Summary Basis of Decision (SBD) for Opdualag

Clinical Pharmacology

Opdualag is a fixed-dose combination of two immune checkpoint inhibitors, nivolumab and relatlimab.

The submitted population pharmacokinetic studies characterized the pharmacokinetics of nivolumab and relatlimab, compared key measures of nivolumab and relatlimab exposures among different dosing regimens, and characterized the relationship between relatlimab concentrations and biomarkers, efficacy, and safety in patients with advanced solid tumours. In addition, these studies provided the basis for extrapolating the efficacy and safety data for the fixed-dose combination of nivolumab and relatlimab in adults with advanced (unresectable or metastatic) melanoma to pediatric patients aged 12 years and older with advanced melanoma.

Following the recommended dosage regimen of 480 mg nivolumab and 160 mg relatlimab every 4 weeks, steady-state concentrations of relatlimab were reached by 16 weeks with 1.9-fold systemic accumulation.

Body weight was a significant covariate on the nivolumab and relatlimab pharmacokinetics. However, the difference in exposure among patients with varying body weights was not deemed clinically relevant. No evidence suggested that efficacy and safety of Opdualag were affected in patients with extremely high or low body weights.

Mild and moderate hepatic or renal impairment had no clinically important effect on the clearance of nivolumab and relatlimab. The number of patients with severe hepatic or renal impairment was too small to permit evaluation of the effect of these conditions on the pharmacokinetics of nivolumab and relatlimab.

The presence of anti-drug antibodies did not appear to have a clinically relevant impact on the efficacy and safety of relatlimab.

A flat exposure-response relationship was observed over a range of nivolumab and relatlimab concentrations produced by different dosing regimens. The addition of relatlimab to nivolumab treatment significantly increased progression-free survival and objective response compared to nivolumab monotherapy. The exposure-response safety analyses showed that the combination of nivolumab and relatlimab significantly increased the risks of Grade 2 or higher immune-mediated adverse events and Grade 3 or higher drug-related adverse events compared to nivolumab monotherapy. The increase in risks of these adverse events was similar across the range of relatlimab exposures produced by the combination dosing regimens studied.

Although the pivotal clinical trial CA224047 allowed for enrollment of patients 12 years of age or older, no pediatric patients were enrolled. Therefore, the benefit-risk profile of Opdualag in pediatric patients 12 years of age or older was extrapolated from the data in the adult study population. The extrapolation was justified by the similarities between adult and adolescent patients in the disease course of unresectable or metastatic melanoma and the pharmacokinetics of nivolumab and relatlimab.

A population pharmacokinetics-based extrapolation study was performed to support the recommended dose of Opdualag in adolescents aged 12 to under 18 years, using a model-based simulation. Relatlimab pharmacokinetic data in the adolescent population were not available. Given the overall similarity in the pharmacokinetic characteristics of nivolumab and relatlimab, the available data on nivolumab clearance in adolescent patients were used to predict relatlimab clearance in this patient population. At the recommended dose of Opdualag, no clinically meaningful differences in the exposure of nivolumab and relatlimab are expected between adults and pediatric patients 12 years of age or older and weighing at least 40 kg; therefore, the efficacy and safety of Opdualag are expected to be similar in adults and adolescents.

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

Clinical Efficacy

The clinical efficacy of Opdualag was evaluated based on the results of the pivotal trial CA224047, a randomized, double-blind, Phase II/III study in patients with previously untreated unresectable or metastatic melanoma. While the study design allowed for inclusion of pediatric patients 12 years of age or older, there were no pediatric patients enrolled. Patients were randomized (1:1) to receive Opdualag (nivolumab 480 mg and relatlimab 160 mg) by intravenous infusion every 4 weeks (355 patients) or nivolumab 480 mg by intravenous infusion every 4 weeks (359 patients). Randomization was stratified by tumour programmed cell death ligand-1 (PD-L1) expression levels (≥1% versus <1%), LAG-3 expression levels (≥1% versus <1%), BRAF (B-Raf proto-oncogene, serine/threonine kinase) V600 mutation status (BRAF V600 mutation-positive versus BRAF wild-type tumour), and M (distant metastasis) stage per the American Joint Committee on Cancer version 8 staging system (M0 with either normal or elevated lactate dehydrogenase [LDH] and all M1 with normal LDH [0] versus all M1 with elevated LDH only [1]).

The primary endpoint of the study was progression-free survival assessed by a blinded independent central review. Secondary endpoints included overall survival and objective response rate. At the primary analysis of progression-free survival, after a median follow-up of 13.2 months, a statistically significant improvement in progression-free survival was demonstrated for patients randomized to the Opdualag arm compared with those randomized to the nivolumab arm (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.62, 0.92; p = 0.0055). The median progression-free survival was 10.1 months (95% CI: 6.4, 15.7) for the Opdualag arm compared to 4.6 months (95% CI: 3.4, 5.6) for the nivolumab arm, representing an improvement of 5.5 months in median progression-free survival. The result of the final analysis of overall survival, after a median follow-up of 19.9 months, was not statistically significant (HR: 0.80, 95% CI: 0.64, 1.01). Median overall survival was not reached (95% CI: 34.2, not reached [NR]) in the Opdualag arm, and it was 34.1 months (95% CI: 25.2, NR) in the nivolumab arm. A higher percentage of patients in the Opdualag arm (43% [95% CI: 38, 48]) achieved objective response compared with the nivolumab arm (33% [95% CI: 28, 38]).

In an exploratory analysis of progression-free survival for the subgroups defined by the tumour PD-L1 expression levels (≥1% versus <1%), the HRs were 0.95 (95% CI: 0.68, 1.33) and 0.66 (95% CI: 0.51, 0.84), respectively. While these results suggest a potential increased benefit of Opdualag in patients with tumour PD-L1 expression levels lower than 1%, the limitations of subgroup analyses preclude conclusions based on tumour PD-L1 expression status. Furthermore, the results do not exclude the possibility that patients with tumour PD-L1 expression levels of 1% or greater could derive benefit from Opdualag. Indeed, subgroup analysis of overall survival indicates an HR of 0.84 (95% CI: 0.57, 1.24) for the subgroup with tumour PD-L1 expression levels of 1% or greater and an HR of 0.78 (95% CI: 0.59, 1.04) for the subgroup with tumour PD-L1 expression levels lower than 1%. Thus, from the clinical and statistical perspectives, the results support the efficacy of Opdualag irrespective of the tumour PD-L1 expression status.

Indication

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

Opdualag (nivolumab and relatlimab) is indicated for the treatment of adult and pediatric patients (12 years and older and weighing at least 40 kg) with unresectable or metastatic melanoma.

Following the review of the submitted data, Health Canada revised the proposed indication to refer to patients with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma. Accordingly, Health Canada approved the following indication:

Opdualag (nivolumab and relatlimab) is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma who have not received prior systemic therapy for unresectable or metastatic melanoma.

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

Clinical Safety

The safety of Opdualag was assessed in 355 adult patients with previously untreated unresectable or metastatic melanoma in the pivotal clinical trial CA224047 (described in the Clinical Efficacy section). The median duration of treatment was 8.3 months (range: 0 to 38.8 months). In the Opdualag treatment arm, 54.9% of patients received Opdualag for at least 6 months and 38% of patients received Opdualag for at least 1 year. The exposure is considered adequate for the assessment of safety of Opdualag at the recommended clinical dosage.

The most frequently reported adverse reactions in patients treated with Opdualag (occurring with an incidence of 15% or greater) were fatigue, musculoskeletal pain, rash, pruritus, arthralgia, diarrhea, headache, nausea, hypothyroidism, cough, and decreased appetite. These adverse reactions are consistent with the known safety profile of nivolumab and the mechanism of action of relatlimab. Serious adverse reactions occurred in 34% of patients treated with Opdualag compared to 28% of patients treated with nivolumab. The most frequently reported serious adverse reactions in patients treated with Opdualag (occurring with an incidence of 1% or greater) were adrenal insufficiency, anemia, myocarditis, colitis, diarrhea, pneumonia, urinary tract infection, and back pain. Fatal adverse reactions considered potentially related to treatment with Opdualag occurred in 4 (1.1%) patients and included hemophagocytic lymphohistiocytosis, acute edema of the lung, pneumonitis, and multiorgan failure. Adverse reactions leading to discontinuation of study therapy were reported more frequently in the Opdualag arm (19.2%) compared with the nivolumab arm (11.7%). The increase in the rates of serious adverse reactions and adverse reactions resulting in discontinuation observed in Opdualag-treated patients was anticipated given that Opdualag is a combination therapy.

Immune-mediated adverse reactions, in some cases severe or fatal, were reported with Opdualag. These adverse reactions were consistent with the established safety profile for immune checkpoint inhibitor therapies. There were no unexpected safety signals identified. The risk of immune-mediated adverse reactions has been specifically addressed in a Serious Warnings and Precautions box in the Opdualag Product Monograph. In addition, recommendations for the management of immune-mediated adverse reactions have been included in the Opdualag Product Monograph.

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

Opdualag is a fixed-dose combination of two immune checkpoint inhibitors, nivolumab and relatlimab. Health Canada’s review of the non-clinical data package of the Opdualag submission focused on the provided non-clinical studies of relatlimab, as nivolumab (Opdivo), an antibody directed against programmed cell death-1 (PD-1) receptor (anti-PD-1 antibody), has been authorized in Canada for the treatment of unresectable or metastatic melanoma.

In vitro functional studies demonstrated that relatlimab binds specifically and with high affinity to the loop insertion sequence of the D1 domain of the receptor known as human lymphocyte-activation gene 3 (LAG-3) to inhibit the negative regulatory function of LAG-3. The antitumour activity of anti-LAG-3 antibody used as a single agent or in combination with an anti-PD-1 antibody was demonstrated in vivo in murine tumour models using murine surrogate anti-LAG-3 antibodies since relatlimab does not cross-react with mouse LAG-3. In these models, the coadministration of anti-LAG-3 antibody and anti-PD-1 antibody exhibited greater antitumour activity compared to the administration of anti-LAG-3 antibody alone.

The results from a single-dose and various repeat-dose toxicokinetic studies in cynomolgus monkeys showed that systemic exposure to relatlimab was similar in males and females and increased in a dose-proportional manner. In repeat-dose toxicity studies, it was observed that monkeys receiving relatlimab (up to 100 mg/kg) or relatlimab (100 mg/kg) in combination with nivolumab (50 mg/kg) had increased drug exposure consistent with antibody accumulation following repeat dosing. While treatment-emergent anti-drug antibodies were detected for relatlimab, their presence did not substantially affect the toxicokinetics of relatlimab or nivolumab.

Safety pharmacology assessments were conducted as part of the repeat-dose toxicology studies. No relatlimab- or nivolumab-related adverse effects on cardiovascular, respiratory, and neurologic functions were observed when relatlimab was administered alone at doses of up to 100 mg/kg or in combination with nivolumab administered at doses of up to 50 mg/kg, or when nivolumab was administered as a single agent at doses of up to 50 mg/kg.

In single-dose and repeat-dose toxicity studies in monkeys, the volume of distribution of relatlimab at steady state ranged from 62 to 79 mL/kg, suggesting limited extravascular distribution.

Reproductive and developmental toxicity studies were performed in mice with murine surrogate anti-LAG-3 antibodies. Repeat-dose toxicity studies conducted in cynomolgus monkeys revealed no notable changes in male or female reproductive organs; however, in the 1-month repeat-dose toxicity study in which animals received nivolumab and relatlimab, one male had inflammation within the central nervous system (choroid plexus, vasculature of the brain parenchyma, meninges, spinal cord) and the reproductive tract (epididymis, seminal vesicles, and testes) associated with clinical signs that necessitated euthanasia. These observations have been included in the Opdualag Product Monograph.

Despite the lack of definitive evidence of negative effects of relatlimab on pregnancy and embryo-fetal development in the non-clinical studies, the risk of adverse effects on pregnancy associated with the coadministration of nivolumab and relatlimab has been highlighted in the Opdualag Product Monograph. Checkpoint targets, including LAG-3, are likely to have a role in maintaining maternal tolerance to the developing fetus, and nivolumab has been shown to increase third trimester pregnancy loss in cynomolgus monkeys. Based on the mechanism of action, inhibition of LAG-3 with relatlimab can have a similar negative effect on pregnancy. Furthermore, human immunoglobulin G4 (IgG4) is known to cross the placenta and since both nivolumab and relatlimab are IgG4 antibodies, they have the potential to be transmitted from the mother to the developing fetus. Accordingly, the Opdualag Product Monograph specifies that the use of Opdualag is not recommended during pregnancy and in women of childbearing potential not using effective contraception.

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

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

Characterization of the Drug Substances

Opdualag is a fixed-dose combination of two human immunoglobulin G4 (IgG4) monoclonal antibodies, nivolumab and relatlimab.

Nivolumab binds to the programmed cell death 1 (PD-1) receptor on T cells and blocks its interaction with its ligands, PD-L1 and PD-L2, expressed on tumour cells, thereby reducing PD-1 pathway-mediated inhibition of the immune response. The antibody consists of four polypeptide chain that include two identical heavy chains and two identical kappa light chains, covalently linked through disulfide bonds. The calculated molecular weight of nivolumab is 146,221 Da. Nivolumab (Opdivo) has been authorized in Canada for the treatment of unresectable or metastatic melanoma.

Relatlimab binds to the lymphocyte-activation gene 3 (LAG-3) receptor on T cells, blocks its interaction with ligands, and reduces LAG-3 pathway-mediated inhibition of the immune response. It consists of four polypeptide chains (two identical heavy chains and two identical kappa light chains, covalently linked through disulfide bonds) and has a calculated molecular weight of 148,178 Da.

Of note, the nivolumab protein used for manufacture of Opdualag is the same as the protein used for manufacture of the authorized drug product Opdivo. However, the protein used for manufacture of Opdivo is formulated in a citrate-based buffer (and herein referred to as nivolumab-citrate), while the protein used for manufacture of Opdualag is formulated at a higher concentration in a histidine-based buffer (and herein referred to as nivolumab-histidine). The change in formulation buffer enables combination of nivolumab with relatlimab in a single vial using the same buffer system. Extended characterization studies demonstrated comparability between nivolumab-histidine and nivolumab-citrate drug substances and supported consistent biological activity of the nivolumab molecule, irrespective of the formulation matrix.

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

In addition, extended characterization studies demonstrated that combining the two protein components in Opdualag does not affect their respective physicochemical and biological properties, and does not lead to any protein-protein interactions beyond those observed for the individual protein components.

The product- and process-related impurities that were reported and characterized were found to be within established limits.

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

The nivolumab-histidine and relatlimab drug substances are produced using respective genetically engineered Chinese hamster ovary (CHO) cell lines. The proteins are secreted products of the CHO cells cultured in fed-batch production bioreactors. After completion of the cell culture process, the secreted monoclonal antibody is purified from the harvest material by a series of chromatography, viral inactivation, and ultrafiltration/diafiltration steps. Subsequently, the purified drug substance is formulated, filtrated, filled into bioprocess containers, and stored frozen at -50 °C to -70 °C.

In comparison to the manufacturing process of nivolumab-citrate drug substance, the manufacturing process of nivolumab-histidine drug substance includes changes to accommodate a different drug substance formulation (protein concentration and final formulation matrix), enable frozen storage of the drug substance, and to align with the manufacturing facilities. Comparability studies demonstrated that the two manufacturing processes produced comparable nivolumab drug substances.

Process validation of the relatlimab manufacturing process consisted of three consecutive commercial-scale batches, followed by three additional batches used to validate process and equipment changes introduced after the initial validation. Process validation of the nivolumab-histidine manufacturing process consisted of four consecutive commercial-scale batches. Deviations during process validation of the nivolumab-histidine and relatlimab manufacturing processes were appropriately investigated and corrective actions were implemented where appropriate. Process validation results for the nivolumab-histidine and relatlimab manufacturing processes met the predefined acceptance criteria for all process parameters, in-process controls, release testing, characterization, and stability. The sponsor has demonstrated that the drug substance manufacturing facility is capable of consistently manufacturing nivolumab-histidine and relatlimab of acceptable quality.

The manufacturing process of the drug product, Opdualag, includes thawing of the two drug substances, mixing, pooling, and diluting to a target total protein concentration of 16 mg/mL, followed by bioburden reduction filtration, sterile filtration, filling into vials, capping, sealing with aluminum seals, visual inspection, and packaging. The drug product is stored at 2 °C to 8 °C. Three process validation lots of the drug product were manufactured at the proposed commercial-scale range, and met the predefined acceptance criteria and proposed commercial limits for all process parameters, in-process controls, release testing, and stability. The sponsor has demonstrated that the drug product manufacturing facility is capable of consistently manufacturing Opdualag of acceptable quality.

The criticality and ranges of process parameters, in-process controls, and quality attributes were appropriately assigned for the relatlimab drug substance, nivolumab-histidine drug substance, and Opdualag drug product. They were based on process development and characterization studies, and (in the case of the nivolumab-histidine drug substance) the sponsor’s past experience with the manufacturing of Opdivo. In addition, the process validation studies support the proposed commercial ranges. Extensive comparability studies were conducted, and all processes were found to be comparable in terms of product quality and consistency.

Control of the Drug Substances and Drug Product

Specifications established for the nivolumab-histidine drug substance, relatlimab drug substance, and Opdualag drug product were based on historical data and clinical experience, and are considered suitable for control of the drug substances and the drug product. Compendial methods were verified, and all the in-house methods were appropriately validated and/or transferred to their respective testing sites.

Opdualag 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 Substances and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substances and drug product were adequately supported and are considered to be satisfactory.

The stability data support the proposed shelf life of 48 months for nivolumab-histidine and relatlimab drug substances, when they are stored protected from light at -60 °C, and 36 months for Opdualag, when the drug product is stored protected from light at 2 °C to 8 °C.

The compatibility of the drug product with the primary container closure system was demonstrated through stability studies and extractables and leachables studies.

Facilities and Equipment

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

Based on the risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and the drug product manufacturing facilities were not deemed necessary.

The sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The manufacturing processes of nivolumab and relatlimab drug substances and the drug product Opdualag incorporate adequate control measures to prevent introduction of non-viral and viral adventitious agents.

The master cell banks, working cell banks, and end-of-production cell banks are tested according to relevant guidelines to demonstrate sterility. In addition, pre-harvest culture fluid from each lot is tested for bioburden, endotoxin, mycoplasma, minute virus of mice (MVM), and other potential adventitious viral agents. Purification process steps designed to remove and inactivate viruses are adequately validated.

No animal-derived and human-derived raw materials are used in the manufacture of the drug substance and drug product. In addition, the excipients in the drug product formulation are not of animal or human origin.