuals with locally advanced or metastatic NSCLC.

Treatment continued until the patient's condition progressed, or the patient experienced an unacceptable level of treatment-related toxicity. Results were assessed by the clinical investigators as well as by an Independent Review Committee (IRC). The primary endpoint used to assess efficacy was the objective response rate (ORR), which refers to the proportion of patients in which the tumour disappeared or reduced in size. The ORR was determined according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1). This is a standardized approach used to measure the size of solid tumours, as well as changes in tumour size in response to treatment. Secondary endpoints included safety and tolerability, progression-free survival, and CNS response.

The confirmed ORR (as calculated by the IRC) among patients on the 180 mg regimen was 54.5%, and median duration of response was 14.8 months. Patients on the 90 mg regimen had a confirmed ORR of approximately 50.9%, and median duration of response was 13.8 months. A substantial difference was observed in progression-free survival between the two treatment groups, with median values of 16.7 months for patients on the 180 mg regimen, and 9.2 months for patients on the 90 mg regimen.

Intracranial ORR was also calculated in patients with measurable brain metastases at study initiation, as 66.7% for patients on the 180 mg regimen and 50% for patients on the 90 mg regimen. Patients on the 180 mg regimen also had a median duration of response of 16.6 months, while this value was unmeasurable for patients on the 90 mg regimen. These observations provide evidence of efficacy within the CNS, which was a limitation with previous treatments. Based on the increased efficacy observed in patients on the 180 mg regimen (180 mg once daily with a seven-day lead-in at 90 mg daily), it was approved as the recommended dosage regimen for Alunbrig.

The most common serious adverse reactions experienced by ALTA patients on the 180 mg dosage regimen were malignant pleural effusion, pneumonia and pneumonitis. Other serious adverse reactions included hypertension, bradycardia, elevation of pancreatic enzymes, hyperglycemia, and creatinine phosphokinase elevation. These have been highlighted in a Serious Warnings and Precautions box in the Alunbrig Product Monograph.

Nausea, diarrhea, fatigue, cough, headache, rash, vomiting, hypertension, dyspnea, myalgia, decreased appetite, muscle spasms, constipation, peripheral neuropathy, arthralgia, visual disturbances, abdominal pain, dizziness, edema, and interstitial lung disease/pneumonitis were among the most commonly reported adverse reactions. Decreased heart rate and prolongation of the PR interval were also observed in connection with brigatinib treatment. Adverse reactions led to discontinuation for 10.9% of patients, and dose reduction in 30% of patients.

Two adverse events have been associated with brigatinib which have not been reported for other ALK inhibitors: early onset pulmonary events and hypertension. These events were managed through dose interruption or dose reduction.

The pharmacokinetics of brigatinib is affected by body weight and by concurrent use with CYP3A inhibitors. Additionally, non-clinical data showed that brigatinib impairs male fertility and is a teratogen at dose levels lower than the recommended clinical dose. Information has been included in the Product Monograph on the safe use of Alunbrig in connection with each of these concerns.

The conditions associated with the market authorization of Alunbrig include submission of an annual Periodic Safety Update Report (PSUR)/Periodic Benefit-Risk Evaluation Report (PBRER) two years after marketing, as well as data from a Phase III study, ALTA-1L. This study is intended to address outstanding questions and verify the clinical benefit of Alunbrig.

Adverse reactions, drug-drug interactions, and other information regarding the safety of Alunbrig are addressed in greater detail in the Clinical Safety section.

A Risk Management Plan (RMP) for Alunbrig was submitted by Takeda Canada Incorporated 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 Alunbrig Product Monograph meet the necessary regulatory labelling, plain language and design element requirements. A Look-alike Sound-alike brand name assessment was performed and the proposed name Alunbrig was accepted.

Overall, the benefits of Alunbrig therapy observed in the pivotal study are promising, and are considered to outweigh the potential risks. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Alunbrig Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Alunbrig will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available.

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 Alunbrig?

 

The sponsor filed a request for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the new drug submission for Alunbrig. An assessment was conducted, and showed that the data was promising and provided evidence of clinical effectiveness. The drug offers a considerable improvement in the overall benefit/risk profile over existing treatment options, and addresses an unmet medical need in patients with non-curative ALK-positive NSCLC who have previously been treated with crizotinib.

 

Submission Milestones: Alunbrig

Submission Milestone Date
Pre-submission meeting: 2017-07-18
Request for priority status  
Filed: 2017-04-25
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance: 2017-10-16
Submission filed: 2017-10-17
Screening  
Screening Acceptance Letter issued: 2017-11-17
Review  
Quality Evaluation complete: 2018-07-06
Clinical Evaluation complete: 2018-07-11
Review of Risk Management Plan complete: 2018-05-02
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-06-29
Review of Response to NOC/c-QN:  
Response filed (Letter of Undertaking): 2018-07-17
Clinical Evaluation complete: 2018-07-20
Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance: 2018-07-26

 

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?

 

In addition to requirements outlined in the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to provide data from a Phase III study, ALTA-1L. Results from this study are expected to provide insights into the safety and efficacy of Alunbrig as a front line treatment compared to crizotinib, as well as to support the current indication. ALTA-1L will also address outstanding questions, including the safety and efficacy of Alunbrig in weight extremes (patients weighing less than 50 kg or more than 100 kg), to work towards lifting the conditions and gaining full approval. This trial is expected to end in March 2020, with the final report submitted by December 2020.

The Risk Management Plan was found acceptable upon review, with revisions expected within 90 days of market authorization.

 

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

Brigatinib, the medicinal ingredient in Alunbrig, is a tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK), ROS1, and insulin-like growth factor 1 receptor (IGF-1R). Among these, brigatinib is most active against ALK. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalling protein STAT3 in in vitro and in vivo assays.

In the ALTA study, a decreased heart rate (<50 beats per minute) was detected in 8.2% of patients on the recommended dosage regimen, 180 mg once daily with a seven-day lead-in at 90 mg once daily. This effect was initially observed in the dose finding study, Study 101, and was associated with higher plasma concentrations of brigatinib. This was also accompanied by a prolonged PR interval, and appeared to be concentration-dependent. Concurrent use of Alunbrig with drugs that decrease heart rate or increase the PR interval, including antiarrhythmics and beta adrenoceptor antagonists, should be avoided.

In patients given a single oral dose of 30 mg to 240 mg, the median time to peak plasma concentration of brigatinib was one to four hours postdose. Systemic exposure to brigatinib was dose proportional in patients receiving 60 mg to 240 mg once daily, following single and repeat dosing of Alunbrig. Alunbrig may be taken with or without food, as it was not found to significantly affect the bioavailability of brigatinib.

Brigatinib is mainly metabolized by CYP2C8 and CYP3A4 in vitro. To monitor the metabolism of brigatinib in humans, healthy male volunteers were given a single 180 mg dose of [14C]-brigatinib (radioactively tagged brigatinib). N-demethylation and cysteine conjugation were identified as major metabolic clearance pathways. Brigatinib remains primarily unchanged in circulation, and accounted for 92% of circulating radioactive components. Its primary metabolite, AP26123, constituted 3.5% of circulating radioactive components. The mean plasma elimination half-life was 25 hours, with 65% of the administered dose recovered in feces and 25% recovered in urine.

Results of a population pharmacokinetic study revealed that brigatinib pharmacokinetics is influenced by body weight. Patients weighing less than 50 kg or more than 100 kg should be closely monitored in case of loss of efficacy. This information is included in the Product Monograph, and the safety and efficacy of Alunbrig will be studied in these patient populations as part of the post-approval commitments.

The pharmacokinetics of brigatinib was not significantly impacted by mild hepatic impairment, or by mild to moderate renal impairment. No dose adjustment is recommended due to these conditions. However, Alunbrig is not recommended for patients with moderate to severe hepatic impairment or with severe renal impairment due to the absence of data on brigatinib pharmacokinetics in these patient populations. The lack of data has been addressed in the Serious Warnings and Precautions box of the Alunbrig Product Monograph.

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

Clinical Efficacy

Evidence of the safety and efficacy of Alunbrig was provided by data from two clinical trials which were ongoing at the time of review: Study 101 and ALTA.

Study 101 was a Phase I/II open-label dose escalation study, conducted in patients with locally advanced or metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Results from this study were used to identify the most appropriate dosage regimens for further study in the pivotal trial, ALTA.

ALTA is a Phase II open-label study to evaluate the safety and efficacy of Alunbrig. All 222 patients enrolled in this study have ALK-positive NSCLC, and have progressed on crizotinib. Patients were randomized to one of two treatment groups, to receive either a 90 mg dose once daily, or a 180 mg dose once daily with a seven-day lead-in at 90 mg once daily (hereafter referred to as the 90 mg regimen and the 180 mg regimen, respectively). Treatment continued until the patient's condition progressed, or the patient experienced an unacceptable level of treatment-related toxicity. Results were evaluated by the investigative team as well as by an Independent Review Committee (IRC).

The primary endpoint was the confirmed objective response rate (ORR), which refers to the proportion of patients in which the tumour disappeared or reduced in size. The ORR was calculated according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1). This is a standardized approach used to measure the size of solid tumours, as well as changes in tumour size in response to treatment. The IRC calculated a slightly higher ORR than the investigators did for the 90 mg regimen (50.9% and 45.5%, respectively), but the two groups calculated similar ORRs for the 180 mg regimen (54.5% and 55.5%, respectively).

Progression-free survival was among the secondary endpoints evaluated in ALTA. Consistent findings were reported by the investigators and the IRC in favour of the 180 mg regimen. Progression-free survival for patients on the 180 mg regimen was calculated as 15.6 months by the investigators and 16.7 months by the IRC. Both groups calculated a progression-free survival period of 9.2 months in patients on the 90 mg regimen.

Other secondary endpoints included intracranial ORR and duration of intracranial response. These were assessed by the IRC in patients in both treatment groups who had measurable brain metastases at study initiation. Intracranial ORR was considerably higher in patients on the 180 mg regimen at 66.7%, versus 50.0% for those on the 90 mg regimen. Duration of intracranial response was 16.6 months for patients on the 180 mg regimen, but could not be measured for patients on the 90 mg regimen. Evidence of intracranial efficacy is especially important, as access to the central nervous system (CNS) has been a challenge with the first- and second-generation treatments currently available. The CNS is therefore the most common site for metastases, which contributes to the development of resistance to these treatments. The ability of brigatinib to access the CNS is a substantial improvement over existing treatments and contributes favourably to the benefit-harm-uncertainty profile of Alunbrig.

The results of bioequivalence studies between the 30 mg, 90 mg, and 180 mg strengths of Alunbrig were also included in the submission. Upon review, Health Canada concluded that all three strengths of Alunbrig will perform in an equivalent fashion when equivalent doses are administered. The bioavailability of brigatinib was also examined under fed and fasted conditions. Results from this study indicated that food does not significantly affect the absorption of brigatinib by the body. This study was considered acceptable upon review.

Indication

Sponsor's proposed indication Health Canada-approved indication
Alunbrig (brigatinib), indicated as a monotherapy for use in adult patients with anaplastic lymphoma kinase (ALK)-positive, locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC), who have progressed on, or who were intolerant to an ALK inhibitor (crizotinib). Alunbrig (brigatinib) is indicated as a monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or who were intolerant to an ALK inhibitor (crizotinib).

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

Clinical Safety

Along with clinical efficacy, the safety and tolerability of Alunbrig were assessed in ALTA. The design of this study is described in the Clinical Efficacy section.

Based on results from a dose finding study, the safety and efficacy of two dosage regimens were further evaluated in ALTA. Patients enrolled in ALTA were randomized in a 1:1 ratio to receive either 90 mg once daily (the 90 mg regimen), or 180 mg once daily with a seven-day lead-in at 90 mg once daily (the 180 mg regimen). The 180 mg regimen was approved as the recommended dosage regimen for Alunbrig due to its increased efficacy over the 90 mg regimen and its acceptable safety profile.

Malignant pleural effusion, pneumonia, and pneumonitis were the most common serious adverse reactions experienced by ALTA patients on the 180 mg regimen (≥2%). Interstitial lung disease/pneumonitis, hypertension, elevation of pancreatic enzymes, hyperglycemia, and creatinine phosphokinase (CPK) elevation were also among the identified serious adverse reactions. The most common adverse reactions, reported in ≥10% of patients, were nausea, diarrhea, fatigue, cough, headache, rash, vomiting, hypertension, dyspnea, myalgia, decreased appetite, muscle spasms, constipation, peripheral neuropathy, arthralgia, visual disturbances, abdominal pain, dizziness, edema, and interstitial lung disease/pneumonitis.

In total, 10.9% of patients on the 180 mg regimen discontinued treatment due to treatment-emergent adverse events. Those which most often led to discontinuation were pneumonitis, neoplasm progression, and pneumonia. Another 30% of patients experienced adverse events that resulted in dose reduction, including blood CPK elevation, pneumonitis, and rash.

While the majority of safety concerns identified for brigatinib are shared with other ALK inhibitors, two adverse events appear to be specific to brigatinib: early onset pulmonary events and hypertension. Early onset pulmonary events typically occur within two days of treatment initiation or re-initiation, or at most within nine days. While other related drugs are also associated with certain pulmonary events, the early onset is unique to brigatinib. In the clinical trials, it was more frequently observed in geriatric patients (≥65 years of age) than in adults under 65 years of age. However, the etiology of early onset pulmonary events in connection with brigatinib treatment remains unclear. Hypertension, including Grade 3 hypertension and hypertensive retinopathy, was detected in 27% of patients on the 180 mg regimen. These events were managed through dose interruption and standard antihypertensive treatments.

A population pharmacokinetics study revealed a significant relationship between body weight and the clearance and volume of distribution of brigatinib. Information has been included in the Product Monograph to support the safe use of Alunbrig in patients weighing less than 50 kg or greater than 100 kg. The safety and efficacy of Alunbrig in these patients are also being studied in a Phase III trial, ALTA-1L, as part of the post-approval conditions.

Decreased heart rate (<50 beats per minute) and a concentration-dependent increase in PR interval have also been associated with Alunbrig. Concurrent use with other drugs that elicit these effects, including antiarrhythmics and beta adrenoceptor antagonists, should be avoided.

As brigatinib is a substrate of CYP3A4, concurrent use with CYP3A4 inducers and CYP3A4 inhibitors will affect brigatinib pharmacokinetics. Concurrent use of Alunbrig with strong CYP3A inhibitors or strong or moderate CYP3A inducers should be avoided. If concomitant use with strong CYP3A inhibitors cannot be avoided, based on a clinical study, brigatinib dose should be reduced by approximately 50%. Additionally, the effect of brigatinib on CYP3A substrates and transporters has not been studied. Patients receiving (cyclosporine, cisapride, tacrolimus) or (digoxin, dabigatran, methotrexate, rosuvastatin, sulfasalazine, metformin) concomitantly with Alunbrig should be monitored closely for loss of their effectiveness or other adverse effects.

While dedicated reproductive toxicity tests were not carried out, the effects observed in the non-clinical repeat-dose toxicity studies were sufficient to determine that brigatinib impairs male fertility at doses lower than the clinical dose. In studies with pregnant rats, brigatinib was also shown to be a teratogen at doses lower than the clinical dose.

Post-Approval Conditions

The sponsor is expected to file an annual Periodic Safety Update Report (PSUR)/Periodic Benefit-Risk Evaluation Report (PBRER) two years after marketing, along with data from a Phase III study, ALTA-1L. This study addresses the outstanding questions in order to confirm the clinical benefit of Alunbrig. ALTA-1L will include an assessment of the efficacy of Alunbrig as a first-line treatment in crizotinib-naïve patients. The relationship between body weight and the pharmacokinetics of brigatinib will also be examined further, to evaluate the safety and efficacy of Alunbrig in weight extremes (patients weighing less than 50 kg or over 100 kg). Updates to the Risk Management Plan (RMP) are also expected.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Although no clinical data are available regarding the effects of Alunbrig on fertility, non-clinical results provided strong evidence that brigatinib is a teratogen at doses lower than the clinical dose, and impairs male fertility.

Repeat-dose toxicology studies in adult rats and monkeys provided evidence of toxicity at all dose levels examined, affecting numerous organs and organ systems. Signs of toxicity were observed in the gastrointestinal system, hematopoietic system, kidneys, heart, immune system, pancreas, and liver. These were partially resolved following a 56-day recovery period. However, toxic effects observed in the eyes and testes were irreversible. Elevated serum insulin and blood glucose levels were also detected.

In in vivo studies with rats, micronuclei were induced in cells from bone marrow in response to a dose five times higher than the clinical dose. The induction of micronuclei is an indicator of chromosomal damage, and additional tests revealed that this was caused by abnormal chromosome segregation (aneugenicity). Genotoxicity is not expected to be a risk in humans, as the dose at which it occurred is considerably higher than the clinical dose.

Patients being treated with Alunbrig are advised not to father a child or become pregnant, due to evidence of teratogenic effects as well as the effects of brigatinib on chromosome segregation. Men and women are also instructed to use non-hormonal contraception while taking Alunbrig and for three months and four months, respectively, after taking their last dose. Alunbrig should not be used during pregnancy unless the clinical condition of the mother requires treatment. Additionally, women should not breastfeed while taking Alunbrig, and for at least one week after taking their last dose.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Alunbrig Product Monograph. In view of the intended use of Alunbrig, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product. For more information, refer to the Alunbrig 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 Alunbrig has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Brigatinib, the drug substance, is manufactured at two facilities using the same validated synthetic process. The design spaces at each site have been approved for this purpose, and the appropriate controls are in place to ensure that the drug substance meets the relevant specifications. Proposed limits of drug-related impurities have been adequately qualified through toxicological studies.

Alunbrig, the drug product, is manufactured at two different facilities through a direct compression process. All three strengths are compositionally proportional and can be manufactured with a common blend. The design spaces at each site have been approved for this purpose. The manufacturing process has been validated at the commercial scale at both facilities and for all three tablet strengths. Based on the stability data submitted, the proposed shelf life of 36 months for the 30 mg tablets and 24 months for the 90 mg and 180 mg tablets is acceptable when the drug product is stored at 15ºC to 30ºC.

All sites involved in manufacturing the drug substance and drug product are compliant with Good Manufacturing Practices relevant to the activities for which they are responsible.

All non-medicinal ingredients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. Lactose monohydrate, an excipient in Alunbrig tablets, is of animal origin. Lactose monohydrate used in the production of Alunbrig was processed in officially approved dairy establishments, and is not considered a risk for bovine spongiform encephalopathy or transmissible spongiform encephalopathy (BSE or TSE). A certification letter attesting to these claims was provided by the sponsor.