Opdualag 240 mg/80 mg concentrate for solution for infusion

Opdualag is indicated for the first line treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older.

Treatment must be initiated and supervised by physicians experienced in the treatment of cancer.

Patients treated with Opdualag must be given the patient card and be informed about the risks of Opdualag (see also package leaflet).

Posology

The recommended dose for adults and adolescents 12 years of age and older is 480 mg nivolumab and 160 mg relatlimab every 4 weeks administered as an intravenous infusion over 30 minutes. This dose is established for adolescent patients weighing at least 30 kg (see section 5.2).

Treatment with Opdualag should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient. Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability. Guidelines for permanent discontinuation or withholding of doses are described in Table 1. Detailed guidelines for the management of immune-related adverse reactions are described in section 4.4.

Table 1: Recommended treatment modifications for Opdualag

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5).

^a Recommendation for the use of hormone replacement therapy is provided in section 4.4.

^b The safety of re-initiating Opdualag in patients previously experiencing immune-related myocarditis is not known.

Special populations

Paediatric population

The safety and efficacy of Opdualag in children below 12 years of age have not been established. No data are available (see section 5.2).

Elderly

No dose adjustment is required for elderly patients (≥ 65 years) (see section 5.2).

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2). Data from patients with severe renal impairment are too limited to draw conclusions on this population.

Hepatic impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment (see section 5.2). Data from patients with severe hepatic impairment are too limited to draw conclusions on this population.

Method of administration

Opdualag is for intravenous use only. It is to be administered as an intravenous infusion over a period of 30 minutes.

Opdualag must not be administered as an intravenous push or bolus injection.

Opdualag can be used without dilution, or may be diluted with sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for injection (see section 6.6).

For instructions on the preparation and handling of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Immune-related adverse reactions

Immune-related adverse reactions can occur with nivolumab in combination with relatlimab which require appropriate management, including initiation of corticosteroids and treatment modifications (see section 4.2).

Immune-related adverse reactions affecting more than one body system can occur simultaneously.

Patients should be monitored continuously (at least up to 5 months after the last dose) as an adverse reaction with Opdualag may occur at any time during or after discontinuation of therapy.

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, Opdualag should be withheld and corticosteroids administered. If immunosuppression with corticosteroids is used to treat an adverse reaction, a taper of at least 1 month duration should be initiated upon improvement. Rapid tapering may lead to worsening or recurrence of the adverse reaction. Non-corticosteroid immunosuppressive therapy should be added if there is worsening or no improvement despite corticosteroid use.

Opdualag should not be resumed while the patient is receiving immunosuppressive doses of corticosteroids or other immunosuppressive therapy. Prophylactic antibiotics may be used to prevent opportunistic infections in patients receiving immunosuppressive therapy.

Opdualag must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.

Immune-related pneumonitis

Severe pneumonitis or interstitial lung disease, including a fatal case, has been observed with nivolumab in combination with relatlimab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis such as radiographic changes (e.g. focal ground glass opacities, patchy infiltrates), dyspnoea, and hypoxia. Infectious and disease-related aetiologies should be ruled out.

For Grade 3 or 4 pneumonitis, Opdualag must be permanently discontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents.

For Grade 2 (symptomatic) pneumonitis, Opdualag should be withheld and corticosteroids initiated at a dose of 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents, and Opdualag must be permanently discontinued.

Immune-related colitis

Severe diarrhoea or colitis has been observed with nivolumab in combination with relatlimab (see section 4.8). Patients should be monitored for diarrhoea and additional symptoms of colitis, such as abdominal pain and mucus and/or blood in stool. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-related colitis. Infectious and other aetiologies of diarrhoea should be ruled out, therefore appropriate laboratory tests and additional examinations must be performed. If diagnosis of corticosteroid-refractory immune-related colitis is confirmed, addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy should be considered.

For Grade 4 diarrhoea or colitis, Opdualag must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

Opdualag should be withheld for Grade 3 diarrhoea or colitis, and corticosteroids initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, Opdualag must be permanently discontinued.

For Grade 2 diarrhoea or colitis, Opdualag should be withheld. Persistent diarrhoea or colitis should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and Opdualag must be permanently discontinued.

Immune-related hepatitis

Severe hepatitis has been observed with nivolumab in combination with relatlimab (see section 4.8). Patients should be monitored for signs and symptoms of hepatitis such as transaminase and total bilirubin elevations. Infectious and disease-related aetiologies should be ruled out.

For AST or ALT increases to more than 5 times ULN regardless of baseline, total bilirubin increases to more than 3 times ULN, or concurrent AST or ALT increase to more than 3 times ULN and total bilirubin increase to more than 2 times ULN, Opdualag must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

For AST/ALT increases to more than 3 and up to 5 times ULN, or total bilirubin increases to more than 1.5 and up to 3 times ULN, Opdualag should be withheld. Persistent elevations in these laboratory values should be managed with corticosteroids at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may be resumed after corticosteroid taper, if needed. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and Opdualag must be permanently discontinued.

Immune-related nephritis and renal dysfunction

Severe nephritis and renal dysfunction have been observed with nivolumab in combination with relatlimab (see section 4.8). Patients should be monitored for signs and symptoms of nephritis or renal dysfunction. Most patients present with asymptomatic increases in serum creatinine. Disease-related aetiologies should be ruled out.

For Grade 4 serum creatinine elevation, Opdualag must be permanently discontinued, and corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

For Grade 2 or 3 serum creatinine elevation, Opdualag should be withheld, and corticosteroids should be initiated at a dose of 0.5 to 1 mg/kg/day methylprednisolone equivalents. Upon improvement, Opdualag may be resumed after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 1 to 2 mg/kg/day methylprednisolone equivalents, and Opdualag must be permanently discontinued.

Immune-related endocrinopathies

Severe endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency (including secondary adrenocortical insufficiency), hypophysitis (including hypopituitarism), and diabetes mellitus have been observed with nivolumab in combination with relatlimab. Cases of diabetic ketoacidosis have been observed with nivolumab monotherapy and could potentially occur with nivolumab in combination with relatlimab (see section 4.8).

Patients should be monitored for clinical signs and symptoms of endocrinopathies, and for hyperglycaemia and changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation). Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate aetiology has been identified, signs or symptoms of endocrinopathies should be considered immune-related.

Thyroid dysfunction

For symptomatic hypothyroidism, Opdualag should be withheld, and thyroid hormone replacement should be initiated as needed. For symptomatic hyperthyroidism, Opdualag should be withheld and antithyroid treatment should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the thyroid is suspected. Upon improvement, Opdualag may be resumed after corticosteroid taper, if needed. Monitoring of thyroid function should continue to ensure appropriate hormone replacement is utilised. Opdualag must be permanently discontinued for life-threatening (Grade 4) hyperthyroidism or hypothyroidism.

Adrenal insufficiency

Opdualag must be permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. For symptomatic Grade 2 adrenal insufficiency, Opdualag should be withheld, and physiologic corticosteroid replacement should be initiated as needed. Monitoring of adrenal function and hormone levels should continue to ensure appropriate corticosteroid replacement is utilised.

Hypophysitis

Opdualag must be permanently discontinued for life-threatening (Grade 4) hypophysitis. For symptomatic Grade 2 or 3 hypophysitis, Opdualag should be withheld, and hormone replacement should be initiated as needed. Corticosteroids at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents should also be considered if acute inflammation of the pituitary gland is suspected. Upon improvement, Opdualag may be resumed after corticosteroid taper, if needed. Monitoring of pituitary function and hormone levels should continue to ensure appropriate hormone replacement is utilised.

Diabetes mellitus

For symptomatic diabetes, Opdualag should be withheld, and insulin replacement should be initiated as needed. Monitoring of blood sugar should continue to ensure appropriate insulin replacement is utilised. Opdualag must be permanently discontinued for life-threatening diabetes.

Immune-related skin adverse reactions

Severe rash has been observed with nivolumab in combination with relatlimab (see section 4.8). Opdualag should be withheld for Grade 3 rash and discontinued for Grade 4 rash. Severe rash should be managed with high-dose corticosteroid at a dose of 1 to 2 mg/kg/day methylprednisolone equivalents.

Rare cases of SJS and TEN, some of them with fatal outcome, have been observed with nivolumab monotherapy and could potentially occur with nivolumab in combination with relatlimab. If symptoms or signs of SJS or TEN are suspected, Opdualag should be withheld and the patient referred to a specialised unit for assessment and treatment. If the patient has confirmed SJS or TEN with the use of Opdualag, permanent discontinuation of treatment is recommended (see section 4.2).

Caution should be used when considering the use of Opdualag in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents.

Immune-related myocarditis

Severe immune-related myocarditis has been observed with nivolumab in combination with relatlimab. The diagnosis of myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, prompt initiation of a high dose of steroids (prednisone 1 to 2 mg/kg/day or methylprednisolone 1 to 2 mg/kg/day) and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be initiated. Once a diagnosis of myocarditis is established, Opdualag should be withheld or permanently discontinued as described below.

For Grade 3 or 4 myocarditis, Opdualag must be permanently discontinued, and corticosteroids should be initiated at a dose of 2 to 4 mg/kg/day methylprednisolone equivalents (see section 4.2).

For Grade 2 myocarditis, Opdualag should be withheld and corticosteroids initiated at a dose of 1 to 2 mg/kg/day methylprednisolone equivalent. Upon improvement, resumption of Opdualag may be considered after corticosteroid taper. If worsening or no improvement occurs despite initiation of corticosteroids, corticosteroid dose should be increased to 2 to 4 mg/kg/day methylprednisolone equivalents, and Opdualag must be permanently discontinued (see section 4.2).

Other immune-related adverse reactions

The following clinically significant immune-related adverse reactions have been rarely reported in patient treated with nivolumab in combination with relatlimab: uveitis, pancreatitis, Guillain-Barré syndrome, myositis/rhabdomyolysis, encephalitis, haemolytic anaemia, Vogt-Koyanagi-Harada syndrome (VKH).

The following additional clinically significant immune-related adverse reactions have been rarely reported with nivolumab monotherapy or nivolumab in combination with other approved agents: demyelination, autoimmune neuropathy (including facial and abducens nerve paresis), myasthenia gravis, myasthenic syndrome, aseptic meningitis, gastritis, sarcoidosis, duodenitis, hypoparathyroidism, and cystitis noninfective.

For suspected immune-related adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, Opdualag should be withheld and corticosteroids administered. Upon improvement, Opdualag may be resumed after corticosteroid taper. Opdualag must be permanently discontinued for any severe immune-related adverse reaction that recurs and for any life-threatening immune-related adverse reaction.

Other important warnings and precautions, including class effects

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. Treatment with nivolumab in combination with relatlimab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with nivolumab in combination with relatlimab versus the risk of possible organ rejection should be considered in these patients.

Haemophagocytic lymphohistiocytosis (HLH) has been observed with nivolumab as monotherapy, nivolumab in combination with relatlimab and nivolumab in combination with other agents with a fatal event reported with nivolumab in combination with relatlimab. Caution should be taken when administering nivolumab in combination with relatlimab. If HLH is confirmed, administration of nivolumab in combination with relatlimab should be discontinued and treatment for HLH initiated.

In patients treated with nivolumab before or after allogeneic Haematopoietic Stem Cell Transplantation (HSCT), rapid-onset and severe graft-versus-host disease (GVHD), some with fatal outcome, have been reported. Treatment with nivolumab in combination with relatlimab may increase the risk of severe GVHD and death in patients who have had prior allogeneic HSCT, mainly in those with prior history of GVHD. The benefit of treatment with nivolumab in combination with relatlimab versus the possible risk should be considered in these patients.

Infusion reactions

Severe infusion reactions have been reported in clinical studies of nivolumab in combination with relatlimab (see section 4.8). In case of a severe or life-threatening infusion reaction, Opdualag infusion must be discontinued and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may receive Opdualag with close monitoring and preventative treatment according to local guidelines for prophylaxis of infusion reactions.

Patients excluded from pivotal advanced melanoma clinical study

Patients with active autoimmune disease, medical conditions requiring systemic treatment with moderate or high dose corticosteroids or immunosuppressive medicinal products, uveal melanoma, active or untreated brain, or leptomeningeal metastases, and those with a history of myocarditis, elevated troponin levels > 2 times ULN or ECOG performance status score ≥ 2, were excluded from the pivotal clinical study of nivolumab in combination with relatlimab. In the absence of data, nivolumab in combination with relatlimab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.

Patient card

The prescriber must discuss the risks of Opdualag therapy with the patient. The patient will be provided with the patient card and instructed to carry the card at all times.

Nivolumab and relatlimab are both human monoclonal antibodies and as such, no interaction studies have been conducted. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other active substances metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal products is not anticipated to affect the pharmacokinetics of relatlimab or nivolumab.

Nivolumab and relatlimab are not expected to affect the pharmacokinetics of other active substances that are metabolised by CYP enzymes given the lack of significant modulation of cytokines by nivolumab and relatlimab and therefore lack of effect on expression of cytochrome P450 enzyme.

Systemic immunosuppression

The use of systemic corticosteroids and other immunosuppressants at baseline, before starting nivolumab in combination with relatlimab, should be avoided because of their potential interference with the pharmacodynamic activity. However, systemic corticosteroids and other immunosuppressants can be used after starting nivolumab in combination with relatlimab to treat immune-related adverse reactions.

Women of childbearing potential/Contraception

Opdualag is not recommended in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk. Effective contraception should be used for at least 5 months following the last dose of Opdualag.

Pregnancy

There is a limited amount of data from the use of nivolumab in combination with relatlimab in pregnant women. Based on its mechanism of action and data from animal studies, nivolumab in combination with relatlimab can cause foetal harm when administered to a pregnant woman. Studies in animals receiving nivolumab have shown embryofoetal toxicity (see section 5.3). Human IgG4 is known to cross the placental barrier and nivolumab and relatlimab are an IgG4; therefore, nivolumab and relatlimab have the potential to be transmitted from the mother to the developing foetus. Opdualag is not recommended during pregnancy and in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk.

Breast-feeding

It is unknown whether nivolumab and/or relatlimab are excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. Afterwards, Opdualag could be used during breast-feeding if clinically needed.

Fertility

Studies to evaluate the effect of nivolumab and/or relatlimab on fertility have not been performed. Thus, the effect of nivolumab and/or relatlimab on male and female fertility is unknown.

Opdualag has a minor influence on the ability to drive and use machines. Because of potential adverse reactions such as fatigue and dizziness (see section 4.8), patients should be advised to use caution when driving or operating machines until they are certain that Opdualag does not adversely affect them.

Summary of the safety profile

Nivolumab in combination with relatlimab is associated with immune-related adverse reactions (see “ Description of selected adverse reactions” below). The management guidelines for these adverse reactions are described in section 4.4.

The most common adverse reactions are fatigue (41%), musculoskeletal pain (32%), rash (29%), arthralgia (26%), diarrhoea (26%), pruritus (26%), headache (20%), nausea (19%), cough (16%), decreased appetite (16%), hypothyroidism (16%), abdominal pain (14%), vitiligo (13%), pyrexia (12%), constipation (11%), urinary tract infection (11%), dyspnoea (10%), and vomiting (10%).

The most common serious adverse reactions are adrenal insufficiency (1.4%), anaemia (1.4%), back pain (1.1%), colitis (1.1%), diarrhoea (1.1%), myocarditis (1.1%), pneumonia (1.1%), and urinary tract infection (1.1%). Incidences of Grade 3-5 adverse reactions in patients with advanced (unresectable or metastatic) melanoma were 43% for nivolumab in combination with relatlimab and 35% for nivolumab treated patients.

Tabulated summary of adverse reactions

The safety of nivolumab in combination with relatlimab has been evaluated in 355 patients with advanced (unresectable or metastatic) melanoma (study CA224047). Adverse reactions reported in the dataset for patients treated with nivolumab in combination with relatlimab, with a median follow-up of 19.94 months, are presented in Table 2. The frequencies included above and in Table 2 are based on all-cause adverse event frequencies. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 2: Adverse reactions in clinical studies

^a Frequencies of laboratory terms reflect the proportion of patients who experienced a worsening from baseline in laboratory measurements.

^b Fatal case has been reported in the clinical study.

Description of selected adverse reactions

Immune-related pneumonitis

In patients treated with nivolumab in combination with relatlimab, pneumonitis, including interstitial lung disease and lung infiltration occurred in 5.1% of patients. Incidences of Grade 3/4 events were 0.8%. Fatal events occurred in 0.28% of patients. Median time to onset was 28 weeks (range: 3.6-94.4). Resolution occurred in 83.3% patients with a median time to resolution of 12.0 weeks (range: 2.1-29.7⁺). Immune-related pneumonitis led to permanent discontinuation of nivolumab in combination with relatlimab in 1.7% of patients and required high dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) in 55.6% of patients with immune-related pneumonitis.

Immune-related colitis

In patients treated with nivolumab in combination with relatlimab, diarrhoea, colitis, or frequent bowel movements occurred in 15.8% of patients. Incidences of Grade 3/4 events were 2.0%. Median time to onset was 14 weeks (range: 0.1-95.6). Resolution occurred in 92.7% patients with a median time to resolution of 3.9 weeks (range: 0.1-136.9⁺). Immune-related colitis led to permanent discontinuation of nivolumab in combination with relatlimab in 2.0% of patients and required high dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) in 33.9% of patients with immune-related colitis.

Immune-related hepatitis

In patients treated with nivolumab in combination with relatlimab, liver function test abnormalities occurred in 13.2% of patients. Incidences of Grade 3/4 events were 3.9%. Median time to onset was 11 weeks (range: 2.0-144.9). Resolution occurred in 78.7% patients with a median time to resolution of 6.1 weeks (range: 1.0-88.1⁺). Immune-related hepatitis led to permanent discontinuation of nivolumab in combination with relatlimab in 2.0% of patients and required high dose corticosteroids in 38.3% of patients with immune-related hepatitis.

Immune-related nephritis and renal dysfunction

In patients treated with nivolumab in combination with relatlimab, nephritis or renal dysfunction occurred in 4.5% of patients. Incidences of Grade 3/4 events were 1.4%. Median time to onset was 21 weeks (range: 1.9-127.9). Resolution occurred in 81.3% patients with a median time to resolution of 8.1 weeks (range: 0.9-91.6⁺). Immune-related nephritis and renal dysfunction led to permanent discontinuation of nivolumab in combination with relatlimab in 1.1% of patients and required high dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) in 25.0% of patients with immune-related nephritis and renal dysfunction.

Immune-related endocrinopathies

In patients treated with nivolumab in combination with relatlimab, endocrinopathies occurred in 26% of patients.

Thyroid disorders, including hypothyroidism or hyperthyroidism, occurred in 20.8% of patients. There were no incidences of Grade 3/4 thyroid disorder. Adrenal insufficiency (including adrenocortical insufficiency acute) occurred in 4.8% of patients. Incidences of Grade 3/4 events adrenal insufficiency occurred in 1.4%. There were no incidences of Grade 3/4 hypopituitarism. Hypophysitis occurred in 1.1% of patients. Incidence of Grade 3/4 hypophysitis were 0.3%. Diabetes mellitus (including Type 1 diabetes mellitus) occurred in 0.3% of patients. Incidences of Grade 3/4 diabetes mellitus were in 0.3%.

Median time to onset of these endocrinopathies was 13 weeks (range: 1.0-73.0). Resolution occurred in 27.7% patients. Time to resolution ranged from 0.4 to 176.0⁺ weeks. Immune-related endocrinopathies led to permanent discontinuation of nivolumab in combination with relatlimab in 1.1% of patients and required high dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) in 7.4% of patients with immune-related endocrinopathies.

Immune-related skin adverse reactions

In patients treated with nivolumab in combination with relatlimab, rash, including pruritis and vitiligo occurred in 45.1% of patients. Incidences of Grade 3/4 events were 1.4%. Median time to onset was 8 weeks (range: 0.1-116.4). Resolution occurred in 47.5% patients. Time to resolution ranged from 0.1-166.9⁺ weeks. Immune-related skin adverse reactions led to permanent discontinuation of nivolumab in combination with relatlimab in 0.3% of patients and required high dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) in 3.8% of patients with immune-related skin adverse reactions.

Immune-related myocarditis

In patients treated with nivolumab in combination with relatlimab, myocarditis occurred in 1.4% of patients. Incidences of Grade 3/4 events were 0.6%. Median time to onset was 4.14 weeks (range: 2.1-6.3). Resolution occurred in 100% of patients with a median time to resolution of 3 weeks (1.9-14.0). Myocarditis led to permanent discontinuation of nivolumab in combination with relatlimab in 1.4% of patients and required high dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) in 100% of patients with immune-related myocarditis.

Infusion-related reactions

In patients treated with nivolumab in combination with relatlimab, hypersensitivity/infusion reactions occurred in 6.8% of patients. All incidents were Grade 1/2.

Laboratory abnormalities

In patients treated with nivolumab in combination with relatlimab, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.6% for anaemia, 5.2% for lymphopaenia, 0.3% for neutropaenia, 0.6% for increased alkaline phosphatase, 2.9% for increased AST, 3.5% for increased ALT, 0.3% for increased total bilirubin, 0.9% for increased creatinine, 1.5% for hyponatraemia, 1.8% for hyperkalaemia, 0.3% for hypokalaemia, 0.9% for hypercalcaemia, 0.6% for hypocalcaemia, 0.9% for hypermagnesaemia, and 0.6% for hypomagnesaemia.

Immunogenicity

In study CA224047, out of the evaluable patients for anti-drug antibodies, the incidence of treatment-emergent anti-relatlimab antibodies and neutralizing antibodies against relatlimab in the Opdualag group were 5.6% (17/301) and 0.3% (1/301), respectively. The incidence of treatment-emergent anti-nivolumab antibodies and neutralizing antibodies against nivolumab in the Opdualag group were 4.0% (12/299) and 0.3% (1/299), respectively, which were similar to that observed in the nivolumab group 6.7% (19/283) and 0.4% (1/283), respectively. There was no evidence of an altered PK, efficacy, or safety profile with anti-nivolumab or anti-relatlimab antibody development.

Special populations

Elderly

Overall, no differences in safety were reported between elderly (≥ 65 years) and younger patients (see section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted immediately.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FY02.

Mechanism of action

Opdualag is a fixed dose combination (FDC) of nivolumab, a programmed death 1 inhibitor (anti-PD-1) and relatlimab, a lymphocyte activation gene 3 inhibitor (anti-LAG-3).

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

Relatlimab is a human IgG4 monoclonal antibody that binds to the LAG 3 receptor, blocks its interaction with ligands, including MHC II, and reduces LAG 3 pathway mediated inhibition of the immune response. Antagonism of this pathway promotes T cell proliferation and cytokine secretion.

The combination of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T cell activation compared to the activity of either antibody alone. In murine syngeneic tumour models, LAG 3 blockade potentiates the anti tumour activity of PD 1 blockage, inhibiting tumour growth and promoting tumour regression.

Clinical efficacy and safety

The safety and efficacy of nivolumab in combination with relatlimab was evaluated in a phase 2/3, randomised, double-blinded study (CA224047) for the treatment of previously untreated metastatic or unresectable melanoma. The study included patients who had ECOG performance status score 0 or 1, and histologically confirmed stage III (unresectable) or stage IV melanoma per American Joint Committee on Cancer (AJCC) version 8. Patients were allowed to have received prior adjuvant or neoadjuvant melanoma therapy (anti-PD-1, anti-CTLA-4, BRAF-MEK or interferon therapy). Patients with active autoimmune disease, medical conditions requiring systemic treatment with moderate or high dose corticosteroids or immunosuppressive medications, uveal melanoma, active or untreated brain or leptomeningeal metastases, history of myocarditis, or elevated troponin levels >2 times ULN or ECOG performance status score ≥ 2 at baseline, were excluded from the study.

A total of 714 patients were randomised to receive either 480 mg nivolumab/160 mg relatlimab over 60 minutes every 4 weeks (n=355) or nivolumab 480 mg every 4 weeks (n=359). Randomisation was stratified by tumor PD-L1 (≥ 1% vs. <1) using PD-L1 IHC 28-8 pharmDx test and LAG-3 expression (≥ 1% vs. <1) as determined by an analytically validated LAG-3 IHC assay, BRAF V600 mutation status, and M stage per the AJCC version 8 staging system (M0/M1any[0] vs. M1any[1]). Patients were treated until disease progression or unacceptable toxicity. The primary efficacy outcome measure was progression-free survival (PFS) determined by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). The secondary efficacy outcome measures were overall survival (OS), and overall response rate (ORR) by BICR. At the time of the primary analysis of PFS, the OS data were not mature.

Baseline characteristics were balanced between the two groups. The median age was 63 years (range: 20-94), 58% were men, and 97% were white. Baseline ECOG performance status was 0 (67%) or 1 (33%). Disease characteristics were: PD-L1 expression ≥ 1% (41%), LAG-3 expression ≥ 1% (75%), AJCC Stage IV disease (92%); M1c (39%), M1d disease (2.4%), baseline elevated LDH (36%) and BRAF mutation-positive melanoma (39%).

The trial demonstrated a statistically significant improvement in PFS for patients randomised to the nivolumab in combination with relatlimab arm compared with the nivolumab arm. The final analysis of OS was not statistically significant.

The Kaplan-Meier curves for PFS are shown in Figure 1. Efficacy results are shown in in Table 3.

Table 3: Efficacy results (CA224047)

^a Assessed by BICR.

^b Final PFS analysis (median follow-up 13.21 months [range: 0-33.1]).

^c Based on stratified Cox proportional hazard model.

^d Based on stratified log-rank test.

^e Kaplan-Meier estimate.

^f At the time of the final OS analysis, which was event-driven and occurred after the final PFS analysis with a median follow-up of 19.3 months (range 0.3-41.4).

^g Not Significant at alpha level 0.04302.

^h Not formally tested based on the testing hierarchy.

NR = Not reached.

Figure 1.: Kaplan-Meier curve of progression-free survival (CA224047)

Relatlimab/nivolumab (events: 180/355), median (95% CI): 10.12 (6.37, 15.74)

--― --*― -- Nivolumab (events: 211/359), median (95% CI): 4.63 (3.38, 5.62)

In the PD-L1 <1% subgroup, the HR (95% CI) for PFS was 0.66 (0.51, 0.84) with median PFS of 6.4 and 2.9 months for the OPDUALAG and nivolumab arms, respectively. In the PD-L1 ≥ 1% subgroup, the HR for PFS was 0.95 (95% CI: 0.68, 1.33) with median PFS of 15.7 and 14.7 months for the OPDUALAG and nivolumab arms, respectively.

Paediatric population

No clinical efficacy and safety data are available in adolescents (12 to 17 years old). Based on population PK simulations, the exposure of nivolumab and relatlimab in adolescents weighing at least 30 kg are expected to result in similar safety and efficacy to that of adults of the same weight, at the same recommended dose (see section 5.2).

The pharmacokinetics (PK) of relatlimab following the administration of nivolumab in combination with relatlimab was characterised in patients with various cancers who received relatlimab doses of 20 to 800 mg every 2 weeks and 160 to 1440 mg every 4 weeks either as a monotherapy or in combination with nivolumab doses of 80 or 240 mg every 2 weeks or 480 mg every 4 weeks.

Steady-state concentrations of relatlimab were reached by 16 weeks with an every 4-week regimen and the systemic accumulation was 1.9-fold. The average concentration (C_avg) of relatlimab after the first dose increased dose proportionally at doses ≥ 160 mg every 4 weeks.

Table 5: Geometric mean (CV%) of nivolumab and relatlimab steady-state exposures following 480 mg nivolumab and 160 mg relatlimab fixed-dose combination every 4 weeks

Based on population PK analyses, the nivolumab and relatlimab FDC infusion duration of 30 min and 60 min were predicted to produce similar (< 1% different) exposures of nivolumab and relatlimab.

In CA224047, the nivolumab geometric mean C_min at steady state in the nivolumab in combination with relatlimab arm was similar to the nivolumab arm with a geometric mean ratio of 0.931 (95% CI: 0.855-1.013).

Distribution

The geometric mean value (CV%) for nivolumab volume of distribution at steady state is 6.65 L (19.2%) and relatlimab is 6.65 L (19.8%).

Biotransformation

Nivolumab and relatlimab are therapeutic mAb IgG4 that are expected to be catabolised into small peptides, amino acids, and small carbohydrates by lysosome or receptor-mediated endocytosis.

Elimination

Nivolumab clearance is 21.1% lower [geometric mean (CV%), 7.57 mL/h (40.1%)] at steady state than that after the first dose [9.59 mL/h (40.3%)] and the terminal half-life (t1/2) is 26.5 days (36.4%).

Relatlimab clearance is 9.7% lower [geometric mean (CV%), 5.48 mL/h (41.3%)] at steady state than that after the first dose [6.06 mL/h (38.9%)]. Following administration of relatlimab 160 mg and nivolumab 480 mg administered every 4 weeks, the geometric mean (CV%) effective half-life (t1/2) of relatlimab is 26.2 days (37%).

Special populations

A population PK analysis suggested that the following factors had no clinically important effect on the clearance of nivolumab and relatlimab: age (range: 17 to 92 years), sex, [male (1056) and female (657)], or race [Caucasian (1655), African American (167) and Asian (41)]. The body weight (range: 37 to 170 kg) was a significant covariate on the nivolumab and relatlimab PK, however, there is no clinically relevant impact based on exposure-response analysis.

Paediatric population

Limited data suggest that nivolumab clearance and volume of distribution in adolescent subjects with solid tumours were 36% and 16% lower, respectively, than those of adult reference patients. It is unknown if the same holds for melanoma patients and if relatlimab clearance and volume of distribution are also lower in adolescents than adults. However, based on population PK simulations, the exposure of nivolumab and relatlimab in adolescents weighing at least 40 kg are expected to result in similar safety and efficacy to that of adults of the same weight, at the same recommended dose.

Renal impairment

The effect of renal impairment on the clearance of nivolumab and relatlimab was evaluated by a population PK analysis in patients with mild or moderate renal impairment compared to patients with normal renal function. No clinically important differences in the clearance of nivolumab or relatlimab were found between patients with renal impairment and patients with normal renal function.

Hepatic impairment

The effect of hepatic impairment on the clearance of nivolumab and relatlimab was evaluated by population PK analysis in patients with mild hepatic impairment (total bilirubin [TB] less than or equal to upper limit of normal [ULN] and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST) or moderate hepatic impairment (TB greater than 1.5 to 3 times ULN and any AST) compared to patients with normal hepatic function. No clinically important differences in the clearance of nivolumab or relatlimab were found between patients with hepatic impairment and patients with normal hepatic function.

Immunogenicity

The observed low incidence rate of treatment emergent anti-nivolumab antibody and treatment emergent anti-relatlimab antibody had no effects on PK of nivolumab and relatlimab.

Nivolumab in combination with relatlimab

No animal studies were conducted with nivolumab in combination with relatlimab to evaluate potential carcinogenicity, genotoxicity or reproductive and developmental toxicity.

In a 1-month study in monkeys dosed with nivolumab and relatlimab, inflammation within the central nervous system (choroid plexus, vasculature, meninges, spinal cord) and the reproductive tract (epididymis, seminal vesicles and testes) was observed. Although safety margins were not established for these effects with the combination, they ocurred at doses that suppose exposure levels significantly higher (13 folds for nivolumab and 97 folds for relatlimab) than those reached in patients.

Relatlimab

There are no available animal data on effect of relatlimab on pregnancy and reproduction. In a embryo-foetal toxicity study in mice using murine anti-LAG-3 antibodies, no maternal or developmental effects were observed. The effects of relatlimab on prenatal and postnatal development have not been evaluated; however, based on the mechanism of action, blockade of LAG-3 with relatlimab can have a similar negative effect as nivolumab on pregnancy. There were no fertility studies performed with relatlimab.

Nivolumab

Blockade of the PD-1/PD-L1 pathway has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to increase foetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis in the first trimester through delivery, at exposure levels either 8 or 35 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). There was a dose-dependent increase in foetal losses and increased neonatal mortality beginning in the third trimester.

The remaining offspring of nivolumab-treated females survived to scheduled termination, with no treatment-related clinical signs, alterations to normal development, organ-weight effects, or gross and microscopic pathology changes. Results for growth indices, as well as teratogenic, neurobehavioral, immunological, and clinical pathology parameters throughout the 6-month postnatal period were comparable to the control group. However, based on their mechanism of action, foetal exposure to nivolumab, and, similarly, relatlimab, may increase the risk of developing immune-related disorders or altering the normal immune response and immune-related disorders have been reported in PD-1 and PD-1/LAG-3 knockout mice. Fertility studies have not been performed with nivolumab.

Histidine

Histidine hydrochloride monohydrate

Sucrose

Pentetic acid (diethylenetriaminepentaacetic acid)

Polysorbate 80 (E433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Opdualag should not be infused concomitantly in the same intravenous line with other medicinal products.

Unopened vial

3 years

After preparation of infusion

Chemical and physical in-use stability from the time of preparation has been demonstrated as follows (times are inclusive of the administration period):

From a microbiological point of view, the prepared solution for infusion, regardless of the diluent, should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 ° C to 8 ° C, unless preparation has taken place in controlled and validated aseptic conditions (see section 6.6).

Store in a refrigerator (2 ° C-8 ° C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

The unopened vials can be stored at controlled room temperature (up to 25 ° C) for up to 72 hours.

For storage conditions after preparation of the infusion, see section 6.3.

Pack of one 25 mL vial (Type I glass), with a stopper (coated butyl rubber) and a yellow flip-off aluminium seal. Each vial is filled with 21.3 mL of solution, which includes an overfill of 1.3 mL.

Opdualag is supplied as a single-dose vial and does not contain any preservatives. Preparation should be performed by trained personnel in accordance with good practices rules, especially with respect to asepsis.

Opdualag can be used for intravenous administration either:

• without dilution, after transfer to an infusion container using an appropriate sterile syringe; or

• after diluting according to the following instructions:

Opdualag concentrate may be diluted with either:

• sodium chloride 9 mg/mL (0.9%) solution for injection; or

• 50 mg/mL (5%) glucose solution for injection.

Preparing the infusion

• Inspect the Opdualag concentrate for particulate matter or discolouration. Do not shake the vial. Opdualag is a clear to opalescent, colourless to slightly yellow solution. Discard the vial if the solution is cloudy, discoloured, or contains particulate matter.

• Withdraw the required volume of Opdualag concentrate using an appropriate sterile syringe and transfer the concentrate into a sterile, intravenous container (ethylvinyl acetate (EVA), polyvinyl chloride [PVC], or polyolefin).

• If applicable, dilute Opdualag solution with the required volume of sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection. For ease of preparation, the concentrate can also be transferred directly into a pre-filled bag containing the appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection.

• Gently mix the infusion by manual rotation. Do not shake.

Administration

Opdualag infusion must not be administered as an intravenous push or bolus injection.

Administer the Opdualag infusion intravenously over a period of 30 minutes.

Use of an infusion set and an in-line or add-on, sterile, non-pyrogenic, low protein binding filter (pore size of 0.2 μ m to 1.2 μ m) is recommended.

Opdualag infusion is compatible with EVA, PVC and polyolefin containers, PVC infusion sets and in-line filters with polyethersulfone (PES), nylon, and polyvinylidene fluoride (PVDF) membranes with pore sizes of 0.2 μ m to 1.2 μ m.

Do not co-administer other medicinal products through the same infusion line.

After administration of the Opdualag dose, flush the line with sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection.

Disposal

Do not store any unused portion of the infusion solution for reuse. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.