Summary Basis of Decision for Alecensaro

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 Alecensaro is located below.

Recent Activity for Alecensaro

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Alecensaro

Updated: 2026-02-09

The following table describes post-authorization activity for Alecensaro, a product which contains the medicinal ingredient alectinib (as alectinib hydrochloride). 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 found in Post-Authorization Activity Tables (PAATs).

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

Drug Identification Number (DIN):

  • DIN 02458136 - 150 mg alectinib, capsule, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 287835 2024-06-18 Issued NOC 2025-03-11 Submission filed as a Level I – Supplement to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.
SNDS # 282375 2023-12-22 Issued NOC 2024-06-27 Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: Alecensaro as adjuvant treatment following tumor resection for patients with anaplastic lymphoma kinase ALK-positive non-small cell lung cancer (NSCLC). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 279361 2023-09-22 Issued NOC 2024-05-01 Submission filed as a Level I – Supplement to add two manufacturing sites for the production of the drug substance, and changes to the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 260345 2022-01-13 Issued NOC 2022-05-11 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration; Warnings and Precautions; and Adverse Reactions sections of the PM. An NOC was issued.
SNDS # 250679 2021-03-17 Issued NOC
2021-07-02		 Submission filed as a Level II – Supplement (Safety) to update the Product Monograph and migrate it to the 2020 format. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 226092 2019-03-25 Issued NOC
2019-05-29		 Submission filed as a Level I - Supplement to update the inner and outer labels and package insert. These revisions were triggered after the implementation of a new packaging facility. These revisions were reviewed and considered acceptable, and an NOC was issued.
PBRER-C #214568 2018-03-13 Filed
2019-05-16		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2017-07-04 to 2018-01-03. The information was reviewed and found acceptable.
SNDS-C # 211291 2017-11-15 Issued NOC
2018-09-26		 Submission filed as a Level I - Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The sponsor provided final analyses from studies NP28761 and NP28673 and the Phase III study BO28984 (ALEX). The data continues to support an acceptable safety profile for the use of Alecensaro, and together, the data support the favourable benefit/risk profile of Alecensaro for the treatment of 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 are intolerant to crizotinib. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued 2016-09-28.
SNDS # 210816 2017-11-02 Issued NOC
2018-06-11		 Submission filed as a Level I – Supplement for a new indication. The authorized indication was for the first-line treatment of patients with anaplastic lymphoma kinase-positive, locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 212795 2018-01-12 Issued NOL
2018-05-28		 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 Serious Warnings and Precautions Box, Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
PBRER-C # 209225 2017-09-11 Filed
2018-03-26		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2017-01-04 to 2017-07-03. The information was reviewed and found acceptable.
PBRER-C # 203793 2017-03-13 Filed
2018-01-10		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2016-07-04 to 2017-01-03. The information was reviewed and found acceptable.
Drug product (DIN 02458136) market notification Not applicable Date of first sale
2016-10-14		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 189442 2015-11-12 Issued NOC under NOC/c Guidance
2016-09-28		 Notice of Compliance issued under the NOC/c Guidance for New Drug Submission.
Summary Basis of Decision (SBD) for Alecensaro

Date SBD issued: 2016-10-31

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

Alectinib (as alectinib hydrochloride), 150 mg, capsule, oral

Drug Identification Number (DIN):

  • 02458136

Hoffmann-La Roche Ltd.

New Drug Submission Control Number: 189442

 

On September 28, 2016, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Hoffmann-La Roche for the drug product Alecensaro. 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. Patients should be advised of the fact that the market authorization was issued with conditions.

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 Alecensaro is favourable as a monotherapy for the treatment of 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 are intolerant to crizotinib.

1 What was approved?

 

Alecensaro, a protein kinase inhibitor, was authorized as a monotherapy for the treatment of 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 are intolerant to crizotinib.

The marketing authorization with conditions is primarily based on tumor objective response rate (ORR) and duration of response (DOR); no overall survival benefit has been demonstrated.

Of the 253 patients in Alecensaro pivotal studies treated at a dose of 600 mg twice daily, 36 (14%) were ≥65 years of age. Safety and efficacy of Alecensaro are generally consistent between older (≥65 years of age) and younger patients, although a greater percentage of older patients compared with younger patients experienced adverse events with fatal outcomes (8% vs. 1%) or leading to withdrawal (14% vs. 4%).  

The safety and efficacy of Alecensaro in children and adolescents have not yet been established.

Alecensaro is contraindicated for patients with known hypersensitivity to alectinib or any of the excipients. Alecensaro was approved for use under the conditions stated in the Alecensaro Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Alecensaro (150 mg alectinib, as alectinib hydrochloride) is presented as a capsule. In addition to the medicinal ingredient, alectinib, the capsule content also contains carboxymethylcellulose calcium, hydroxypropylcellulose, lactose monohydrate, magnesium stearate, and sodium lauryl sulfate. The capsule shell contains carnauba wax, carrageenan, corn starch, hypromellose, potassium chloride, titanium dioxide, and trace of printing ink.

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 Alecensaro Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Alecensaro approved?

 

Health Canada considers that the benefit/risk profile of Alecensaro is favourable as monotherapy for the treatment of 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 are intolerant to crizotinib.

The marketing authorization with conditions is primarily based on tumour objective response rate and duration of response; no overall survival benefit has been demonstrated.

Anaplastic lymphoma kinase (ALK)-positive NSCLC accounts for approximately 5% of all NSCLC cases in Canada and is an incurable disease at advanced stages (that is, locally advanced, not amenable to curative therapies or metastatic). Crizotinib, a small molecule inhibitor of ALK is the standard of care for ALK-positive, locally advanced (not amenable to curative therapy) or metastatic NSCLC. However, most patients will eventually discontinue crizotinib therapy due to tumour resistance or intolerable toxicities. Following crizotinib, ceritinib is the only targeted therapy for this patient population. Ceritinib was granted market authorization under Health Canada’s Notice of Compliance with Conditions (NOC/c) guidance. As such, the clinical benefit of ceritinib is considered promising, but not substantial, pending confirmation by results from ongoing confirmatory studies. In addition to ceritinib, patients may be treated with cytotoxic agents (if not received previously) or immune checkpoint monoclonal antibodies recently authorized for metastatic NSCLC; however, these agents were authorized in patient populations not selected for ALK status and the efficacy evidence is limited for ALK-positive, locally advanced or metastatic NSCLC previously treated with crizotinib.

Alecensaro (alectinib) is a highly selective and potent ALK and RET (Rearranged during Transfection) tyrosine kinase inhibitor. Alecensaro demonstrated activity against mutant forms of ALK, including mutations responsible for resistance to crizotinib. In mouse xenograft models, alectinib induced tumour regression of ALK-driven cell lines and prolonged survival, including mouse models of intracranially implanted ALK-driven tumours.

Market authorization with conditions was based primarily on two pivotal Phase I/II, single-arm, multicentre studies (NP28761 and NP28673) which enrolled patients with ALK-positive, mostly metastatic NSCLC who had progressed on crizotinib. Objective response rate (ORR), determined by an Independent Review Committee (IRC) was the primary efficacy endpoint in both studies. Key secondary efficacy endpoints included duration of response (DOR), as well as ORR and DOR in central nervous system (CNS) metastases. Both studies were ongoing at the time of the drug submission.

At the time of data cutoff, the IRC-determined ORRs in the Response Evaluable Population (REP) were 47.8% and 50% with corresponding median DOR of 7.5 and 11.2 months in studies NP28761 and NP28673, respectively. Objective response rate (ORR) in the CNS was a pre-specified secondary efficacy endpoint. In pooled analyses, CNS ORR was 60.8% with a median CNS DOR of 9.1 months. This level of anti-tumor activity was considered clinically significant and promising evidence of clinical effectiveness. The uncertainties about Alecensaro’s efficacy included lack of robust evidence of survival or quality of life benefit and insufficient representation of patients with locally advanced disease (not amenable to curative therapy) or who discontinued crizotinib due to toxicities. Alecensaro’s clinical benefit will be confirmed by the results of updated analyses based on longer term follow-up of ongoing studies NP28761 and NP28673, along with the results of ongoing Phase III study BO28984 (ALEX).

Alecensaro’s safety profile is considered acceptable for the specified indication. Adverse reactions (ARs) were very common in Alecensaro-treated patients. In Alecensaro clinical trials, the most common ARs per investigator’s assessment (≥10%) were fatigue (41%), constipation (34%), edema (30%), myalgia (29%), nausea (18%), headache (17%), diarrhea (16%), increased aspartate aminotransferase (AST, 16%), increased bilirubin (15%), anemia (14%), increased alanine aminotransferase (ALT, 14%), rash (18%), vomiting (12%), increased blood creatine phosphokinase (CPK, 12%), increased weight (11%), vision disorders (10%), arthralgia (10%), dizziness (10%) and photosensitivity reaction (10%), most of which were Grades 1 to 2 in severity. Serious adverse reactions were reported in 19% of the patients and the most frequently reported serious adverse reactions were pulmonary embolisms, dyspnea and hyperbilirubinemia (1.2% each). Adverse events resulting in Alecensaro discontinuation occurred in 6% of the patients treated with Alecensaro (increased blood bilirubin being the most common in 1.6% patients). Fatal ARs in patients treated with Alecensaro occurred in 2.8% of patients, consisting of hemorrhage (2 patients, 0.8%), intestinal perforation, dyspnea, pulmonary embolism, endocarditis and death (unspecified) (1 patient each, 0.4%). These safety findings, as well as related monitoring and management are properly labelled throughout Alecensaro Product Monograph in the Warnings and Precautions as well as the Adverse Reactions sections. Additionally, to ensure safe and effective drug use and to enhance communication of toxicity to prescribers and patients, the following safety risks are labelled in the Serious Warnings and Precautions box: gastrointestinal perforation, bradycardia, hepatotoxicity, and interstitial lung disease, along with the information that Alecensaro has not been studied in patients with moderate to severe hepatic impairment or severe renal impairment.

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

The brand name originally proposed by the sponsor was Alecensa. However, a Look-Alike Sound-Alike (LASA) brand name assessment was performed and the proposed name Alecensa was deemed unacceptable. The LASA assessment results demonstrated there may be the potential for confusion between the brand name Alecensa and Alysena. Both these drugs share similar characteristics including dosage form, single dosage strength, route of administration, and clinical setting for dispensing. Although both drugs frequency of administration and usual dose are distinct, it was determined to be unsafe to rely on this as a mitigating factor. As such, Hoffmann-La Roche revised the proposed brand name to Alecensaro which was consequently determined to be acceptable.

Overall, the therapeutic benefits seen in the pivotal studies are promising and the benefits of Alecensaro therapy are considered to outweigh the potential risks. Alecensaro has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can generally be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Alecensaro 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 Alecensaro?

 

Submission Milestones: Alecensaro

Submission Milestone Date
Submission filed: 2015-11-12
Screening  
Screening Deficiency Notice issued: 2015-12-17
Response filed: 2016-01-22
Screening Acceptance Letter issued: 2016-02-11
Review  
Biopharmaceutics Evaluation complete: 2016-06-28
Quality Evaluation complete: 2016-07-08
Biostatistics Evaluation complete: 2016-06-23
Labelling Review complete: 2016-08-24
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued: 2016-08-25
Review of Response to NOC/c-QN:  
Clinical Evaluation complete: 2016-09-23
Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance: 2016-09-28

 

The Canadian regulatory decision on the non-clinical and clinical review of Alecensaro was based on a critical assessment of the Canadian data package. The foreign reviews completed by the United States Food and Drug Administration (FDA) were used as an added reference.

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, Hoffmann-La Roche Limited has agreed to provide the following studies to confirm Alecensaro’s clinical benefit:

  • Study NP28761: (a Phase I/II study of the anaplastic lymphoma kinase [ALK] inhibitor CH5424802/R05424802 [alectinib] in patients with ALK-rearranged non-small cell lung cancer [NSCLC] previously treated with crizotinib): an updated analysis based on longer term follow-up should be submitted. The data submitted should permit the confirmation of objective response rate (ORR) and contain reliable estimate of time to event endpoints, e.g. duration of response (DOR), and progression-free survival (PFS).
  • Study NP28673: (an open-label, non-randomized, multicentre Phase I/II study of R05424802 given orally to NSCLC patients who have ALK mutation and who have failed crizotinib treatment): an updated analysis based on longer term follow-up should be submitted. The data submitted should permit the confirmation of ORR and contain reliable estimate of time to event endpoints, e.g. DORand PFS.
  • Study B028984: (ALEX, a randomized, Phase III study comparing alectinib with crizotinib in treatment-naïve ALK-positive advanced NSCLC participants): a full clinical study report should be submitted based on the pre-specific primary analysis, in order to confirm Alecensaro’s clinical benefit, e.g. PFS, overall survival, and health-related quality of life, in comparison with crizotinib.

 

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

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 Alecensaro 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

Alectinib, the active ingredient in Alecensaro, demonstrated in vitro and in vivo activity against mutant forms of the anaplastic lymphoma kinase (ALK) enzyme, including mutations responsible for resistance to crizotinib. The major metabolite of alectinib (M4) has shown similar in vitro potency and activity.

Following oral administration of 600 mg twice daily under fed condition, maximum plasma concentration was reached after approximately 4 to 6 hours. With continuous dosing, alectinib steady-state was reached by Day 7 with an estimated geometric mean accumulation ratio of 5.6. Based on a population pharmacokinetic analysis, alectinib exposure increased proportionally across the dose range of 300 to 900 mg. The absolute bioavailability of alectinib was 36.9% under fed conditions in healthy volunteers. Alectinib and M4 were the main circulating moieties in plasma (together accounting for 76%). Following a single dose administration, 98% of the drug products were excreted in faeces in healthy volunteers. Eighty-four percent of the dose excreted in faeces was unchanged alectinib. Excretion of alectinib and its metabolites in urine was less than 0.5% of the administered dose. Based on the population pharmacokinetic analysis, the geometric mean elimination half-life estimates for alectinib was 32.5 hours for alectinib and 30.7 hours for M4. The pharmacokinetics of alectinib were not investigated in paediatrics. Based on the population pharmacokinetic analysis, age does not have an effect on alectinib exposure. The pharmacokinetics of alectinib have not been studied in patients with moderate to severe hepatic impairment or severe renal impairment.

The cytochrome P450 (CYP) enzyme CYP3A4 is the primary enzyme mediating the metabolism of Alecensaro and its major active metabolite, M4. Drug interactions were observed when alectinib was co-administered with a strong CYP3A4 inducer or an inhibitor. Accordingly, Alecensaro Product Monograph recommends caution and patient monitoring, if Alecensaro and a strong CYP3A inhibitor or inducer are co-administered. Based on in vitro data, Alecensaro may have the potential to increase plasma concentrations of co-administered substrates of CYP2C8 enzymes or P-glycoprotein or Breast Cancer Resistance Protein (BCRP) transporters. As Alecensaro resulted in a decrease in heart rate in patients, drug interactions may occur and should be avoided to the extent possible when Alecensaro is co-administered with a drug that decreases heart rate and/or prolongs the PR interval.

Overall, the Alecensaro clinical pharmacology dataset is considered acceptable to support this drug submission. Key clinical pharmacology findings and uncertainties are properly labelled in the Alecensaro Product Monograph.

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

Clinical Efficacy

The clinical efficacy of Alecensaro was studied in two pivotal Phase I/II, multicentre, open-label clinical studies (studies NP28761 and NP28673) in patients with crizotinib-treated, ALK-positive, locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC). At the time of the drug submission, both studies were ongoing for long-term efficacy and safety evaluations.

The Phase I phase of study NP28761 was a dose-finding study based on a modified 3+3 design. The recommended Phase II dose was determined to be 600 mg twice daily (BID), based on evidence of tolerability and efficacy (two dose-limiting toxicities of neutropenia and headache were observed in the next higher dose cohort of 900 mg BID). In the Phase II part of the two studies, all patients received a starting dose of 600 mg BID using the 150 mg strength formulation consistent with the proposed commercial formulation.

In both pivotal studies, the primary analyses were carried out when all patients had been followed for tumour assessment for 12 and 16 weeks for Phase II studies NP28761 and NP28673, respectively. A total of 87 and 138 patients were enrolled in the Phase II part of studies NP28761 and NP28673, respectively. Patient demographic and disease characteristics were generally consistent with this patient population; for example, younger age, more female patients, mostly never smoked or former smoker etc. Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at baseline. All patients received prior crizotinib. The great majority of patients had received prior chemotherapy (74% and 80% for studies NP28761 and NP28673, respectively). Ninety-nine percent of patients had a metastatic disease (stage V) and approximately 60% had brain metastases (only those with stable central nervous system [CNS] metastases were permitted in the studies).

At the primary analyses, objective response rates (ORRs) determined by an Independent Review Committee (IRC) were 47.8% (95% confidence interval [CI]: 35.6%, 60.2%) and 49.2% (95% CI: 40.0%, 58.4%) in Response Evaluable (RE) Populations in studies NP28761 and NP28673, respectively, with lower boundaries of the 95% CI values above the 35% threshold of statistical significance defined in the study protocols. Supporting the primary efficacy results, investigator-assessed ORRs and an ORR by IRC from the updated analysis in study NP28673 (50%, 95% CI: 40.8%, 59.1%) were generally consistent. Due to the relative shorter follow-up, numbers of progression events were not sufficient at the time of analyses to permit reliable estimate of duration of response (DOR) and other time-to-event endpoints including progression-free survival (PFS) and overall survival (OS). Nonetheless, median DOR of 7.5 (median follow up 20.7 weeks) and 11.2 months (median follow up 47.3 weeks) were reported in studies NP28761 and NP28673, respectively. Objective response rates in the central nervous system (CNS ORR) were a pre-specified secondary efficacy endpoint. Patients with stable metastases in the central nervous system (CNS) were enrolled in the studies and Alecensaro demonstrated promising anti-tumour against CNS lesions. In pooled analyses, CNS ORR was 60.8% with a median CNS DOR of 9.1 months. To aid the interpretation of CNS ORR and DOR results, inclusion criteria regarding patients with baseline CNS metastases were included in the Alecensaro Product Monograph.

There were few patients with locally advanced NSCLC (not amenable to curative therapy) in both studies, likely because patients with that stage of the disease are not commonly seen in the clinic. As ALK-positive, locally advanced NSCLC not amenable to curative therapy is often managed similarly to metastatic disease and it should maintain sensitivity to ALK inhibition, Health Canada considered it acceptable to include patients with locally advanced (not amenable to curative therapy) in the specified indication, so that these patients may benefit from Alecensaro therapy.

There were few patients who discontinued crizotinib due to toxicities, at least partly due to the exclusion of patients who had unrecovered toxicities from previous therapies in both studies. However, there are likely clinical scenarios when such patients may prefer to be treated with and may still benefit from Alecensaro, as their tumours should retain sensitivity to ALK inhibition. Therefore, Health Canada did not consider that these patients should be excluded from the specified indication. To inform the limitation of efficacy and safety evidence in these patients, the exclusion criteria regarding unrecovered toxicities from previous therapies were included in the Alecensaro Product Monograph.

The New Drug Submission for Alecensaro was filed with the following indication:

Alecensaro (alectinib) is indicated as monotherapy for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

Health Canada recommended the following indication for reasons mentioned above.

Alecensaro (alectinib) is indicated as monotherapy for the treatment of 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 are intolerant to crizotinib.

The marketing authorization with conditions is primarily based on tumor objective response rate and duration of response; no overall survival benefit has been demonstrated.

Overall, the level of anti-tumour activity of Alecensaro, as demonstrated by ORR and preliminary DOR results in the two pivotal studies (NP28761 and NP28673), is considered clinically significant and provides promising evidence of clinical benefit, in the context of the specified indication and reported activities of other available therapies.

Under the Notice of Compliance with Conditions (NOC/c) Guidance, Hoffmann-La Roche Limited has agreed to submit to Health Canada more mature efficacy data from the two on-going pivotal studies along with the results of the on-going Phase III study BO28984 (ALEX), in order to confirm the clinical benefit of Alecensaro.

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

Clinical Safety

The pivotal safety analysis supporting the submission was based on a pooled safety database from studies NP28761 and NP28673 previously described in the Clinical Efficacy section. A total of 253 patients with ALK-positive NSCLC were treated with the recommended dose of Alecensaro 600 mg BID. The median duration of exposure to Alecensaro was 41 weeks.

Adverse reactions (ARs) were very common in Alecensaro-treated patients. In Alecensaro clinical trials, the most common ARs per investigator’s assessment (≥10%) were fatigue (41%), constipation (34%), edema (30%), myalgia (29%), nausea (18%), headache (17%), diarrhea (16%), increased aspartate aminotransferase (AST, 16%), increased bilirubin (15%), anemia (14%), increased alanine aminotransferase (ALT, 14%), rash (18%), vomiting (12%), increased blood creatine phosphokinase (CPK, 12%), increased weight (11%), vision disorders (10%), arthralgia (10%), dizziness (10%) and photosensitivity reaction (10%). Severe (Grades 3 to 4) ARs occurring in at least 1% of patients included diarrhea (1.2%), fatigue (1.2%), myalgia (1.2%), increased AST (2.8%), increased ALT (3.2%), increased bilirubin (2.8%), increased blood CPK (3.6%), and anemia (1.6%). Serious adverse reactions (SARs) were reported in 19% of the patients and the most frequently reported SARs were dyspnea and hyperbilirubinemia (1.2% of patients each). Adverse events resulting in Alecensaro discontinuation occurred in 6% of the patients treated with Alecensaro. The most frequent ARs that led to permanent discontinuation were increased levels of blood bilirubin which occurred in 1.6% of the patients treated with Alecensaro. Fatal adverse events occurred in 2.8% of the patients, consisting of hemorrhage (0.8%, 2 patients) and intestinal perforation, dyspnea, pulmonary embolism, endocarditis and death unspecified (1 patient each).

The following serious risks of Alecensaro were identified during the review and are adequately labelled with monitoring and management recommendations in the Alecensaro Product Monograph.

Gastrointestinal Perforation

A total of 8 cases of gastrointestinal (GI) perforation were identified as of July 18, 2016; 1 case in the Alecensaro clinical studies and 7 cases in the post-market setting. All cases had other risk factors for GI perforation, however a causal role of Alecensaro could not be ruled out. Cases of GI perforation have been reported in clinical studies for other therapies in patients with advanced NSCLC. Insufficient case numbers and limited patient exposure precluded an in-depth assessment of the role of Alecensaro in GI perforation. This safety concern is adequately labelled in the Serious Warnings and Precautions box in the Alecensaro Product Monograph.

Bradycardia

Cases of bradycardia were reported in patients treated with Alecensaro in both Phase II clinical studies. Of the 253 patients treated with Alecensaro, sinus bradycardia and bradycardia were observed in 13 patients (5.1%) and 7 patients (2.8%); respectively. Alecensaro treatment resulted in a decrease in heart rate of approximately 11 to 13 beats per minutes (bpm) at Week 2 which was stable thereafter, maintained throughout the treatment period, and was reversible upon discontinuation. Twenty percent of patients displayed lowest post-baseline heart rates below 50 bpm. Although all cases of bradycardia were non-severe and no serious cases were reported in the clinical studies, patients with significant cardiovascular disease at baseline could be at a higher risk for severe and/or serious cardiovascular adverse events. Bradycardia is listed in the Serious Warnings and Precautions box in the Alecensaro Product Monograph. Bradycardia precautions regarding the potential for a drug interaction with a co-administered heart rate-lowering drug or a PR interval-prolonging drug were included in the Alecensaro Product Monograph.

Hepatotoxicity

Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 5 times the upper limit of normal (ULN) as well as bilirubin elevations of more than 3 times the ULN occurred in patients in the Alecensaro clinical studies. The majority of these events (76% of the patients with hepatic transaminase elevations and 68% of the patients with bilirubin elevations) occurred during the first 3 months of treatment. In the pivotal clinical studies, two patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy (liver biopsy for drug-induced liver injury was not mandatory in these studies). Concurrent elevations in ALT or AST ≥3 times the ULN and total bilirubin ≥2 times the ULN, with normal alkaline phosphatase, occurred in 1 patient treated in the Alecensaro clinical studies. Hepatotoxicity is listed in the Serious Warnings and Precautions box in the Alecensaro Product Monograph.

Myalgia and Blood Creatine Phosphokinase Elevation

Myalgia or musculoskeletal pain occurred in 29% of patients in the two pivotal Phase II studies.The incidence of Grade 3 myalgia/musculoskeletal pain was 1.2%. Dose modifications for myalgia/musculoskeletal pain were required in 0.8% of patients. Elevations of creatine phosphokinase (CPK) occurred in 43% of 218 patients with CPK laboratory data available. The incidence of Grade 3 elevations of CPK was 4.6%. Median time to Grade 3 CPK elevation was 14 days. Dose modifications for elevations of CPK occurred in 5.0% of the patients treated with Alecensaro.

Interstitial Lung Disease Pneumonitis

Cases of interstitial lung disease (ILD) were uncommonly reported in the Alecensaro clinical studies. Additional cases were reported in the post-market database. In the pivotal Phase II clinical studies, 1 out of 253 patients treated with Alecensaro (0.4%) had a Grade 3 ILD leading to withdrawal from Alecensaro treatment. There were no fatal cases of ILD.The risk ofILD appears in the Serious Warnings and Precautions box in the Alecensaro Product Monograph.

Other Safety Concerns

New serious adverse reactions; i.e. atrioventricular block complete and eosinophilic pneumonia were identified in the post-marketing safety database. Alecensaro was not studied in pregnant women; however, non-clinical reproductive studies indicated a risk of fetal harm and loss. In vitro, alectinib is aneugenic, but not mutagenic or clastogenic. Alecensaro’s safety has not been studied in patients with baseline moderate or severe hepatic impairment. Safety evidence is limited in patients with significant comorbidities and/or unrecovered toxicities from previous therapies including crizotinib.

In general, the ARs associated with the use of Alecensaro appeared mostly mild or moderate and manageable. Serious, life-threatening ARs can occur, many of which are known to other drug products in the same class of drugs and familiar to Canadian Healthcare professionals. Serious ARs and unexpected SARs are to be monitored in the post-market setting, as outlined in the Risk Management Plan (RMP). Health Canada has assessed the RMP and considered it acceptable.

In summary, Alecensaro was shown to provide clinically significant anti-tumor activity in patients with crizotinib-treated, ALK-positive, locally advanced (not amenable to curative therapy) or metastatic NSCLC. In the context of the specified indication for a life-threatening and incurable condition not adequately managed by available therapies in Canada, the clinical benefit of Alecensaro is considered to outweigh the associated risks. Taken together, the data in the submission provides promising clinical evidence that Alecensaro has the potential to provide a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile of Alecensaro is improved over existing therapies for the specified indication. Clinical benefit will need to be confirmed with the submission of results from confirmatory studies.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical profile of the medicinal ingredient, alectinib hydrochloride, was established in a comprehensive investigational program that included studies in vitro and in vivo pharmacodynamics, safety pharmacology, pharmacokinetics, toxicity, genotoxicity, carcinogenicity, antigenicity, and reproductive and developmental toxicity.

Alectinib demonstrated in vitro and in vivo activity against several mutant forms of the ALK enzyme, including mutations responsible for resistance to crizotinib. The major metabolite of alectinib (M4) has shown similar in vitro potency and activity. Alectinib inhibited human ether-a-go-go related gene (hERG) potassium currents with an IC50 of 0.45 mM (217 ng/mL). The IC50 is the concentration of an inhibitor where the response is reduced by half. Alectinib also blocked the L-type Ca2+ channel current (IC50: 222 ng/mL), indicating that alectinib is a calcium channel antagonist. Alectinib showed high-level tissue distribution in rats including the CNS at a level comparable to that in the plasma, indicating that alectinib can cross the blood/brain barrier and reach therapeutic concentrations in the CNS. No carcinogenicity studies have been conducted with Alecensaro. Alectinib is aneugenic, but not mutagenic or clastogenic in vitro. In non-clinical repeated-dose toxicity studies, major histology findings common to both rats and monkeys were seen in the erythroid system, gastrointestinal tract, hepatobiliary system, generally consistent with clinical safety findings in patients. In pregnant rabbits and rats, an exposure between 2.7- and 4.5-fold the estimated human exposure measured at the recommended dose of alectinib 600 mg BID resulted in maternal toxicities, fetal harm and litter loss, indicating that Alecensaro has the potential to cause fetal harm in humans and therefore pregnancy prevention is warranted. These key non-clinical findings were adequately labelled in the Alecensaro Product Monograph. The non-clinical investigations of alectinib were considered acceptable.

For more information, refer to the Alecensaro 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 Alecensaro 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 24 months is considered acceptable when Alecensaro capsules are stored between 15-30°C and kept in the original container to protect from light and moisture.

The Alecensaro formulation contains sodium lauryl sulphate (SLS) at a level corresponding to 50% by weight of the weight of alectinib (free base). Based on the maximum daily dose of alectinib (1,200 mg), patient exposure to SLS from this drug product will be 600 mg per day. Health Canada conducted a toxicology assessment for SLS exposure to patients and considered the proposed limit of 50% of the weight of alectinib base (or 600 mg/day) qualified, based on the following clinical evidence and considerations, but not the non-clinical evidence provided:

  • Alecensaro was shown to be generally tolerable in patients in the pivotal Phase II clinical trials in which patients were treated with clinical batches fully representative of the proposed commercial formulation and manufacturing process.
  • SLS targeted adverse events, i.e., gastrointestinal tract, liver and kidney adverse events, were generally similar, if not less frequent and severe in some incidences, relative to other targeted therapies for locally advanced or metastatic non-small cell lung cancer.
  • Serious, life-threatening adverse reactions (ARs) were relatively uncommon in Alecensaro clinical trials and might be explained by the mechanism of action of alectinib. The risk of serious ARs is adequately labeled in the Alecensaro Product Monograph, along with monitoring and management recommendations.
  • The safety and efficacy of Alecensaro was assessed in the context of a product which is not likely to be taken for a prolonged duration and the indication is for a patient population with an incurable disease.
  • The benefit and risk assessment of Alecensaro for the proposed indication is considered positive. This Alecensaro New Drug Submission was filed under the Notice of Compliance with Conditions (NOC/c) Guidance for a life-threatening, incurable disease for which there is promising clinical evidence that Alecensaro has the potential to provide a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile of Alecensaro is improved over existing therapies.

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

A professed standard is claimed for the drug product with specifications that conform to the current Health Canada requirements.

The excipients used in the drug product formulation are not of animal or human origin with the exception of lactose monohydrate, which is derived from cow’s milk. Safety information on the suitability of lactose monohydrate was provided.

 

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