Summary Basis of Decision for Lorbrena
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 Lorbrena is located below.
Recent Activity for Lorbrena
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.
The following table describes post-authorization activity for Lorbrena, a product which contains the medicinal ingredient lorlatinib. 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.
Updated: 2024-03-13
Drug Identification Number (DIN):
DIN 02485966 - 25 mg lorlatinib, tablet, oral administration
DIN 02485974 - 100 mg lorlatinib, tablet, oral administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
PBRER-C # 264569 |
2022-05-25 |
Filed 2022-09-28 |
Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER‑C for the period 2021-09-21 to 2022-03-20. The information was reviewed and found acceptable. |
|
SNDS-C # 255326 |
2021-07-30 |
Issued NOC 2022-05-20 |
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) to remove the conditions from the NOC (NDS # 215733) for the indication to use Lorbrena as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive metastatic non-small cell lung cancer (NSCLC) who have progressed on crizotinib and at least one other ALK inhibitor, or patients who have progressed on ceritinib or alectinib. The marketing authorization for the second and later line indication with conditions was based on a primary efficacy endpoint of tumor objective response rate and duration of response; no overall survival benefit has been demonstrated. The sponsor provided the efficacy and safety data from the pivotal ongoing Phase III study B7461006. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued 2019-02-22. |
|
PSUR-C # 259197 |
2021-12-01 |
Filed 2022-04-07 |
Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C for the period 2021-03-21 to 2021-09-20. The information was reviewed and found acceptable. |
|
SNDS # 248101 |
2021-01-07 |
Issued NOC 2021-12-01 |
Submission filed as a Level I – Supplement to update the PM with data from studies B7461010 and B7461026, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; Drug Interactions; Dosage and Administration; and Clinical Pharmacology sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package inserts. An NOC was issued. |
|
PSUR-C # 253364 |
2021-06-02 |
Filed 2021-10-29 |
Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C for the period 2020-09-21 to 2021-03-20. The information was reviewed and found acceptable. |
|
SNDS # 247174 |
2020-12-10 |
Issued NOC 2021-06-07 |
Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Lorbrena is indicated as 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. |
|
PSUR-C # 247469 |
2020-12-11 |
Filed 2021-05-11 |
Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C for the period 2020-03-21 to2020-09-20. The information was reviewed and found acceptable. |
|
PSUR-C # 240025 |
2020-05-27 |
Filed 2020-10-15 |
Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C for the period 2019-09-21 to 2020-03-20. The information was reviewed and found acceptable. |
|
PSUR-C # 234654 |
2019-12-20 |
Filed 2020-04-30 |
Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C for the period 2019-03-21 to 2019-09-20. The information was reviewed and found acceptable. |
|
NC # 235243 |
2020-01-17 |
Issued NOL 2020-04-08 |
Submission filed as a Level II (90 day) Notifiable Change to update the PM with data from clinical trial B7461001. As a result of the NC, modifications were made to the Drug Interactions section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 232764 |
2019-10-21 |
Issued NOL 2020-01-21 |
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 Contraindications; Warnings and Precautions; Adverse Reactions; Drug Interactions; Overdosage; and Action and Clinical Pharmacology sections of the PM. Corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
PSUR-C # 229490 |
2019-07-08 |
Filed 2020-01-09 |
Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C for the period 2018-09-21 to 2019-03-20. The information was reviewed and found acceptable. |
|
Drug product (DINs 02485966, 02485974) market notification |
Not applicable |
Date of first sale: 2019-04-22 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NDS # 215733 |
2018-04-26 |
Issued NOC under NOC/c Guidance 2019-02-22 |
NOC issued under the NOC/c Guidance for New Drug Submission. |
Summary Basis of Decision (SBD) for Lorbrena
Date SBD issued: 2019-07-18
The following information relates to the New Drug Submission for Lorbrena.
Lorlatinib
Drug Identification Number (DIN):
- DIN 02485966 - 25 mg, tablet, oral administration,
- DIN 02485974 - 100 mg, tablet, oral administration
Pfizer Canada ULC
New Drug Submission Control Number: 215733
On February 22, 2019, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Pfizer Canada ULC for the drug product Lorbrena. 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 Lorbrena, as monotherapy, is favourable for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer whose disease has progressed on crizotinib and at least one other ALK inhibitor, or patients whose disease has progressed on ceritinib or alectinib.
1 What was approved?
Lorbrena, an antineoplastic drug, is a tyrosine kinase inhibitor. It was authorized as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on crizotinib and at least one other ALK inhibitor, or patients whose disease has progressed on ceritinib or alectinib.
The marketing authorization with conditions was based on a primary efficacy endpoint of tumour objective response rate and duration of response; no overall survival benefit has been demonstrated.
Patients treated with Lorbrena must have a documented ALK-positive status based on a validated ALK assay. The assessment of ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized.
No data are available to Health Canada regarding the use of Lorbrena in patients younger than 18 years of age. Consequently, an indication for pediatric use has not been authorized.
Of the 275 ALK-positive NSCLC patients treated with Lorbrena in clinical trials, 53 (19.3%) were 65 years of age or older. The limited data on the safety and efficacy of Lorbrena in elderly patients do not suggest that a dose adjustment is required in these patients.
Lorbrena 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. In addition, concomitant use of strong cytochrome P450 (CYP) 3A (CYP3A) inducers with Lorbrena is contraindicated.
Lorbrena 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.
Lorbrena (25 mg and 100 mg lorlatinib) is presented as a tablet. In addition to the medicinal ingredient, the film-coated tablet contains dibasic calcium phosphate anhydrous, ferrosofferic oxide/black iron oxide, hydroxypropyl methylcellulose/hypromellose, iron oxide red, lactose monohydrate, macrogol/polyethylene glycol, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, titanium dioxide, and triacetin.
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 Lorbrena Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Lorbrena approved?
Health Canada considers that the benefit-risk profile of Lorbrena, as monotherapy, is favourable for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on crizotinib and at least one other ALK inhibitor, or patients whose disease has progressed on ceritinib or alectinib. Lorbrena 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.
Lung cancer is the most commonly diagnosed cancer in Canada, representing about 14% of all new cancer cases. Non-small cell lung cancer (NSCLC) accounts for between 80% and 90% of all lung cancers. Histologically, adenocarcinoma comprises about 50% of the NSCLC cases. Approximately 15% of lung adenocarcinomas are characterized by the presence of oncogenic driver mutations in the kinase domain of the epidermal growth factor receptor (EGFR) gene. A small subset of lung adenocarcinomas (approximately 5%) may have a rearrangement involving the ALK gene, most commonly resulting in a fusion oncogene, echinoderm microtubule-associated protein-like 4 (EML4)-ALK. Rearrangements in the ALK gene are largely mutually exclusive with EGFR and KRAS mutations. Tumours that contain ALK gene rearrangements are commonly found in younger patients who have never smoked or are light smokers. These tumours are highly sensitive to therapy with ALK-targeted inhibitors. Accordingly, for patients with ALK-positive NSCLC, first-line treatment options include tyrosine kinase inhibitors such as crizotinib (Xalkori), a first-generation ALK inhibitor, and alectinib (Alecensaro) and ceritinib (Zykadia), second-generation ALK inhibitors. These treatments can provide good response rates. However, tumours eventually develop treatment resistance and patients will experience disease progression, most commonly to the central nervous system (CNS). Second-line treatments may include the aforementioned ALK inhibitors as well as recently approved brigatinib (Alunbrig), another second-generation ALK inhibitor.
Lorlatinib, the medicinal ingredient in Lorbrena, is a selective, adenosine triphosphate (ATP)-competitive, brain-penetrant, small-molecule inhibitor of ALK and c-ros oncogene 1 (ROS1) kinase. It has been developed to address mechanisms of acquired tumour resistance following previous treatment with ALK inhibitor therapy.
The efficacy and safety of lorlatinib have been evaluated in a pivotal, ongoing Phase I/II study B7461001 in 334 patients with ALK-positive or ROS1-positive metastatic NSCLC. The Phase II portion investigated the efficacy of Lorbrena in 276 patients who were enrolled in six expansion (EXP) cohorts based on tumour mutation status (ALK- or ROS1-positive NSCLC) and prior therapies received. The patients received Lorbrena at the dose identified in the Phase I portion of the study, 100 mg orally once daily.
The primary efficacy endpoint in the Phase II portion of the study was objective response rate, including intracranial objective response rate, as per an independent central review according to the modified Response Evaluation Criteria in Solid Tumours (modified RECIST version 1.1). Secondary endpoints included duration of response, intracranial duration of response, time to tumour response, and progression-free survival.
Data pooled from 197 patients with ALK-positive advanced NSCLC who had been treated with one or more ALK tyrosine kinase inhibitors (expansion cohorts EXP-2 to EXP-5) were considered to be clinically compelling and appropriate to represent the target patient population. Among these 197 patients, the objective response rate as assessed by an independent central review was 47.2% (95% confidence interval [CI]: 40.1, 54.4). The median time to tumour response was 1.4 months (range: 1.1 to 11.0 months) among the 93 patients who had a confirmed objective response. While the median duration of response was not reached at the time of data cut-off, the lower boundary of the 95% CI of duration of response was 11.1 months (95% CI: 11.1, not reached).
In the study, the most common (≥20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, fatigue, weight gain, arthralgia, mood effects, and diarrhea. The most common (≥20%) laboratory abnormalities were hypercholesterolemia, hyptertriglyceridemia, anemia, increased creatinine, hyperglycemia, hypoalbuminemia, increased aspartate aminotransferase (AST), lymphopenia, increased alkaline phosphate, increased alanine aminotransferase (ALT), increased lipase, increased amylase, hypomagnesemia, decreased platelet count, hypophosphatemia, hyponatremia, and hyperkalemia. Serious adverse reactions were reported in 6.1% of patients. The most frequent serious adverse reactions reported were mental status changes in 1.4% of patients and cognitive effects in 1.0% of patients.
The risks of hypercholesterolemia/hypertriglyceridemia, pneumonitis, and hepatotoxicity are listed in a Serious Warnings and Precautions box in the Lorbrena Product Monograph. Of note, due to the risk of serious hepatotoxicity with concomitant use of strong cytochrome P450 (CYP) 3A (CYP3A) inducers, Lorbrena is contraindicated in patients who are receiving strong CYP3A inducers. All pertinent in vitro and clinical drug interaction studies are outlined in the Drug-Drug Interactions section of the Lorbrena Product Monograph. Furthermore, the Warnings and Precautions section of the Lorbrena Product Monograph includes recommendations for monitoring ALT, AST, bilirubin, lipase, amylase, serum cholesterol and triglycerides, prior to initiating Lorbrena and periodically thereafter. Electrocardiogram monitoring is also recommended as PR interval prolongation and atrioventricular block events have been reported in patients receiving Lorbrena.
A Risk Management Plan (RMP) for Lorbrena 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 Lorbrena 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 Lorbrena was accepted.
Overall, the therapeutic benefits of Lorbrena seen in the pivotal study are promising and are considered to outweigh the potential risks in the intended patient population. The data demonstrate that Lorbrena has the potential to fulfill an unmet medical need for patients with ALK-positive NSCLC whose disease has progressed following treatment with first- and second-generation ALK inhibitors. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Lorbrena Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring of the use of Lorbrena will be ongoing. Further evaluation will take place upon the submission of data from the ongoing confirmatory study B7461006 (see What follow-up measures will the company take?).
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 Lorbrena?
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 Lorbrena. An assessment was conducted and it was determined there was promising evidence of clinical effectiveness. Lorbrena has the potential to provide an improvement in the benefit-risk profile over existing therapies for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer, a disease that is not adequately managed by a drug marketed in Canada.
Submission Milestones: Lorbrena
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2018-02-06 |
| Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance: | 2018-04-04 |
| Submission filed: | 2018-04-26 |
| Screening | |
| Screening Deficiency Notice issued: | 2018-05-24 |
| Response filed: | 2018-06-07 |
| Screening Acceptance Letter issued: | 2018-06-18 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2018-11-09 |
| Review of Risk Management Plan complete: | 2018-12-19 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-12-20 |
| Quality Evaluation complete: | 2018-12-31 |
| Clinical/Medical Evaluation complete: | 2018-12-31 |
| Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued: | 2019-01-02 |
| Review of Response to NOC/c-QN: | |
| Response filed (Letter of Undertaking): | 2019-01-23 |
| Clinical/Medical Evaluation complete: | 2019-02-20 |
| Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance: | 2019-02-22 |
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, he sponsor has agreed to submit to Health Canada a Supplement to a New Drug Submission - Confirmatory, which will include the results of the confirmatory trial B7461006. This trial is an ongoing, randomized, open-label, Phase III clinical study comparing the safety and efficacy of lorlatinib to crizotinib in the first-line treatment of patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer.
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 clinical pharmacology data support the use of Lorbrena for the recommended indication.
Lorlatinib is a selective, adenosine triphosphate (ATP)-competitive, brain-penetrant, small-molecule inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) kinase.
The pharmacokinetic properties of lorlatinib were generally well characterized across studies in healthy volunteers and in the Phase I/II study B7461001 (described in the Clinical Efficacy section) in patients with advanced ALK-positive and ROS1-positive non-small-cell lung cancer (NSCLC). Results from planned studies in patients with hepatic and renal impairment and from an additional drug-drug interaction sub-study of study B7461001 are expected to provide a more complete pharmacokinetic profile of lorlatinib.
In humans, the primary metabolic pathways of lorlatinib include oxidation and glucuronidation. In vitro, metabolism of lorlatinib is mediated primarily by cytochrome P450 (CYP) 3A4 (CYP3A4) and uridine diphosphate (UDP)-glucuronosyltransferase 1A4 (UGT1A4), with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3 enzymes.
Following oral administration of radioactively labelled lorlatinib, the compound and its benzoic acid metabolite, PF-06895751 (M8), were the most abundant circulating components in human plasma, comprising 44% and 21% of total plasma radioactivity, respectively. The metabolite M8 is considered pharmacologically inactive.
Population pharmacokinetic analyses in patients with advanced NSCLC and healthy volunteers indicate that there are no clinically relevant effects of age, gender, race, body weight, or phenotypes for CYP3A5 and CYP2C19.
For more information, please refer to the Lorbrena Product Monograph, approved by Health Canada and available through the Drug Product Database
Clinical Efficacy
The clinical efficacy of Lorbrena in patients with ALK-positive or ROS1-positive advanced NSCLC was supported by interim data (with a data cut-off date of March 15, 2017) from an ongoing, multi-cohort, multinational, non-comparative, dose-finding and activity-estimating Phase I/II study, B7461001.
The dose-finding Phase I portion of study B7461001 enrolled 55 patients. It identified the recommended Phase II dose of Lorbrena as 100 mg orally once daily.
The Phase II portion of study B7461001 investigated the efficacy of Lorbrena in 276 patients enrolled in six expansion (EXP) cohorts based on tumour mutation status (ALK- or ROS1-positive NSCLC) and prior therapies received.
Five of the six cohorts included patients with advanced ALK-positive NSCLC, with or without asymptomatic CNS metastases, and with prior therapy status as follows:
- EXP-1: Treatment-naive patients
- EXP-2: Patients with disease progression after prior crizotinib only
- EXP-3A: Patients with disease progression after prior crizotinib and chemotherapy regimens
- EXP-3B: Patients with disease progression after one prior non-crizotinib ALK inhibitor therapy with or without prior regimens of chemotherapy
- EXP-4: Patients with disease progression after two prior ALK inhibitor therapies with any number of chemotherapy regimens
- EXP-5: Patients with disease progression after three prior ALK inhibitor therapies with any number of chemotherapy regimens
- EXP-6: Patients with advanced ROS1-positive NSCLC (with or without asymptomatic CNS metastases) who were treatment naive or have had any number of prior cancer therapies
The ALK-positive status of patients' tumours was determined by fluorescence in situ hybridization (FISH) assay or by immunohistochemistry.
The primary efficacy endpoint in the Phase II portion of the study was objective response rate, including intracranial objective response rate, as per an independent central review according to the modified Response Evaluation Criteria in Solid Tumours (modified RECIST version 1.1).
Secondary endpoints included duration of response, intracranial duration of response, time to tumour response, and progression-free survival.
A prespecified efficacy analysis was performed on data pooled from expansion cohorts EXP-2 to EXP-5, which included 197 patients with ALK-positive advanced NSCLC treated with one or more ALK tyrosine kinase inhibitors. Among these 197 patients, the objective response rate as assessed by an independent central review was 47.2% (95% confidence interval [CI]: 40.1, 54.4). The median time to tumour response was 1.4 months (range: 1.1 to 11.0 months) among the 93 patients who had a confirmed objective response. While the median duration of response was not reached at the time of data cut-off, the lower boundary of the 95% CI of duration of response was 11.1 months (95% CI: 11.1, not reached [NR]), with 67.7% of patients censored (i.e., patients were alive and without progressive disease at the time of data cut-off). The median follow-up time for duration of response was 6.9 months (95% CI: 6.9, 7.2). Of the 93 patients with a confirmed objective response, 43 (46.2%) patients had a duration of response of at least 6 months at the time of data cut-off.
Among the 132 patients with baseline brain metastases in the pooled cohorts EXP-2 to EXP-5, the intracranial objective response rate was 53.0% (95% CI: 44.2, 61.8). The best overall response was complete response in 35 (26.5%) patients and partial response in 35 (26.5%) patients. Among the 70 patients with a confirmed objective tumour response, the median intracranial time to tumour response was 1.4 months (range: 1.1 to 6.2 months), whereas the median intracranial duration of response was 14.5 months (95% CI: NR, NR). Of the 70 patients with a confirmed objective tumour response, 39 (55.7%) patients had an intracranial duration of response of at least 6 months at the date of data cut-off.
The clinical benefit of Lorbrena will be verified in the confirmatory trial B7461006, an ongoing, randomized, open-label, Phase III clinical study comparing the safety and efficacy of lorlatinib to crizotinib in the first-line treatment of patients with advanced ALK-positive NSCLC. Study B7461006 is a global study with 280 patients planned for enrollment. The study report is expected by the end of 2021.
Indication
The New Drug Submission for Lorbrena was filed by the sponsor with the following indication:
- Lorbrena (lorlatinib) is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with one or more ALK tyrosine kinase inhibitors (TKIs).
Health Canada revised the proposed indication to reflect a patient population evaluated in study B7461001 and to address the unmet medical need for patients whose disease has progressed following treatment with crizotinib and second-generation ALK inhibitors, or following treatment with second generation ALK inhibitors, alectinib or ceritinib. Accordingly, Health Canada approved the following indication:
- Lorbrena (lorlatinib) is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on crizotinib and at least one other ALK inhibitor, or patients who have progressed on ceritinib or alectinib.
For more information, refer to the Lorbrena Product Monograph, approved by Health Canada and available through the Drug Product Database
Clinical Safety
The clinical safety of Lorbrena has been evaluated in the pivotal, ongoing, single-arm, Phase I/II study, B7461001 (described in the Clinical Efficacy section).
The sponsor provided a 120-day safety update report (with a data cut-off date of September 15, 2017) that included data from a pooled group of 295 patients treated with the recommended dose of 100 mg lorlatinib orally once daily (referred to as the 100 mg-pooled group). The 100 mg-pooled group included 17 patients from the Phase I portion of study B7461001, 275 patients from the Phase II portion of study B7461001, and 3 patients from a Japanese lead-in cohort. As of the data cut-off date, the 100 mg-pooled group of study B7461001 had a median duration of treatment of 12.5 months (range: 0.03 to 35.12 months).
The most common (≥20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, fatigue, weight gain, arthralgia, mood effects, and diarrhea.
The most common (≥20%) laboratory abnormalities were hypercholesterolemia, hyptertriglyceridemia, anemia, increased creatinine, hyperglycemia, hypoalbuminemia, increased aspartate aminotransferase (AST), lymphopenia, increased alkaline phosphate, increased alanine aminotransferase (ALT), increased lipase, increased amylase, hypomagnesemia, decreased platelet count, hypophosphatemia, hyponatremia, and hyperkalemia.
Serious adverse reactions were reported in 18 patients (6.1%). The most frequent serious adverse reactions reported were mental status changes in four patients (1.4%) and cognitive effects in three patients (1.0%).
Permanent discontinuations associated with adverse reactions occurred in eight patients (2.7%) receiving Lorbrena. The most frequent adverse reaction that led to a permanent discontinuation were hallucinations in two patients (0.7%), cognitive effects in two patients (0.7%), and mood effects in two patients (0.7%).
The identified safety concerns have been addressed in the approved Lorbrena Product Monograph. A Serious Warnings and Precautions box highlights the risks of hypercholesterolemia/hypertriglyceridemia, pneumonitis, and hepatotoxicity. Furthermore, due to the risk of serious hepatotoxicity with concomitant use of strong CYP3A inducers, Lorbrena is contraindicated in patients who are receiving strong CYP3A inducers. In addition, the Warnings and Precautions section of the Lorbrena Product Monograph includes recommendations for monitoring ALT, AST, bilirubin, lipase, amylase, serum cholesterol and triglycerides, prior to initiating Lorbrena and periodically thereafter. Electrocardiogram monitoring is also recommended as PR interval prolongation and atrioventricular block events have been reported in patients receiving Lorbrena.
The safety profile of Lorbrena will be further evaluated in the confirmatory trial B7461006, an ongoing, randomized, open-label, Phase III clinical study comparing the safety and efficacy of lorlatinib to crizotinib in the first-line treatment of patients with advanced ALK-positive NSCLC. The clinical study report will be submitted to Health Canada by the end of 2021.
For more information, refer to the Lorbrena Product Monograph, approved by Health Canada and available through the Drug Product Database
7.2 Non-Clinical Basis for Decision
The non-clinical pharmacology and toxicology studies support the use of Lorbrena for the specified indication.
The medicinal ingredient in Lorbrena, lorlatinib, is a potent and selective, ATP-competitive, small-molecule inhibitor of ALK and ROS1 kinase. Lorlatinib is active when administered orally and able to cross the blood-brain barrier.
Safety pharmacology studies conducted in rats and dogs identified the potential of lorlatinib to cause cardiovascular, neurofunctional, and respiratory adverse effects.
The major circulating metabolite of lorlatinib found in humans, PF-06895751 (M8), did not inhibit human ether-a-go-go related gene (hERG) potassium ion channels with a half-maximal inhibitory concentration (IC50) of >300 µM. The metabolite is considered pharmacologically inactive.
In rats and dogs, the pharmacokinetics of lorlatinib was characterized by low plasma clearance, a steady-state volume of distribution which exceeded total body water (suggesting an extensive distribution to tissues), and high oral bioavailability.
In in vitro studies, the metabolism of lorlatinib was mediated primarily by CYP3A4 and UGT1A4, with minor contribution from CYP2C8, CYP2C19, CYP3A5, and UGT1A3 enzymes.
In vitro, lorlatinib is an inhibitor of CYP2C9 and CYP3A4/5, and it also induces CYP3A4 and activates the human pregnane X receptor (hPXR) (a nuclear receptor that serves as a regulator of CYP3A4 transcription). In humans, lorlatinib exhibits a net induction effect on CYP3A4/5. In vitro studies have also demonstrated that lorlatinib induces CYP2B6 and activates human constitutive androstane receptor 1 (hCAR1, a nuclear receptor that mediates the expression of several cytochrome P450 genes, certain phase II enzymes, and several ABC-type transporters). Further studies are needed to evaluate the potential for clinically relevant drug-drug interactions (e.g., with CYP2B6, CYP2C9, and CYP3A4 substrates). The inhibitory and inductive effects of lorlatinib on the activities of metabolizing enzymes could represent a potential mechanism for liver toxicity after prolonged exposure to lorlatinib.
Lorlatinib is an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)1, organic anion transporter (OAT)3, and multidrug and toxin extrusion protein (MATE1). Thus, lorlatinib may potentially cause drug-drug interactions with substrates of the aforementioned transporters. Further studies are needed to confirm the potential for clinically significant drug-drug interactions.
The metabolite M8 is unlikely to cause drug-drug interactions by inhibiting and/or inducing the evaluated cytochrome enzymes, UDP-glucuronosyltransferases, and drug transporters at clinically relevant concentrations.
In toxicology studies, the maximum tolerated dose (MTD) following a single dose of lorlatinib was 100 mg/kg/day in rats and dogs. Following one week of lorlatinib administration, the MTD was 15 mg/kg/day, suggesting cumulative toxicity.
Following repeat-dose administration of lorlatinib, main toxicities included inflammation across multiple tissues and changes in the pancreas, hepatobiliary system, male reproductive system, cardiovascular system, and gastrointestinal tract of rats and dogs. Additional important findings were changes observed in the peripheral nerves and central nervous system, and the kidneys of rats. Bile duct hyperplasia associated with elevations in liver enzymes (ALT, AST, alkaline phosphatase, glutamate dehydrogenase, and/or gamma-glutamyl transferase) was observed in rats and dogs. Full or partial reversibility was established for all lorlatinib-related target organ toxicities with the exception of hepatic bile duct hyperplasia after 13 weeks of lorlatinib administration in rats. This could indicate liver toxicity.
Lorlatinib was associated with severe embryo-fetal toxicity. In addition, lorlatinib was identified as an aneugen in micronucleus assays in vitro and in vivo.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Lorbrena Product Monograph. In view of the intended use of Lorbrena, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
Appropriate warnings and precautionary measures are in place in the Lorbrena Product Monograph to address the identified safety concerns.
For more information, refer to the Lorbrena 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 Lorbrena 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 acceptable when the drug product is stored at room temperature (15ºC to 30ºC).
Proposed limits of drug-related impurities are considered adequately qualified, i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies.
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of lorlatinib with the excipients is supported by the stability data provided.
The excipient lactose monohydrate is derived from milk obtained from healthy animals under the same conditions as milk collected for human consumption. 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 |
|---|---|---|---|
| LORBRENA | 02485966 | PFIZER CANADA ULC | LORLATINIB 25 MG |
| LORBRENA | 02485974 | PFIZER CANADA ULC | LORLATINIB 100 MG |