Summary Basis of Decision for Libtayo

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 Libtayo is located below.

Recent Activity for Libtayo

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’s life cycle.

 

The following table describes post-authorization activity for Libtayo, a product which contains the medicinal ingredient cemiplimab. 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: 2024-12-06

Drug Identification Number (DIN):

  • DIN 02487144 – cemiplimab 350 mg/7 mL (50 mg/mL), solution, intravenous administration
  • DIN 02487152 – cemiplimab 250 mg/5 mL (50 mg/mL), solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 291392

2024-10-15

Issued NOL 2024-11-14

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of a new quality control testing site and for changes to controls applied during the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 289694

2024-08-19

Cancellation Letter Received 2024-10-09

Submission filed as a Level I – Supplement for the addition of a new quality control testing site. The change was not in scope of an SNDS but was considered to be a Level II change. The sponsor cancelled the submission administratively.

SNDS # 286502

2024-04-30

Issued NOC 2024-09-25

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 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 # 279566

2023-09-29

Issued NOC 2024-09-13

Submission filed as a Level I – Supplement to update the PM with data from study 16113. Based on the data presented to date, the benefit-risk ratio of the product is considered to remain favourable. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials section of the PM. An NOC was issued.

SNDS # 289478

2024-08-09

Cancellation Letter Received 2024-08-16

Submission filed as a Level I – Supplement for the addition of a new quality control testing site and for changes to controls applied during the drug product manufacturing process. The sponsor cancelled the submission administratively.

NDS # 282193

2023-12-18

Issued NOC 2024-06-11

Submission filed to transfer ownership of the drug product from Sanofi-Aventis to Regeneron Canada. An NOC was issued.

SNDS # 276628

2023-08-17

Issued NOC 2024-01-19

Submission filed as a Level I – Supplement to update the PM. The changes were in response to an Advisement Letter issued by Health Canada to manufacturers of immune check-point inhibitors (ICIs) drugs, dated June 27, 2023, requesting revisions related to risk of aplastic anemia. 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. An NOC was issued.

SNDS # 277229

2023-07-14

Issued NOC 2023-12-15

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 Warnings and Precautions; Adverse Reactions; and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

DIN 02487152 cancelled post market

Not applicable

Discontinuation date 2023-12-08

The manufacturer notified Health Canada that sale of the drug has been discontinued post market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations.

SNDS-C # 267523

2022-08-31

Issued NOC 2023-08-15

Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission contained the final clinical trial report for Groups 1, 2, and 3 of the pivotal study R2810-ONC-1540, and fulfilled the commitments in the Letter of Undertaking dated March 14, 2019 issued under NDS # 218718. The submission was reviewed and considered acceptable. The conditions were removed and an NOC was issued.

SNDS # 263700

2022-04-26

Issued NOC 2023-04-27

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Libtayo, in combination with platinum-based chemotherapy, for the first-line treatment of adult patients with NSCLC whose tumours have no EGFR, ALK or ROS1 aberrations, and is 1) locally advanced NSCLC where patients are not candidates for surgical resection or definitive chemoradiation; or 2) metastatic NSCLC. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and package insert. An NOC was issued and a Regulatory Decision Summary was published.

NC # 269759

2022-11-16

Issued NOL 2023-02-01

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of a new quality control testing site and changes to drug substance and drug product analytical procedures. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 262893

2022-03-28

Issued NOL 2022-06-10

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the controls applied during the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 256178

2021-08-30

Issued NOC 2022-03-23

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: Libtayo for the treatment of adult patients with cervical cancer who have progressed on or after prior platinum-based chemotherapy and who require additional systemic therapy to treat recurrent or metastatic disease. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications; Warnings and Precautions; Adverse Reactions; Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and package insert. An NOC was issued and a Regulatory Decision Summary was published.

SNDS # 246918

2020-12-01

Issued NOC 2021-10-26

Submission filed as a Level I – Supplement for two new indications. The indications authorized were: Libtayo for 1) the first-line treatment of adult patients with non-small cell lung cancer (NSCLC) expressing programmed cell death ligand 1 (PD-L1) in ≥50% of tumour cells (Tumour Proportion Score [TPS] ≥50%), as determined by a validated test, with no Epithelial Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK) or c-ROS oncogene 1 (ROS1) aberrations, who have locally advanced NSCLC who are not candidates for surgical resection or definitive chemoradiation, or have metastatic NSCLC; and 2) the treatment of patients with locally advanced basal cell carcinoma (BCC) previously treated with a hedgehog pathway inhibitor. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications; Warnings and Precautions; Adverse Reactions; Dosage and Administration; Clinical Pharmacology; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and package insert. An NOC was issued and a Regulatory Decision Summary was published.

PSUR-C 253892

2021-06-16

Filed 2021-09-10

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C for the period 2020-09-28 to 2021-03-27. The information was reviewed and found to be acceptable.

SNDS-C # 242320

2020-08-12

Issued NOC under NOC/c Guidance 2021-08-13

Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission contained data from the pivotal study R2810-ONC-1540 to fulfill a commitment in the Letter of Undertaking dated March 14, 2019 issued under NDS # 218718. The submission was reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance.

NC # 252040

2021-07-14

Issued NOL 2021-07-14

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the drug product shelf life. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 247434

2020-12-10

Issued NOC 2021-06-23

Submission filed as a Level I – Supplement for the addition of a drug substance manufacturing site and scale-up of the drug substance and drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 243824

2020-09-11

Issued NOL 2020-12-08

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to controls applied during the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 238215

2020-04-17

Issued NOC 2020-08-26

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 Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and package insert. An NOC was issued.

SNDS # 235369

2020-01-22

Issued NOC 2020-08-19

Submission filed as a Level I – Supplement for the addition of an alternate drug product manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS-C # 234679

2020-01-03

Cancellation Letter Received 2020-02-20

Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission contained data from the pivotal study R2810-ONC-1540 to fulfill a commitment in the Letter of Undertaking dated March 14, 2019 issued under NDS # 218718. A number of issues were identified with the submission during screening and the submission was cancelled by the sponsor.

NC # 231373

2019-09-05

Issued NOL 2019-11-13

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a drug substance and drug product analytical procedure. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 227276

2019-04-29

Issued NOL 2019-07-19

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the parameters of an approved holding step. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DINs 02487144, 02487152) market notification

Not applicable

Date of first sale: 2019-05-24

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NC # 227354

2019-04-30

Issued NOL 2019-07-04

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the drug product shelf life. The submission was reviewed and considered acceptable, and an NOL was issued.

NDS # 218718

2018-07-27

Issued NOC under NOC/c Guidance 2019-04-10

NOC issued under the NOC/c Guidance for New Drug Submission.
Summary Basis of Decision (SBD) for Libtayo

Date SBD issued: 2019-08-27

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

Cemiplimab

Drug Identification Number (DIN):

  • DIN 02487144 - 350 mg/7 mL (50 mg/mL), solution, intravenous administration
  • DIN 02487152 - 250 mg/5 mL (50 mg/mL), solution, intravenous administration

Sanofi-Aventis Canada Inc.

New Drug Submission Control Number: 218718

 

On April 10, 2019, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Sanofi-Aventis Canada Inc. for the drug product Libtayo. 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 Libtayo is favourable for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation.

 

1 What was approved?

 

Libtayo is an antineoplastic agent, a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed cell death-1 (PD-1) receptor. It was authorized for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation.

The marketing authorization with conditions is based on tumour response rate and durability of response. An improvement in overall survival or progression-free survival has not yet been established.

The safety and efficacy of Libtayo in pediatric (younger than 18 years of age) patients have not been established.

No overall differences in efficacy were observed between patients younger than 75 years of age and elderly patients (75 years of age and older).

Libtayo 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.

Libtayo 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.

Libtayo (50 mg/mL cemiplimab) is presented as a solution. In addition to the medicinal ingredient, the solution contains L-histidine, L-histidine monohydrochloride monohydrate, L-proline, polysorbate 80, sucrose, and water for injection.

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

 

2 Why was Libtayo approved?

 

Health Canada considers that the benefit-risk profile of Libtayo is favourable for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or curative radiation. Libtayo 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.

In Canada, CSCC is the second most common non-melanoma skin cancer, after basal cell carcinoma. The vast majority of patients with localized disease are managed surgically, with or without radiation therapy. However, in a small number of patients (less than 5%), the disease may metastasize. Other patients may have recurrence of disease or locally advanced disease that is unresectable due to anatomical or other issues. For this small subset of patients, no approved treatments are currently available and there is no standard of care.

Cemiplimab, the medicinal ingredient in Libtayo, is an IgG4 monoclonal antibody that binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with the PD-1 ligands, PD-L1 and PD-L2.

Libtayo has been shown to be efficacious in adult patients with advanced CSCC, including patients with metastatic disease and those with locally advanced disease who are not candidates for curative surgery or curative radiation. The market authorization with conditions was based on an integrated analysis of data from two clinical trials. Namely, interim data from a pivotal Phase II uncontrolled study of 82 patients with metastatic or locally advanced CSCC (Study R2810-ONC-1540) and a Phase I study enrolling 26 patients with advanced CSCC (Study R2810-ONC-1423) were pooled to form the primary efficacy set. The patients received 3 mg/kg Libtayo every two weeks for up to 96 weeks. Study R2810-ONC-1540 also enrolled patients receiving 350 mg Libtayo every three weeks for up to 54 weeks; however, data from these patients were not yet available for efficacy analysis at the time of interim analysis. The primary efficacy endpoint was objective response rate as assessed by an independent review committee. The integrated analysis showed clinical benefit with Libtayo monotherapy, i.e., an overall objective response rate of 47.2%, which was considered clinically meaningful. The key secondary endpoint was duration of response. Although the median duration of response was not yet reached at the time of data cut-off, the results suggest durability of response.

The clinical safety of Libtayo was evaluated as a monotherapy in patients with advanced CSCC and in all patients who had received at least one dose of Libtayo for various advanced solid malignancies, as a monotherapy or in combination with other anticancer treatments. Overall, the safety profile of Libtayo is found to be consistent with that of previously marketed PD-1/PD-L1 inhibitors. Immune-mediated adverse events were relatively common, most often of low grade and/or manageable with the use of corticosteroids or dose delays. Notable safety findings for Libtayo for which post-marketing surveillance is recommended include immune-mediated skin reactions and infusion-related reactions.

In the submitted clinical studies, the study population mainly comprised elderly, white, male patients. Considering the known risk factors for the disease, this is a fair representation of a typical patient population with advanced CSCC. However, uncertainties remain regarding any clinically significant differences in efficacy and safety in other subgroups. In particular, female and non-white patients were underrepresented in these studies. While exploratory subgroup analyses did not reveal any trends, the numbers of patients were too small to draw meaningful conclusions. Furthermore, certain patients were excluded from the studies. Patients who were immunosuppressed or had a history of solid organ transplant were excluded as per the key exclusion criteria of the studies. Although the exclusion is appropriate given the study phases, this particular subpopulation is notable for having a higher risk of developing CSCC due to immunosuppression. Similarly, patients with a primary CSCC occurring on the lip or in the anogenital region were excluded, as the CSCCs in these locations are considered "high-risk" tumours that are more likely to metastasize. Despite these uncertainties, the overall benefit of cemiplimab is considered to outweigh potential risks, given the lack of standard therapies and the poor prognosis of advanced CSCC.

A randomized trial to show overall survival or progression-free survival benefit is not feasible for a relatively rare disease for which no standard of care exists. Therefore, the conditional authorization of Libtayo is based on the endpoints of objective response rate and duration of response. As part of the conditions under the NOC/c Guidance, the sponsor will provide the mature data from the pivotal study and the integrated results for objective response rate and duration of response (see What follow-up measures will the company take?).

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

The submitted inner and outer labels, package insert and Patient Medication Information section of the Libtayo 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 Libtayo was accepted.

Overall, a favourable benefit-risk profile of Libtayo for the treatment of adult patients with metastatic or locally advanced CSCC who are not candidates for curative surgery or curative radiation was established from an integrated analysis of data from two clinical trials. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Libtayo Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring of the use of Libtayo will be ongoing. Further evaluation of the clinical benefit of Libtayo will take place upon the submission of the final report of the pivotal study R2810-ONC-1540.

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 Libtayo?

 

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 (NDS) for Libtayo. An assessment was conducted and it was determined there was promising evidence of clinical effectiveness. Libtayo has the potential to provide effective treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, a disease for which no drug is presently marketed in Canada.

 

Submission Milestones: Libtayo

Submission Milestone Date
Pre-submission meeting 1 2018-04-19
Pre-submission meeting 2 2018-06-28
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance: 2018-07-25
Submission filed: 2018-07-27
Screening  
Screening Acceptance Letter issued: 2019-08-24
Review  
Review of Risk Management Plan complete: 2018-12-27
Quality Evaluation complete: 2019-03-07
Clinical/Medical Evaluation complete: 2019-03-11
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2019-03-12
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued: 2019-03-12
Review of Response to NOC/c-QN:  
Response filed (Letter of Undertaking): 2019-03-14
Clinical/Medical Evaluation complete: 2019-04-08
Notice of Compliance (NOC) issued by Director General, Biologics and Genetic Therapies Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance: 2019-04-10

 

The Canadian regulatory decision on the quality, non-clinical and clinical reviews of Libtayo was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference. Questions and answers documents from the European Medicines Agency (EMA) were consulted in lieu of issuing specific questions to the sponsor.

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 submit to Health Canada:

  • As a Supplement to a New Drug Submission (SNDS), the following information from the pivotal clinical study (R2810-ONC-1540) "A Phase II Study of REGN2810, a fully human monoclonal antibody to programmed death-1 (PD-1) in patients with advanced cutaneous squamous cell carcinoma":
    • Final primary endpoint efficacy analyses of objective response rate as assessed by a central review for Group 2 (3 mg/kg REGN2810 every second week [Q2W]; locally advanced cutaneous squamous cell carcinoma [laCSCC]) and Group 3 (350 mg REGN2810 every three weeks [Q3W]; metastatic CSCC).
    • Secondary endpoint analyses of duration of response, progression-free survival, overall survival, safety, and pharmacokinetics (including updated exposure-response analyses for efficacy and safety).
    • An update for Group 1 (3 mg/kg REGN2810 Q2W; metastatic CSCC) of duration of response, progression-free survival, overall survival, safety, and pharmacokinetics.
    • An updated integrated efficacy analysis of data from patients with advanced CSCC from studies R2810-ONC-1423 and R2810-ONC-1540.

The SNDS is expected by the end of 2019.

  • A Supplement to a New Drug Submission-Confirmatory (SNDS-C) for the pivotal study R2810-ONC-1540 (Groups 1, 2 and 3). This will include the final clinical trial report with the final analysis of objective response rate and duration of response in patients with advanced CSCC, including patients with metastatic disease and patients with locally advanced CSCC who are not candidates for surgery or radiation. The SNDS-C is expected in the third quarter of 2022.

 

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

 

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 decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Libtayo 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

Cemiplimab, the medicinal ingredient in Libtayo, is a recombinant human immunoglobulin G (IgG) 4 monoclonal antibody that binds to the programmed cell death-1 receptor (PD-1) and blocks its interaction with the programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2), thereby countering PD-1-mediated inhibition of the immune response, including the antitumour immune response.

A population pharmacokinetic model was developed to describe the pharmacokinetics of cemiplimab in patients with a range of solid tumours including cutaneous squamous cell carcinoma (CSCC). The model was used to simulate steady-state exposure following dosing with a flat dosage regimen of 350 mg cemiplimab every three weeks (Q3W) as compared to a weight-based dosage regimen of 3 mg/kg cemiplimab every two weeks (Q2W). Data from two clinical studies (R2810-ONC-1423 and R2810-ONC-1540, described in the Clinical Efficacy section) were combined for the analysis. Study R2810-ONC-1423 evaluated cemiplimab as a monotherapy or combination therapy over a dose range of 1 mg/kg Q2W to 10 mg/kg Q2W in patients with various advanced solid malignancies, including advanced CSCC. Study R2810-ONC-1540 evaluated cemiplimab 3 mg Q2W and 350 mg Q3W in patients with advanced CSCC. Of note, there were very limited pharmacokinetic data available for analysis from patients dosed with the 350 mg Q3W dosage regimen.

A two-compartment model with zero-order intravenous infusion, first-order elimination and time varying clearance adequately described the pharmacokinetic characteristics of cemiplimab. The population pharmacokinetic modelling and simulation results supported similar steady-state exposure following dosing with the 350 mg Q3W dosage regimen as compared to the 3 mg/kg Q2W dosage regimen in a typical patient (median body weight of 76.1 kg). However, when dosing with the proposed flat 350 mg Q3W dosage regimen, overexposure or underexposure occurs in patients with low or high body weights, respectively. This raised concerns given the limited clinical information available on the safety and efficacy of cemiplimab in patients with extreme body weights. In particular, it is unclear if underexposures in patients with high body weights (>120 kg) would result in a loss of efficacy. The sponsor reported that three patients weighing ≥120 kg have been treated to date with the 350 mg Q3W dosage regimen. While one patient responded to treatment, the two other patients discontinued treatment due to a lack of response or due to adverse events. Given the limited data available in patients with high body weights, conclusions on the impact of underexposures cannot be made at this time. The underdosing will likely be of concern in patients with extreme high body weights. From a safety perspective, concerns of overexposure exist, as one death occurred in a non-CSCC patient dosed at the 10 mg/kg Q2W dosage regimen from Study R2810-ONC-1423. While confounding factors were reported to have contributed to the death, there is limited safety information in patients dosed above the 3 mg/kg Q2W dosage regimen (only six non-CSCC patients were evaluated at doses above 3 mg/kg Q2W [i.e., 10 mg/kg Q2W]). Therefore, to mitigate the risks, particularly in patients with low body weights, the sponsor was requested to retain the option of a dosage regimen of 3 mg/kg Q2W. Consequently, both dosage regimens are included in the Libtayo Product Monograph.

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

Clinical Efficacy

The efficacy of Libtayo in patients with advanced cutaneous squamous cell carcinoma was evaluated in a pivotal Phase II trial (Study R2810-ONC-1540) and a supportive Phase I trial (Study R2810-ONC-1423).

Study R2810-ONC-1540 was a non-randomized, multicentre, uncontrolled study that had enrolled 137 adult patients with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced cutaneous squamous cell carcinoma (laCSCC) at the time of data cut-off. The study included three treatment groups. Patients in Group 1 (mCSCC patients) and Group 2 (laCSCC patients) were treated with 3 mg/kg Libtayo as monotherapy administered as an intravenous infusion over 30 minutes every two weeks (Q2W) for up to 96 weeks. Patients in Group 3 (mCSCC) received 350 mg Libtayo as monotherapy administered as an intravenous infusion over 30 minutes every three weeks (Q3W) for up to 54 weeks.

Study R2810-ONC-1423 was a first-in-human, open-label study of Libtayo as monotherapy and combination therapy, conducted in 397 patients with various advanced solid malignancies. The study included 26 patients with advanced CSCC who were treated with 3 mg/kg Q2W dosage regimen of Libtayo for 48 weeks.

The primary efficacy endpoint was confirmed objective response rate, as assessed by an independent central review. For patients with metastatic CSCC without externally visible target lesions, the objective response rate was determined by the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1). For patients with externally visible target lesions (locally advanced CSCC and metastatic CSCC), the objective response rate was determined by a composite endpoint that integrated independent central review assessments of radiologic data (according to RECIST 1.1) and digital medical photography (according to World Health Organization criteria). The key secondary endpoint was duration of response.

The main efficacy analysis was performed as an integrated analysis of data pooled from 108 CSCC patients in studies R2810-ONC-1540 and R2810-ONC-1423 who had sufficient follow-up, i.e., at least six months for the mCSCC patients and at least nine months for the laCSCC patients. The pooled study population included 75 patients with mCSCC and 33 patients with laCSCC. The median age of the patients was 71 years (range: 38 to 96 years). Ninety-two patients (85.2%) were male and 105 patients (97.2%) were white. The majority of patients (57.4%) had an Eastern Cooperative Oncology Group (ECOG) performance score of 1, whereas the remaining 42.6% of patients had an ECOG performance score of 0. Half (50%) of the study population had received previous anticancer systemic therapy, while 78.7% had had prior radiotherapy. All patients received the 3 mg/kg Q2W dosage regimen of Libtayo, with the exception of one CSCC patient in Study R2810-ONC-1423 who was part of a dose-escalation cohort and received a dosage regimen of 1 mg/kg Q2W.

For the total advanced CSCC (including mCSCC and laCSCC) analysis set of 108 patients, the objective response rate was 47.2% (51/108; [95% CI: 37.5 to 57.1]). There were 43.5% (47/108) of patients who had a best overall tumour response of partial response, and 3.7% (4/108) with a best overall tumour response of complete response.

Of note, results from previous studies of systemic therapies in CSCC have suggested that response rates in patients with laCSCC may be higher than in patients with mCSCC. Accordingly, the sponsor specified different thresholds for determining a clinically meaningful objective response rate, i.e., greater than 15% for mCSCC, and greater than 25% for laCSCC. The integrated efficacy results showed comparable objective response rates between mCSCC and laCSCC. For patients with mCSCC, the objective response rate was 46.7% (95% CI: 35.1 to 58.6), including 41.3% (31/75) of patients who had a best overall tumour response of partial response and 5.3% (4/75) with a complete response. For patients with laCSCC, the objective response rate was 48.5% (95% CI: 30.8 to 66.5) and all responses were partial responses.

Although the median duration of follow-up was 8.92 months for the efficacy set at the time of data cut-off, the median duration of response had not yet been reached. The range of duration of response was 1.0 to 15.2+ months ("+" indicates ongoing response at data cut-off). The median time to response was 1.87 months (range: 1.7 to 7.6 months).Of the 51 responders at the time of data cut-off, only four patients had subsequent disease progression.

Exploratory subgroup analyses suggested that efficacy was consistent in patients who had received prior anticancer systemic therapy and radiotherapy. However, due to small sample sizes and wide confidence intervals, statistical conclusions cannot be drawn.

Indication

The New Drug Submission for Libtayo was filed by the sponsor with the following indication:

  • Libtayo is indicated for the treatment of patients with metastatic cutaneous squamous cell carcinoma or patients with locally advanced cutaneous squamous cell carcinoma who are not candidates for surgery.

To ensure safe and effective use of the product, Health Canada approved the following indication:

  • Libtayo (cemiplimab) is indicated for treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation.

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

Clinical Safety

The safety of Libtayo was assessed for the patients with advanced CSCC (number of patients [n] = 163) and for the entire patient population (n = 534) with various advanced solid malignancies who received at least one dose of Libtayo as a monotherapy or combination therapy in Studies R2810-ONC-1423 or R2810-ONC-1540 (described in the Clinical Efficacy section). Overall, the rates and types of treatment-emergent adverse events were comparable between CSCC and non-CSCC patients.

Most CSCC patients (95.1%) experienced at least one treatment-emergent adverse event, and 38% of the patients had a treatment-emergent adverse event of Grade 3 or higher. Treatment-emergent adverse events considered related to treatment occurred in 66.9% of patients and 12.3% of the events were Grade 3 or higher. The most common adverse events considered treatment-related in CSCC patients were fatigue (19%), diarrhea (11.7%), maculopapular rash (9.8%), and pruritus (9.8%). Of the Grade ≥3 treatment-related treatment-emergent adverse events, those occurring in more than one patient included maculopapular rash, increased aspartate aminotransferase, pneumonitis, and autoimmune hepatitis. Thirteen patients (8%) had a serious adverse event that was considered related to treatment.

The incidence of infusion-related reactions was slightly higher than what was observed in clinical trials of other authorized PD-1/PD-L1 inhibitors. All infusion-related reactions were Grade 1 or 2 in severity, except for one case of a Grade 3 infusion-related reaction.

Among the 534 patients, there were four deaths resulting from treatment-related adverse events (pneumonitis, hepatic failure, paraneoplastic encephalomyelitis, and unknown cause).

Overall, the safety profile of Libtayo appears consistent with that observed with other PD-1/PD-L1 inhibitors. Immune-mediated adverse events were relatively common, most often of low grade and/or manageable with the use of corticosteroids or dose delays. Notable safety findings for Libtayo for which post-marketing surveillance is recommended include immune-mediated skin reactions and infusion-related reactions.

Severe immune-mediated skin reactions occurred in a separate clinical trial evaluating Libtayo in non-Hodgkin's lymphoma, in three patients with prior exposure to idelalisib. Due to confounding factors, such as concurrent use of sulfa-containing antibiotics, the relationship between cemiplimab and idelalisib is unclear. However, given the severity of the reactions observed, continued pharmacovigilance for potential future cases is recommended.

Appropriate warnings and precautions are in place in the approved Libtayo Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Cemiplimab (also referred to as REGN2810), the medicinal ingredient in Libtayo, binds to the programmed cell death-1 receptor (PD-1) and blocks interaction with its ligands, PD-L1 and PD-L2.

An ex vivo tissue cross-reactivity study performed with normal human and cynomolgus monkey tissues, using biotinylated REGN2810, demonstrated similar staining patterns in both species.

Given that REGN2810 does not bind to rodent PD-1, the cynomolgus monkey represents the only pharmacologically relevant species for toxicity assessment. Three repeat-dose toxicology studies were conducted in female and male cynomolgus monkeys. The animals were intravenously administered REGN2810 at doses ranging from 2 mg/kg to 50 mg/kg once weekly, for periods of up to 26 weeks Recovery periods lasted up to 12 weeks following the last dose. The studies characterized the toxicokinetic profile, anti-drug antibody responses, immunotoxicology and fertility parameters, and safety pharmacology parameters (i.e., effects on the cardiovascular system, central nervous system, and respiratory system) of REGN2810.

No adverse toxicological effects directly attributable to the pharmacological properties of REGN2810 were observed. Two deaths occurred early in the 26-week study and were attributed to anti-drug-antibody formation and subsequent immune complex deposition. There was no functional or anatomic evidence of cardiovascular, respiratory or central nervous system disruptions attributable to REGN2810 during the toxicology studies, nor were there any injection-site reactions. The no-observed-adverse-effect level (NOAEL) following repeated weekly dosing of REGN2810 for up to 26 weeks was considered to be 50 mg/kg/week intravenously, i.e., the highest dose administered in the study. In the 13-week fertility assessment toxicology study, there were no REGN2810-related microscopic findings in male or female reproductive organs or effects on fertility parameters (menstrual cycle, semen analysis or testicular measurements).

The results of the non-clinical studies as well as the potential risks to humans have been included in the Libtayo Product Monograph. In view of the intended use of Libtayo, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Quality Basis for Decision

 

Characterization of the Drug Substance

The medicinal ingredient in Libtayo, cemiplimab, is a recombinant monoclonal antibody of immunoglobulin G4 (IgG4) isotype that binds specifically to the programmed cell death-1 receptor (PD-1), blocking the interaction with its ligands, PD-L1 and PD-L2. Cemiplimab is a heterotetramer comprised of two disulfide-linked human heavy chains, each covalently linked through a disulfide bond to a human kappa light chain. The protein has a molecular mass of 143.57 kDa.

Detailed characterization studies were performed to provide assurance that cemiplimab consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

Cemiplimab is expressed in a Chinese Hamster Ovary (CHO) cell line developed using recombinant deoxyribonucleic acid (DNA) techniques. The cell line is cryopreserved using a two-tier cell banking system. The cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated the stability of these cell banks.

Cemiplimab drug substance manufacture is initiated using cells recovered from a thawed working cell bank vial. The cell mass is progressively expanded until sufficient for the inoculation of the production bioreactor. After a predetermined cell culture period, the contents of the production bioreactor are harvested and clarified to remove cells and cell debris. The clarified harvest is then processed by chromatographic and membrane filtration steps. The ranges of critical process parameters and the routine in-process controls along with acceptance criteria were described for each step. The cemiplimab drug substance manufacturing process is considered acceptable.

The drug product manufacturing process consists of thawing of the frozen active substance under controlled conditions, mixing, bioburden reduction filtration, sterile filtration, filling into vials, stoppering, and capping. Vials are visually inspected and stored at 2°C to 8°C. The sponsor has demonstrated the capability of the drug product manufacturing site to consistently produce drug product of acceptable quality.

The materials used in the manufacture of the drug substance and drug product are considered suitable and meet standards appropriate for their intended use.

The control strategy, including the specifications, for cemiplimab drug substance and drug product, was defined based on the enhanced process knowledge and product understanding. The proposed control strategy ensures a suitable level of robustness for the manufacturing process performance and quality of the resulting drug substance and drug product. Analytical procedures have been carefully selected according to their ability to confirm the quality of the drug substance and drug product, and validated in compliance with International Council for Harmonisation (ICH) guidelines.

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 cemiplimab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with the ICH guidelines.

Through Health Canada's lot release testing and evaluation program, drug product lots were tested using a subset of release methods. The results meet specifications and are comparable to the release results reported in the certificates of analysis. The methods are considered suitable for their intended use.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed shelf life for Libtayo, when stored at a temperature of 2ºC to 8ºC and protected from light, is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured.

On-site evaluations were not conducted.

Both production sites are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The manufacturing of cemiplimab incorporates adequate control measures to prevent contamination and maintain microbial control. The purification process demonstrates a high level of viral clearance for a variety of virus types.

The excipients used in the drug product formulation are not of animal or human origin.

 

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