Summary Basis of Decision for Tevimbra

Clinical Pharmacology

Tislelizumab, the medicinal ingredient in Tevimbra, is a recombinant, humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds with high affinity to the human programmed cell death 1 (PD-1) receptor on T cells to enhance the activity of T-cell-mediated antitumour activity.

The pharmacokinetic parameters of tislelizumab were characterized in 131 patients with nasopharyngeal carcinoma from the pivotal Phase III Study-309 described in the Clinical Efficacy section. Following tislelizumab dosing at 200 mg every 3 weeks in combination with gemcitabine and cisplatin, the trough concentrations (C_trough) and maximum concentrations (C_max) of tislelizumab in patients with nasopharyngeal carcinoma were consistent with those previously observed in patients with different tumour types (classical Hodgkin lymphoma, esophageal squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, non-small cell lung cancer, small cell lung cancer, and urothelial carcinoma) who had received the same dose of tislelizumab as monotherapy or in combination with chemotherapy.

A population pharmacokinetic (PopPK) model for tislelizumab was developed based on pharmacokinetic data from 2,596 patients with various tumour types from 12 clinical studies. The PopPK model showed that the pharmacokinetics of tislelizumab were described by a three-compartment disposition model with linear clearance. No time-varying clearance was observed in this analysis. Steady state was expected to be reached by the fifth dose at approximately Day 84. At steady state, tislelizumab was estimated to have a terminal half-life of 23.8 days and an accumulation ratio of 2.14. Covariates such as body weight, age, sex, tumour size, tumour type, race, Eastern Cooperative Oncology Group (ECOG) status, renal and hepatic impairment, and the presence of albumin and anti-drug antibodies (ADAs) did not have a clinically relevant impact on tislelizumab exposure, and therefore, a dose adjustment is not warranted. The lack of an impact of race on tislelizumab exposure also supported the extrapolation of the results from Study-309, which was conducted solely in Asian patients, to the generalized Canadian population.

Exposure-response analyses showed that tislelizumab exposure was not a significant predictor for the efficacy endpoints of objective response rate, progression-free survival, and overall survival. There was also no correlation between tislelizumab exposure and the probability of Grade 3 or higher treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to dose modification, TEAEs leading to treatment discontinuation, immune-mediated adverse events, infusion related reactions, and adverse events of special interest in patients with nasopharyngeal carcinoma. Based on a relatively flat relationship between tislelizumab exposure and the efficacy or safety profile reported in the exposure-response analyses, no dose adjustment for Tevimbra is considered necessary for patients with nasopharyngeal carcinoma.

Immunogenicity data were available from 125 patients with nasopharyngeal carcinoma who were treated with tislelizumab in combination with gemcitabine and cisplatin in Study-309. Of these patients, 11 patients (8.8%) were identified as positive for treatment-emergent ADAs; however, no patients were positive for neutralizing antibodies (NAbs). In the integrated analysis of 3,395 ADA-evaluable patients from 14 clinical studies who received tislelizumab 200 mg every 3 weeks either as monotherapy or in combination with chemotherapy, the incidence of treatment-emergent ADAs was 16.5% (236 out of 1,427 patients) and 22.2% (357 out of 1,607 patients), respectively, and the incidence of NAbs was 0.8% (11 out of 1,427 patients) and 1.0% (16 out of 1,607 patients), respectively. Therefore, the overall immunogenicity risk of tislelizumab observed in Study-309 is considered low. Based on PopPK analyses, immunogenicity did not have clinically relevant impacts on the pharmacokinetics, efficacy, or safety of tislelizumab.

Overall, the clinical pharmacology data support the use of Tevimbra for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Tevimbra in combination with cisplatin and gemcitabine for the first-line treatment of adult patients with recurrent or metastatic nasopharyngeal carcinoma was investigated in Study-309, a Phase III, randomized, multicentre, single-region (Asia), double-blind, placebo-controlled study. The study enrolled 263 patients with metastatic or recurrent nasopharyngeal carcinoma who had not received previous systemic chemotherapy for recurrent or metastatic disease and had no past history of exposure to PD-1 or programmed death-ligand 1 (PD-L1) inhibitors. Ninety-six percent of patients had metastatic disease at study entry and 87% had a non-keratinizing histology subtype.

Patients were randomized (1:1) to receive either Tevimbra 200 mg (131 patients) or placebo (132 patients), in combination with cisplatin 80 mg/m² on Day 1 and gemcitabine 1 g/m² on Day 1 and Day 8 of each 21-day cycle for 4 to 6 cycles, followed by monotherapy with Tevimbra 200 mg or placebo every 3 weeks until disease progression, unacceptable toxicity, or death. Patients were stratified by gender and the presence of liver metastasis, which are factors linked to poor prognosis. Crossover to the Tevimbra monotherapy arm was permitted for patients in the placebo arm after completion of 4 to 6 cycles of chemotherapy.

At baseline, patients had a median age of 50 years (min, max: 23, 74), 91.6% of patients were under 65 years of age, 78.3% of patients were male, 63.1% of patients had an ECOG performance status score of 1, and 95% of patients were never or former smokers.

All patients enrolled in the study were Asian, as Study-309 accrued patients only in China, Taiwan, and Thailand since the geographic distribution of nasopharyngeal carcinoma presents challenges with enrolling patients into clinical trials outside of endemic regions. To this end, data supporting the current standard of care chemotherapy regimen for metastatic nasopharyngeal carcinoma was generated solely in Asian patients. In regard to the results of Study-309, the sponsor provided an acceptable rationale supporting the applicability of the clinical study results to the North American population. Furthermore, the results of the PopPK analysis indicated that race is not expected to have a clinically meaningful impact on the efficacy or safety of Tevimbra.

The primary endpoint of the study was progression-free survival as assessed by a Blinded Independent Central Review (BICR). Secondary exploratory endpoints by BICR included objective response rate, duration of response, overall survival, and time to response. Secondary endpoints by the investigator included progression-free survival, objective response rate, duration of response, time to response, disease control rate, second progression-free survival, health-related quality of life, safety, and tolerability.

Study-309 met its primary endpoint at the pre-specified interim analysis, whereby treatment with Tevimbra in combination with cisplatin and gemcitabine resulted in a clinically meaningful and statistically significant improvement in BICR-assessed progression-free survival compared with placebo in combination with cisplatin and gemcitabine, with a hazard ratio (HR) of 0.52 (95% confidence interval [CI]: 0.38 to 0.73; p<0.0001), indicating a 48% reduction in the risk of experiencing a progression-free survival event of progressive disease or death. The median progression-free survival was 9.2 months (95% CI: 7.6, 10.1 months) in the Tevimbra arm and 7.4 months (95% CI: 5.6, 7.5 months) in the placebo arm, suggesting a 1.8-month benefit with the addition of Tevimbra to chemotherapy. Results from the updated descriptive efficacy analysis with approximately 17 additional months of follow-up showed a sustained progression-free survival improvement in patients receiving Tevimbra plus chemotherapy over placebo plus chemotherapy.

The secondary endpoints of the study were descriptive in nature; however, at the final analysis, the secondary exploratory endpoint of overall survival was in favour of the Tevimbra arm, with an HR of 0.73 (95% CI: 0.51, 1.05), representing a 27% reduction in the risk of experiencing a death event. The median overall survival was 45.3 months (95% CI: 33.4, not estimable [NE]) in the Tevimbra arm compared with 31.8 months (95% CI: 25.0, NE) in the placebo arm, suggesting a potential benefit of 13.5 months in favour of the Tevimbra plus chemotherapy arm. The overall survival result is exploratory and not alpha controlled and, therefore, must be interpreted with caution.

Indication

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

Tevimbra (tislelizumab for injection) in combination with gemcitabine and cisplatin is indicated for the first-line treatment of patients with recurrent or metastatic nasopharyngeal carcinoma (NPC), and then as a single agent after up to 6 cycles of combination therapy.

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

Tevimbra (tislelizumab for injection) is indicated in combination with gemcitabine and cisplatin for the first line treatment of adult patients with recurrent or metastatic nasopharyngeal carcinoma (NPC).

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

Clinical Safety

The clinical safety of Tevimbra in combination with gemcitabine and cisplatin for the first-line treatment of adult patients with recurrent or metastatic nasopharyngeal carcinoma was evaluated in Study-309 described in the Clinical Efficacy section. The median duration of exposure to Tevimbra was 11.4 months, with 51.9% of patients exposed for greater than one year.

The types and severity of observed adverse events in Study-309 were consistent with what has been observed with the individual safety profiles of cisplatin and gemcitabine. The most common adverse events (occurring in more than 50% of patients in either arm) for all grades were anemia, decreased white blood cell count, decreased neutrophil count, nausea, decreased platelet count, decreased appetite, and vomiting. The incidence of serious adverse events was similar in the Tevimbra and placebo arms (35.3% versus [vs.] 35.4%). Serious adverse events occurring in 2% or more of patients in either arm were decreased platelet count, sepsis, thrombocytopenia, decreased neutrophil count, anemia, decreased white blood cell count, pneumonia, and leukopenia. The incidence of TEAEs leading to death was 4.5% (6 patients) in the Tevimbra arm and 1.5% (2 patients) in the placebo arm. In both arms, the deaths were single events with no concerning pattern. The incidence of permanent discontinuation of any study treatment due to an adverse event was 16.5% in the Tevimbra arm and 10.8% in the placebo arm. Treatment modification of any component of study treatment (interruption, dose delay, decreased infusion rate) due to an adverse event occurred in 72.9% of patients in the Tevimbra arm and in 71.5% of patients in the placebo arm.

Immune-mediated adverse events were reported at a higher frequency in the Tevimbra arm (53.4% vs. 37.7%). The majority of them were immune-mediated endocrinopathies (mainly hypothyroidism) and low grade immune-mediated skin reactions. Other less common immune-mediated adverse events (pneumonitis, hepatitis, myocarditis, and hypophysitis) were few in number and of low grade. There were no Grade 4 or 5 immune-mediated adverse events in Study-309. Infusion-related reactions were infrequent and none of the infusion-related reactions in the Tevimbra arm required treatment with corticosteroids.

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

The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Tevimbra:

• Tevimbra may cause severe and fatal immune-mediated adverse reactions in any organ system or tissue, including: colitis, endocrinopathies, hepatitis, myocarditis, myositis, nephritis with renal dysfunction, organ transplant rejection, pancreatitis, pneumonitis, and severe cutaneous adverse reactions (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis).

• Tevimbra can cause severe or life-threatening infusion-related reactions including hypersensitivity and anaphylaxis.

• Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation before or after being treated with a PD1/PD-L1-blocking antibody.

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

The non-clinical data package demonstrates that tislelizumab, the medicinal ingredient in Tevimbra, exhibits potent target modulation activity in biochemical binding assays, immune cell functional assays, and in vivo efficacy studies. Tislelizumab binds to programmed cell death-1 (PD-1) but is devoid of any detectable non-specific binding to secondary targets (e.g., human serum proteins or cellular proteins). Tislelizumab has the potential to enhance the T-cell-mediated immunological response, consistent with that observed for other approved anti-PD-1/programmed death ligand 1 (PD-L1) antibodies. Tislelizumab did not show any evidence of inducing antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. No apparent cytokine release was noted in assays with human whole blood cells or peripheral blood mononuclear cells.

The pharmacokinetics of tislelizumab in cynomolgus monkeys showed long half-lives and limited extravascular distribution, which are typical characteristics of a monoclonal antibody.

In non-clinical toxicology studies in cynomolgus monkeys, no treatment-related toxicity was noted at single doses of up to 100 mg/kg of tislelizumab administered by intravenous infusion, or at repeated doses of up to 30 mg/kg administered by intravenous infusion every 2 weeks for 13 weeks. At high doses, moderate to severe immunogenic reactions were observed in several animals, likely due to the development of anti-drug antibodies. In two 13-week intravenous toxicology studies, cynomolgus monkeys were administered 30 mg/kg of tislelizumab. This was determined to be the no-observed-adverse-effect level (NOAEL) and represented a 5- to 8-fold higher systemic exposure (as measured by the area under the concentration-time curve [AUC]) than that observed clinically.

In cynomolgus monkeys, no safety concerns were identified in the vital functions of the cardiovascular, respiratory, or central nervous systems. No specific tissue cross-reactivity or off-target binding with tislelizumab was noted in cynomolgus monkey or human tissues.

No gross lesions or histopathological changes were noted in the reproductive organs of male or female cynomolgus monkeys in the 13-week repeat-dose study. An embryo-fetal toxicity literature-based review indicated that the pharmacologically mediated blockade of PD-1/PD-L1 interaction in animal models can result in fetal loss due to the modulation of checkpoint molecules on regulatory T cells, and therefore, reduces maternal-fetal tolerance. Furthermore, tislelizumab is a humanized immunoglobulin G4 (IgG4) variant monoclonal antibody targeted against PD-1, and IgG4 is known to cross the placental barrier. Therefore, tislelizumab has the potential to cross the placenta during pregnancy and cause harm to the fetus.

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

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

Characterization of the Drug Substance

Tislelizumab, the medicinal ingredient in Tevimbra, is a recombinant humanized monoclonal antibody based on a human immunoglobulin G4 (IgG4) framework. The monoclonal antibody binds to the human programmed cell death protein 1 (PD-1) receptor expressed mainly on T cells, B cells, and antigen-presenting cells. Tislelizumab binding to PD-1 disrupts the inhibition of PD-1 expressing cells by blocking the interactions between PD-1 and its ligands (programmed death ligand 1 [PD-L1] and PD-L2), thereby restoring the anti-tumour effector functions of the immune cells.

Detailed characterization studies were performed to provide assurance that tislelizumab consistently exhibits the desired characteristic structure and biological activity. The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

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. A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

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

The drug substance is produced using a recombinant Chinese hamster ovary cell line and a standard monoclonal antibody manufacturing process. Cells from a working cell bank are expanded and cultured in a fed-batch bioreactor. After harvest, tislelizumab is purified through protein A chromatography, viral inactivation, depth filtration, ion-exchange chromatography, and retaining viral filtration. Purified tislelizumab is concentrated and formulated, then sterile-filtered, filled into single-use bags, and stored frozen.

Tevimbra is supplied as a sterile, preservative-free solution in a single-use vial (100 mg/10 mL) for intravenous infusion after dilution. The drug product manufacturing process includes thawing the drug substance, bioburden reduction filtration, pooling, sterile filtration, aseptic vial filling, stoppering, capping, visual inspection, and storage at 2 °C to 8 °C. None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

Process validation studies were conducted. All critical process parameters, in-process controls, and release testing results met pre-established acceptance criteria across all validation batches. No critical deviations were reported that could impact product quality and process validation. Ancillary validation studies were performed to support in-process hold times, impurity clearance, resin and membrane reuse, extractables and leachables, media fills, and shipping. The process validation data collectively confirm that the commercial manufacturing processes consistently yield drug substance and drug product batches that comply with established specifications and quality standards.

Control of the Drug Substance and Drug Product

The control strategy for Tevimbra consists of several control elements including control of materials, process parameters, in-process controls, release specifications, as well as facility and equipment controls.

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 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

Tevimbra is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

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 36-month shelf life is acceptable when Tevimbra is stored between 2 °C and 8 °C and protected from light. For the diluted solution, the in-use hold time is 20 hours when stored between 2 °C and 8 °C, followed by up to 4 hours at room temperature (a maximum of 25 °C), including time for infusion.

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 all facilities and equipment involved in the production are considered suitable. The manufacturing sites are compliant with current good manufacturing practices.

An on-site evaluation (OSE) of the facilities involved in the manufacture and testing of the drug substance and drug product was not conducted as the review of the quality component of the New Drug Submission for Tevimbra was based primarily on the foreign reviews completed by the United States Food and Drug Administration and Australia's Therapeutic Goods Administration.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure absence of adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Raw materials of animal and recombinant deoxyribonucleic acid origin used in the manufacturing process are adequately tested to ensure absence of adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.