Adverse reactions : תופעות לוואי

4.8   Undesirable effects

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
Infections and infestations
Very common        urinary tract infection
Common             upper respiratory tract infection
Uncommon           folliculitis
Blood and lymphatic system disorders
Very common        anaemiaa, lymphopaeniaa, neutropaeniaa, leucopaeniaa Common             thrombocytopaenia a, eosinophilia
Uncommon           haemolytic anaemia
Endocrine disorders
Very common        hypothyroidism
Common             adrenal insufficiency, hypophysitis, hyperthyroidism, thyroiditis Uncommon           hypopituitarism, hypogonadism
Metabolism and nutrition disorders
Very common        decreased appetite
Common             diabetes mellitus, hypoglycaemiaa, weight decreased, hyperuricaemia, hypoalbuminaemia, dehydration
Psychiatric disorders
Common             confusional state
Nervous system disorders
Very common        headache
Common             peripheral neuropathy, dizziness, dysgeusia
Uncommon           encephalitis, Guillain-Barré syndrome, optic neuritis Eye disorders
Common             uveitis, visual impairment, dry eye, increased lacrimation Uncommon           Vogt-Koyanagi-Harada disease, ocular hyperaemia
Cardiac disorders
Common             myocarditis
Uncommon           pericardial effusion
Vascular disorders
Common             phlebitis
Respiratory, thoracic and mediastinal disorders
Very common        dyspnoea, cough
Common             pneumonitisb, nasal congestion
Uncommon           asthma
Gastrointestinal disorders
Very common        diarrhoea, vomiting, nausea, abdominal pain, constipation Common             colitis, pancreatitis, gastritis, dysphagia, stomatitis, dry mouth Uncommon           oesophagitis
Rare               Pancreatic exocrine insufficiency
Not known          Coeliac disease
Hepatobiliary disorders
Common             hepatitis
Uncommon           cholangitis
Skin and subcutaneous tissue disorders
Very common        rash, vitiligo, pruritus
Common             alopecia, lichenoid keratosis, photosensitivity reaction, dry skin Uncommon           pemphigoid, psoriasis, urticaria
Musculoskeletal and connective tissue disorders
Very common        musculoskeletal pain, arthralgia
Common             arthritis, muscle spasms, muscular weakness
Uncommon           myositis, Sjogren’s Syndrome, polymyalgia rheumatica, rheumatoid arthritis, systemic lupus erythematosus
Renal and urinary disorders
Common             renal failure, proteinuria
Uncommon           nephritis
Reproductive system and breast disorders
Uncommon           azoospermia


General disorders and administration site conditions
Very common         fatigue, pyrexia
Common              oedema, influenza-like illness, chills
Investigations
Very common         increased ASTa, increased ALTa, hyponatraemiaa, increased creatininea, increased alkaline phosphatasea, hyperkalaemiaa, hypocalcaemiaa, hypomagnesaemiaa, hypercalcaemiaa, hypokalaemiaa
Common              increased bilirubina, hypernatraemiaa, hypermagnesaemiaa, troponin increased, gamma- glutamyl transferase increased, blood lactate dehydrogenase increased, lipase increased, amylase increased
Uncommon            c-reactive protein increased, red blood cell sedimentation rate increased Injury, poisoning and procedural complications
Common              infusion-related reaction 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.
Any suspected adverse event should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il