4.1. Therapeutic indications

LOQTORZI, in combination with cisplatin and gemcitabine, is indicated for the first‑line treatment of adult patients with recurrent, not amenable to surgery or radiotherapy, or metastatic nasopharyngeal carcinoma.

LOQTORZI, in combination with cisplatin and paclitaxel, is indicated for the first‑line treatment of adult patients with unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma.

4.2. Posology and method of administration

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

Posology

The recommended dosing regimen of LOQTORZI is 240 mg every 3 weeks (Q3W) as an intravenous infusion over 60 minutes for the first infusion. If no significant infusion‑related reactions occurred during the first infusion, the subsequent infusions may be administered over 30 minutes.

Treatment should continue until disease progression, unacceptable toxicity or up to a maximum duration of 24 months.

Dose modifications

Recommended modifications to manage adverse reaction are provided in Table 1.

See the Summary of Product Characteristics (SmPC) of other products to be used in combination with LOQTORZI.

Table 1: Recommended treatment modifications for LOQTORZI

Adverse reaction

Severity1

Treatment modification

Immune‑related adverse reactions

Pneumonitis

Grade 2

Withhold2

Grades 3 or 4

Permanently discontinue

Diarrhoea/colitis

Grade 2 or 3

Withhold2

Grade 4

Permanently discontinue

Hepatitis

Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) increases to more than 3 and up to 5 times the upper limit of normal (ULN)

or

Total bilirubin increases to more than 1.5 and up to 3 times ULN

Withhold2

AST or ALT increases to more than 5 times ULN

or

Total bilirubin increases to more than 3 times ULN

Permanently discontinue

Endocrinopathies

Grade 2‑4 adrenal insufficiency or hypophysitis

Withhold until clinically stable on hormone replacement therapy2

Grades 3 or 4 hyperthyroidism or thyroiditis

Withhold until clinically stable on appropriate medical management

Grade 3‑4 diabetes mellitus

Withhold until clinically stable on antihyperglycemic (insulin) therapy

Grade 1‑4 hypothyroidism

Manage with hormone replacement therapy without toripalimab interruption

Nephritis with renal dysfunction

Grade 2‑3 increased blood creatinine

Withhold2

Grade 4 increased blood creatinine

Permanently discontinue

Exfoliative dermatologic conditions

Suspected Stevens‑Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS)

Withhold2

Confirmed SJS, TEN, or DRESS

Permanently discontinue

Myocarditis

Grades 2, 3, or 4

Permanently discontinue

Myositis

Grade 2‑3

Withhold or permanently discontinue depending on severity2

Grade 4

Permanently discontinue

Other adverse reactions (including but not limited to neurologic toxicities, pancreatitis, iritis, uveitis, immune‑related cystitis, and immune‑related inflammatory arthritis)

Grade 2‑3

Withhold or permanently discontinue depending on type and severity2

Grade 4

Permanently discontinue

Infusion‑related reactions

Infusion‑related reactions

Grade 1 or 2

Interrupt or slow the rate of infusion

Grade 3 or 4

Stop infusion.

Permanently discontinue

1 Based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

2 Resume LOQTORZI in patients with resolution to Grade 0‑1 after corticosteroid taper. Permanently discontinue if not less than Grade 1 within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids, or for endocrinopathies cannot be clinically stabilized on hormone replacement therapy.

Patient card

All prescribers of LOQTORZI should inform patients about the patient card, explaining what to do should they experience any symptom of immune‑related adverse reactions. The physician will provide the patient card to each patient.

Special populations

Elderly

No dose adjustment is recommended for patients who are aged 65 years or over (see section 5.2).

Renal impairment

No dose adjustment is needed for patients with mild or moderate renal impairment. There are insufficient data in patients with severe renal impairment for dosing recommendations (see section 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with mild hepatic impairment. There are insufficient data in patients with moderate or severe hepatic impairment for dosing recommendations (see section 5.2).

Paediatric population

The safety and efficacy of LOQTORZI in children and adolescents aged under 18 years have not been established. No data are available.

Method of administration

LOQTORZI is for intravenous use only and must be administered by infusion. The first infusion should be administered over 60 minutes via an infusion pump through an in‑line filter (0.2 micron or 0.22 micron pore size). If no infusion‑related reactions occurred during the first infusion, subsequent infusions may be administered over 30 minutes.

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

When administered on the same day as chemotherapy, LOQTORZI should be administered prior to chemotherapy.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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, which may be severe or fatal, can occur in patients treated with antibodies blocking the programmed cell death protein‑1 / programmed death‑ligand 1 (PD‑1/PD‑L1) pathway, including toripalimab. While immune‑related adverse reactions usually occur during treatment with PD‑1/PD‑L1 blocking antibodies, symptoms can also manifest after discontinuation of treatment. Immune‑related adverse reactions may occur in any organ or tissue and may affect more than one body system simultaneously. Important immune‑related adverse reactions listed in this section are not inclusive of all possible severe and fatal immune‑related reactions.

Early identification and management of immune‑related adverse reactions are essential to ensure safe use of PD‑1/PD‑L1 blocking antibodies. Patients should be monitored closely for symptoms and signs of immune‑related adverse reactions. Clinical chemistries including liver enzymes, creatinine, and thyroid function should be evaluated at baseline and periodically during treatment. In cases of suspected immune‑related adverse reactions, appropriate workup should be initiated to exclude alternative aetiologies, including infection. Medical management should be instituted promptly, including specialty consultation as appropriate.

Toripalimab should be withheld or permanently discontinued depending on the type and severity of the adverse reaction (see section 4.2). If treatment with toripalimab should be withheld or permanently discontinued, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. If myocarditis is suspected, initiate high‑dose steroids (e.g., methylprednisolone 1 g/day intravenously for 3–5 days). Upon improvement to Grade 1 or less, initiate corticosteroid taper. Consider administration of other systemic immunosuppressants in patients whose immune‑related adverse reactions are not controlled with corticosteroid therapy. Hormone replacement therapy for endocrinopathies should be instituted as warranted.

Treatment with toripalimab may be restarted within 12 weeks after last dose of toripalimab if the adverse reaction recovers to Grade ≤1 and corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent per day.

Treatment with toripalimab must be permanently discontinued for any Grade 3 immune‑related adverse reaction that recurs and for any Grade 4 immune‑related adverse reaction toxicity, except for endocrinopathies that are controlled with replacement hormones (see sections 4.2 and 4.8).

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and skin reactions) are discussed below.

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest that the risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapy may be increased as compared with the risk in patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable.

Immune‑related pneumonitis

Toripalimab can cause immune‑related pneumonitis (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other causes excluded. Patients should be managed with toripalimab treatment modifications and corticosteroids, as clinically indicated (see section 4.2 and directions for corticosteroid treatment in section 4.4 above).

Immune‑related colitis

Toripalimab can cause immune‑related colitis, which may present with diarrhoea (see section 4.8). Patients should be monitored for signs and symptoms of colitis and managed with toripalimab treatment modifications, anti‑diarrhoeal agents and corticosteroids, as clinically indicated (see section 4.2 and directions for corticosteroid treatment in section 4.4 above). In cases of corticosteroid‑refractory colitis, consider repeating infectious workup to exclude alternative aetiologies. Cytomegalovirus (CMV) infection/reactivation has been reported in patients receiving other PD‑1/PD‑L1 blocking antibodies with corticosteroid‑refractory immune‑related colitis.

Hepatotoxicity and immune‑related hepatitis

Toripalimab can cause immune‑related hepatitis (see section 4.8). Patients should be monitored for changes in liver function periodically and as indicated, based on clinical evaluation. Patients should be managed with toripalimab treatment modifications (see sections 4.2) and corticosteroids, as clinically indicated (see directions for corticosteroid treatment in section 4.4 above).

Immune‑related endocrinopathies

Adrenal insufficiency

Toripalimab can cause primary or secondary adrenal insufficiency (see section 4.8). Patients should be monitored for clinical signs and symptoms of adrenal insufficiency. For Grade 2‑4 adrenal insufficiency, toripalimab should be withheld until patient is clinically stable on physiologic hormone replacement therapy (see section 4.2).

Hypophysitis

Toripalimab can cause immune‑related hypophysitis (see section 4.8). Hypophysitis can present with acute symptoms associated with mass effects such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Patients should be monitored for signs and symptoms of hypophysitis. For Grade 2‑4 hypophysitis, toripalimab should be withheld until patient is clinically stable on physiologic hormone replacement therapy (see section 4.2).

Thyroid disorders

Toripalimab can cause immune‑related thyroid disorders (see section 4.8). Patients should be monitored for signs and symptoms of thyroid disorders prior to and periodically during treatment, and as indicated based on clinical evaluation.

Hypothyroidism may be managed with replacement therapy without toripalimab interruption and without corticosteroids (see section 4.2). Thyroiditis can present with or without concomitant thyroid dysfunction. Thyroiditis and hyperthyroidism may be managed symptomatically which may include thyroid suppression and/or corticosteroid therapy for acute thyroiditis. Toripalimab should be withheld for Grade ≥ 3 thyroiditis or hyperthyroidism until controlled with medical management and patient is clinically stable. Patients should be monitored for hypothyroidism that may follow hyperthyroidism or thyroiditis. Thyroid function and hormone levels should be monitored to ensure appropriate hormone replacement.

Type 1 diabetes mellitus, which can present with diabetic ketoacidosis

Toripalimab can cause immune‑related type I diabetes mellitus (see section 4.8). Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Insulin treatment should be initiated for type I diabetes mellitus as clinically indicated and toripalimab should be withheld in patients with Grade ≥ 3 hyperglycaemia. Treatment with toripalimab may be resumed when diabetes is controlled with medical management including insulin therapy and the patient is clinically stable (see section 4.2).

Immune‑related nephritis

Toripalimab can cause immune‑related nephritis (see section 4.8). Patients should be monitored for changes in renal function and other causes of renal dysfunction excluded. Toripalimab treatment should be modified (see section 4.2) and corticosteroids instituted, as clinically indicated (see instructions for corticosteroid treatment in section 4.4 above).

Immune‑related skin adverse reactions

Toripalimab can cause immune‑related rash or dermatitis (see section 4.8). Exfoliative dermatitis, including Stevens‑Johnson Syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has been reported in patients receiving PD‑1/PD‑L1 blocking antibodies.

Patients should be monitored for skin adverse reactions and managed with toripalimab treatment modifications (see section 4.2) and corticosteroids, as clinically indicated (see instructions for corticosteroid treatment in section 4.4 above).

Immune‑related myocarditis

Toripalimab can cause immune‑related myocarditis (see section 4.8). Patients should be monitored for signs and symptoms of myocarditis. If myocarditis is suspected, high‑dose steroids should be promptly initiated and prompt cardiology consultation with diagnostic workup according to current clinical guidelines should be started. Patients should be managed with toripalimab treatment modifications (see section 4.2) and corticosteroids, as clinically indicated (see instructions for corticosteroid treatment in section 4.4 above). Consider addition of immunosuppressants if the event does not improve within 48 hours after start of corticosteroid therapy.

Immune‑related myositis

Toripalimab can cause immune‑related myositis (see section 4.8). Patients should be monitored for signs and symptoms of myositis. For suspected myositis, monitor serial aldolase and creatine kinase and consider diagnostic workup according to current clinical guidelines. Patients should be managed with toripalimab treatment modifications (see section 4.2) and corticosteroids, as clinically indicated (see instructions for corticosteroid treatment in section 4.4 above).

Other immune‑related adverse reactions

Given the mechanism of action of toripalimab, other potential immune‑related adverse reactions may occur, including potentially serious events (e.g., encephalitis, demyelinating neuropathy [including Guillain Barré syndrome] myasthenic syndrome, sarcoidosis, vasculitis, rhabdomyolysis). Clinically significant immune‑related adverse reactions reported in less than 1 % of patients treated with toripalimab in the clinical studies include pancreatitis, iritis, uveitis, immune‑related inflammatory arthritis, and immune‑related cystitis. Patients should be monitored for signs and symptoms of immune‑related adverse reactions and managed with toripalimab treatment modifications (see section 4.2) and corticosteroids, as clinically indicated (see instructions for corticosteroid treatment in section 4.4 above).

Transplant‑related adverse reactions

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

Fatal and other serious complications can occur in patients who received an allogeneic haematopoietic stem cell transplantation (HSCT) before or after being treated with a PD‑1/PD‑L1 blocking antibody. Transplant‑related complications include hyperacute graft‑versus‑host‑disease (GVHD), acute GVHD, chronic GVHD, hepatic veno‑occlusive disease after reduced intensity conditioning, and steroid‑requiring febrile syndrome without an identified infectious cause. These complications may occur despite intervening therapy between PD‑1/PD‑L1 blockade and the allogeneic HSCT. Follow patients closely for evidence of transplant‑related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD‑1/PD‑L1 blocking antibody prior to or after an allogeneic HSCT.

Infusion‑related reactions

Toripalimab can cause severe and potentially life‑threatening infusion‑related reactions (see section 4.8). Patients should be monitored for signs and symptoms of infusion‑related reactions. Patients should be managed with toripalimab treatment modifications and supportive care, as clinically indicated (see section 4.2). For patients with infusion related reactions, pre‑medications with antipyretics and antihistamines to mitigate the risk of subsequent infusion reactions may be considered.

Patients excluded from clinical studies

Patients with active infections (active tuberculosis or hepatitis B or C or HIV infection), an immunocompromised state (systemic corticosteroids > 10 mg daily prednisone equivalents within 2 weeks of randomisation), active, systemic autoimmune diseases (except for controlled hypothyroidism or diabetes mellitus), active or untreated central nervous system metastases, eastern cooperative oncology group (ECOG) performance status (PS) ≥ 2, or a history of interstitial lung disease were not eligible for enrolment in clinical studies of toripalimab. There is limited information in patients with severe renal or moderate to severe hepatic impairment (see section 5.2).

In the absence of data, toripalimab should be used with caution in these populations after careful evaluation of the balance of benefits and risks for the patient.

Excipient with known effect

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

No formal interaction studies have been performed. Since toripalimab is cleared from the circulation through catabolism, no metabolic drug‑drug interactions are expected. Toripalimab is not a substrate for cytochrome P450 or active substance transporters. Toripalimab is not a cytokine and is unlikely to be a cytokine modulator. Additionally, pharmacokinetic (PK) interaction of toripalimab with small molecule active substances is not expected. There is no evidence of interaction mediated by non‑specific clearance of lysosome degradation for antibodies.

The use of systemic corticosteroids or immunosuppressants before starting toripalimab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of toripalimab. However, systemic corticosteroids or other immunosuppressants can be used after starting toripalimab to treat immune‑related adverse reactions (see section 4.4). Corticosteroids can also be used as premedication, when toripalimab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy‑related adverse reactions.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

Women of childbearing potential should use effective contraception during treatment with toripalimab and for at least 4 months after the last dose of toripalimab.

Pregnancy

There are no data on the use of toripalimab in pregnant women. Animal studies have not been conducted with toripalimab; however, animal studies have demonstrated that inhibition of the PD‑1/PD‑L1 pathway can lead to increased risk of immune‑related rejection of the developing foetus and result in foetal death (see section 5.3). Human immunoglobulin G4 (IgG4) is known to cross the placental barrier; therefore, toripalimab can potentially be transmitted from the mother to the developing foetus. Toripalimab should not be used during pregnancy or in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk.

Breast‑feeding

It is unknown whether toripalimab is secreted in human milk. It is known that antibodies (including IgG4) are secreted in human milk; a risk to the breast‑feeding newborn/infant cannot be excluded. A decision must be made whether to discontinue breast‑feeding or to discontinue/abstain from toripalimab therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

If a woman chooses to be treated with toripalimab, she should be instructed not to breast‑feed while receiving toripalimab and for at least 4 months after the last dose of toripalimab.

Fertility

Studies to evaluate the effect of toripalimab on fertility have not been performed (see section 5.3).

4.7. Effects on ability to drive and use machines

Toripalimab has minor influence on the ability to drive and use machines. In some patients, dizziness and fatigue have been reported following administration of toripalimab (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

Toripalimab in combination with platinum containing chemotherapy (see section 4.2)

The safety of toripalimab in combination with platinum containing chemotherapy has been evaluated in 403 patients with NPC or oesophageal squamous cell carcinoma (OSCC) receiving 240 mg toripalimab every 3 weeks in JUPITER‑02 or JUPITER‑06. The median duration of treatment in these patients was 6.5 months (range 1 day‑2.1 years). The frequencies included below and in Table 2 are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. In this patient population, the most frequent adverse reactions were anaemia (44.9%), leukopenia (41.7%), neutropenia (39.0%), thrombocytopenia (30.3%), nausea (29.8%), vomiting (27.3%), decreased appetite (23.8%), rash (23.8%), fatigue (23.6%), liver function test abnormal (22.3%), hypothyroidism (18.4%), constipation (16.6%), neuropathy (15.1%), colitis (14.1), pyrexia (13.6%), cough (11.4%), pruritus (11.4%), creatinine renal clearance decreased (11.2%), and hyponatraemia (10.2%). Incidences of grades 3‑5 adverse reactions in patients with NPC were 81.5% for toripalimab combination therapy and 83.9% for chemotherapy alone and in patients with OSCC were 24.9% for toripalimab combination therapy and 13.6% for chemotherapy alone.

Tabulated list of adverse reactions

Adverse reactions observed in clinical studies of toripalimab as monotherapy or in combination with chemotherapy are listed in Table 2. Adverse 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); 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 includes only treatment related adverse drug reactions. The adverse reaction frequencies from clinical studies are based on all‑cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes than the medicinal product such as the disease, other medicines or unrelated causes. Adverse reactions reported in clinical studies are listed by system organ class and by frequency.

The safety data is based on 1 514 patients exposed to toripalimab (of which 1 100 patients were exposed to toripalimab monotherapy and 514 patients in combination with chemotherapy) with a mean (range 0.03 months to 35.9 months) duration of exposure to toripalimab of 7.0 months and a median duration of exposure of 3.7 months (interquartile range 8.7 months) in 15 Phase 1, 2 or 3 clinical studies. See Section 5.1 for information on the demographics and baseline characteristics of participants in the main clinical studies.

When toripalimab is administered in combination with chemotherapy, refer to the SmPCs for the respective combination therapy components prior to initiation of treatment.

Table 2: Adverse reactions in patients treated with toripalimab

Infections and infestations

Very common

upper respiratory tract infection

Common

pneumonia, urinary tract infection, infection (not specified by site or pathogen), ear infections1, dental and oral soft tissue infections2, herpes simplex/herpes zoster infection

Uncommon

conjunctivitis, gingivitis, skin and subcutaneous tissue infections3, skin infections, bacteraemia, toe infection, paronychia/dermatophytosis of nail, osteomyelitis, pulmonary tuberculosis

Rare

diverticulitis, hepatitis B reactivation, muscle abscess, urosepsis

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Common

tumour pain

Uncommon

tumour haemorrhage, tumour rupture

Rare

myelodysplastic syndrome

Blood and lymphatic system disorders

Very common

anaemia, leukopenia, neutropenia, thrombocytopenia

Common

leukocytosis, neutrophilia, lymphopenia

Uncommon

coagulopathy, bone marrow failure, myelosuppression

Rare

eosinopenia, pancytopenia

Immune system disorders

Uncommon

hypersensitivity/serum sickness

Endocrine disorders

Very common

hypothyroidism

Common

hyperthyroidism

Uncommon

thyroiditis, adrenal insufficiency/cortisol decreased, thyroid disorder (excluding hypothyroidism and hyperthyroidism), hypophysitis/empty sella syndrome

Rare

hyperparathyroidism, hypopituitarism

Metabolism and nutrition disorders

Very common

decreased appetite, hyponatraemia, weight decreased, hypoproteinaemia, hyperglycaemia, hypokalaemia, hyperuricaemia/gout

Common

hypochloraemia, hypomagnesaemia, hypocalcaemia, hypophosphataemia, hyperkalaemia, hypercalcaemia, hypoglycaemia, dehydration

Uncommon

electrolyte imbalance, hyperphosphataemia, hypernatraemia, acid base disorder4, diabetes mellitus, malnutrition, hypovolaemia

Rare

hypolipidaemia

Psychiatric disorders

Common

hypersomnia/insomnia

Uncommon

depression/dysphoria, anxiety

Rare

mental disorder, tic

Nervous system disorders

Very common

neuropathy5

Common

dizziness, headache, neurotoxicity, dysgeusia

Uncommon

somnolence, syncope, encephalopathy, epilepsy, tremor, memory impairment, dysarthria, nervous system disorder, speech disorder

Rare

disturbance in attention, haemorrhage intracranial, paraplegia

Eye disorders

Common

vision blurred

Uncommon

eye inflammation6, eye movement disorder, papilloedema

Rare

blepharochalasis, glaucomatocyclitic crises, hypermetropia, retinal haemorrhage

Ear and labyrinth disorders

Common

ear disorder7

Uncommon

vertigo, deafness

Cardiac disorders

Very common

arrhythmia8

Uncommon

pericardial effusion, cardiac failure/cardiac dysfunction, myocarditis/immune‑mediated myocarditis, myocardial injury/myocardial ischaemia, cardiac discomfort

Rare

aortic valve disease, cardiac disorder

Vascular disorders

Common

hypertension, hypotension/orthostatic hypotension, embolism and thrombosis

Uncommon

phlebitis

Rare

aortic aneurysm, flushing

Respiratory, thoracic and mediastinal disorders

Very common

cough

Common

dyspnoea, pneumonitis/immune‑mediated lung disease/interstitial lung disease, upper respiratory tract disorders9, haemoptysis, epistaxis, pleural effusion, hiccups, dysphonia, rhinitis allergic

Uncommon

nasal congestion, respiratory failure, bronchospasm, sinus disorder, pneumonia aspiration, sputum increased, tracheo‑esophageal fistula

Rare

hydrothorax, pleurisy, vocal cord thickening

Gastrointestinal disorders

Very common

nausea/dyspepsia/eructation, vomiting, constipation/dyschezia, colitis/diarrhoea, abdominal pain

Common

stomatitis, abdominal distension/flatulence, dry mouth, dysphagia, toothache, gastrointestinal haemorrhage, gastrooesophageal reflux disease/hyperchlorhydria

Uncommon

intestinal obstruction/subileus, gastritis, gastroenteritis, oesophageal obstruction, pancreatitis, proctalgia, gastric disorder, gastric ulcer, gastrointestinal disorder, gastric dilatation, gastric fistula, hypoaesthesia oral

Rare

faecaloma, oesophageal ulcer, pancreatic disorder, pneumatosis intestinalis, swollen tongue, tongue discolouration

Hepatobiliary disorders

Very common

Hyperbilirubinaemia/jaundice

Common

hepatitis10, total bile acids increased

Uncommon

hepatic pain, cholecystitis, hepatic steatosis

Skin and subcutaneous tissue disorders

Very common

rash11, pruritus

Common

alopecia, vitiligo, pigmentation disorder

Uncommon

night sweats, skin disorder, skin exfoliation, hyperhidrosis, dry skin, skin ulcer, hair colour changes, psoriasis, photosensitivity reaction, skin hyperpigmentation

Rare

dermatomyositis, leukoderma, neurodermatitis, onychomadesis, pain of skin, panniculitis, pemphigus, purpura senile, telangiectasia

Musculoskeletal and connective tissue disorders

Very common

musculoskeletal pain

Common

muscular weakness, arthritis/joint range of motion decreased/periarthritis

Uncommon

muscle spasms, intervertebral disc protrusion, myositis

Rare

limb mass

Renal and urinary disorders

Very common

proteinuria, haematuria

Common

renal injury/nephropathy

Uncommon

pollakiuria, hydronephrosis, pyelocaliectasis, ureteric dilatation

Rare

cystitis noninfective, hydroureter, immune‑mediated renal disorder

Reproductive system and breast disorders

Uncommon

benign prostatic hyperplasia, breast pain, oedema genital, scrotal oedema

Rare

hypomenorrhoea, menorrhagia, menstrual disorder, menstruation irregular, prostatic calcification, vulvovaginal inflammation

General disorders and administration site conditions

Very common

fatigue, pyrexia, pain12

Common

oedema, influenza like illness, face oedema, chills, eye disorder13

Uncommon

facial pain, swelling, temperature intolerance, thirst

Rare

administration site reactions, hyperplasia, medical device pain, secretion discharge

Investigations

Very common

liver function test abnormal, thyroid function test abnormal, increased or decreased lipids, urine analysis abnormal14

Common

creatinine renal clearance decreased, blood creatine phosphokinase decreased/blood creatine phosphokinase increased, blood lactate dehydrogenase increased, amylase increased, lymphocyte count abnormal/monocyte count abnormal, blood alkaline phosphatase increased, blood urea increased, weight increased, lipase increased, electrocardiogram abnormal, C‑reactive protein increased, occult blood positive, cardiac investigation abnormal15

Uncommon

platelet count increased, anti‑thyroid antibody positive, eosinophil count abnormal, blood prolactin increased, blood testosterone decreased, blood follicle stimulating hormone increased, blood luteinising hormone increased, urine output decreased

Injury, poisoning and procedural complications

Uncommon

infusion related reaction, contusion/muscle injury, rib fracture

The following terms represent a group of related events that describe a medical condition rather than a single event.

1Ear infections includes mastoiditis, myringitis, and otitis media

2Dental and oral soft tissue infections includes oral candidiasis, pericoronitis, and periodontitis.

3Skin and subcutaneous tissue infections includes cellulitis, folliculitis, and subcutaneous abscess.

4Acid base disorder includes metabolic acidosis, metabolic alkalosis, and metabolic disorder.

5Neuropathy includes anaesthesia, anosmia, formication, hypoaesthesia, Lhermitte's sign, nerve injury, neuropathy peripheral, paraesthesia, parosmia, peripheral motor neuropathy, peripheral sensory neuropathy, peroneal nerve palsy, tongue paralysis, VIth nerve disorder, VIth nerve injury, and vocal cord paralysis.

6Eye inflammation includes eye inflammation, iritis, keratitis, and uveitis.

7Ear disorder includes ear pain, eustachian tube disorder, hypoacusis, middle ear inflammation, otorrhoea, and tinnitus.

8Based on a standard query including bradyarrhythmias and tachyarrhythmias.

9Upper respiratory tract disorders includes catarrh, dry throat, laryngeal oedema, laryngeal pain, nasal obstruction, rhinalgia, rhinorrhoea, and throat irritation.

10Hepatitis includes drug‑induced liver injury, hepatic failure, hepatic function abnormal, and immune‑mediated hepatitis.

11Rash includes dermatitis, dermatitis acneiform, dermatitis allergic, drug eruption, eczema, erythema, erythema multiforme, hand dermatitis, palmar‑plantar erythrodysaesthesia syndrome, papule, rash, rash erythematous, rash generalised, rash maculo‑papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin plaque, and urticaria.

12Pain includes chest discomfort, chest pain, eye pain, lymph node pain, non‑cardiac chest pain, and pain.

13Eye disorder includes cataract, diplopia, dry eye, eye pruritus, and eye swelling.

14Urine analysis abnormal includes bilirubin urine present, crystal urine present, glucose urine present, urea urine increased, urinary casts, urinary casts present, urinary sediment present, urine bilirubin increased, urine ketone body present, urobilinogen urine increased, and white blood cells urine positive.

15Cardiac investigation abnormal includes blood creatine phosphokinase MB increased, brain natriuretic peptide increased, and troponin increased.

Description of selected adverse reactions

Data for the following immune‑related adverse reactions are based on 403 patients who received toripalimab at a dose of 240 mg Q3W in combination with platinum and gemcitabine chemotherapy (n=146) or in combination with cisplatin and paclitaxel (n=257). The management guidelines for these adverse reactions are described in sections 4.2 and 4.4.

Immune‑related adverse reactions (see section 4.4)

Immune‑related pneumonitis

Immune-related pneumonitis occurred in 3.2% (13/403) patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, including, 2 (0.5%) Grade 3, and 7 (1.7%) Grade 2 adverse reactions. The median time to onset of pneumonitis was 5.4 months (range 1.3 to16.6 months). The median duration was 2.8 months (range 0.8 to 20.9 months). Corticosteroids were administered to 69.2% (9/13) of patients. Permanent discontinuation occurred in 3 (0.7%) and withholding of toripalimab in 5 (1.2%) patients. Immune‑related pneumonitis resolved in 31.0% (4/13) patients.

Immune‑related colitis

Immune‑related colitis occurred in 0.7% (3/403) of patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, including 2 (0.5%) Grade 3 and 1 (0.2%) Grade 2 adverse reactions. The median time to onset of colitis was 3.7 months (range 1.5 to 5.1 months). The median duration was 1.3 months (range 1.3 to 1.3 months). Corticosteroids were administered to 66.7% (2/3) of these patients. Permanent discontinuation occurred in 2 (0.5%) patients and withholding of toripalimab in 1 (0.2%) patient. Immune‑related colitis resolved in 33% (1/3) of these patients.

Hepatotoxicity and immune‑related hepatitis

Immune‑related hepatitis occurred in 2.0% (8/403) of patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, including 2 (0.5%) Grade 4, 5 (1.2%) Grade 3, and 1 (0.2%) Grade 2 adverse reactions. The median time to onset of hepatitis was 4.0 months (range 0.7 to 22.7 months). The median duration was 0.6 months (range 0.4 to 3.2 months). Corticosteroids were administered to 7 of the 8 (87.5%) patients. Permanent discontinuation occurred in 5 (1.2%) and withholding of toripalimab in 2 (0.5%) patients. Immune‑related hepatitis resolved in 87.5% (7/8) of these patients.

Immune‑related endocrinopathies

Immune‑related adrenal insufficiency occurred in 0.2% (1/403) of patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, including 1 (0.2%) Grade 3adverse reaction. The time to onset of the adverse reaction was 2.0 months. Corticosteroids were administered to this patient. Toripalimab was permanently discontinued.

Thyroiditis occurred in 2.0% (8/403) of patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, including 4 Grade 2 (1.0%) and 4 Grade 1 (1.0%) adverse reactions. The median time to onset of thyroiditis was 5.9 months (range 0.7 to 13.5 months). The median duration was 11.7 months (range 7.4 to 17.8 months). Corticosteroids were required in 1/8 (12.5%) of patients and hormone replacement in 5/8 (62.5%). Permanent discontinuation occurred in 1/403 (0.2%) and dose interruption in 1/403 (0.2%) patients. Thyroiditis resolved in 12.5% (1/8) of these patients.

In patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, hyperthyroidism occurred in 2.0% (8/403) of patients, all of which were Grade 1 adverse reactions. The median time to onset of hyperthyroidism was 6.5 months (range 1.5 to 12.5 months). The median duration was 1.4 months (range 0.7 to 3.7 months).

Hypothyroidism occurred in 17.1% (69/403) of patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, with 46 Grade 2 (11.4%) and 23 Grade 1 (5.7%) adverse reactions. The median time to onset of hypothyroidism was 5.9 months (range 1.2 to 20.7 months). The median duration was 3.2 months (range 0.4 to 30.6 months). Thyroid hormone replacement therapy was required in 72.5% (50/69) of patients. Corticosteroids were administered to 1/69 (1.4%) patients. No patients permanently discontinued and 1.2% (5/403) of the patients interrupted toripalimab.

In patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, diabetes mellitus occurred in 0.2% (1/403) of patients, including 1 (0.2%) Grade 3, and no Grade 2 adverse reactions. The time to onset of diabetes mellitus was 0.7 month. The patient did not receive corticosteroids but was treated with insulin. The patient did not permanently discontinue or interrupt toripalimab.

In patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, hypophysitis occurred in 0.2% (1/403) of patients with 1 (0.2%) Grade 2 adverse reaction. The time to onset of hypophysitis was 23.7 month. Corticosteroids were administered and the patient did not permanently discontinue toripalimab or interrupt dosing.

Immune‑related skin adverse reactions

Immune‑related skin adverse reactions occurred in 9.4% (38/403) of patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, including 12 Grade 3 (3.0%) and 8 Grade 2 (2.0%) adverse reactions. The median time to onset of immune‑related skin adverse reactions was 1.0 month (range 0.1 to 23.1 months). The median duration was 1.2 months (range 0.1 to 13.1 months). Systemic corticosteroids were required in 18.4% (7/38) of the patients with immune‑related skin adverse reactions. Immune‑related skin adverse reactions led to permanent discontinuation or interruption of toripalimab in 1.5% (6) of patients. Immune‑related skin adverse reactions resolved in 73.7% (28/38) of these patients.

Immune‑related myocarditis

Immune‑related myocarditis occurred in 0.7% (3/403) of patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, including 2 (0.5%) Grade 4 and 1 (0.2%) Grade 3adverse reactions. The median time to onset of immune‑related myocarditis was 1.7 months (range 1.4 to 4.1 months). The median duration was 1.3 months (range 1.0 to 1.6 months). All three patients with immune‑related myocarditis received corticosteroids. Two patients permanently discontinued toripalimab and no patients interrupted dosing. Immune‑related myocarditis resolved in 33.3% (1/ 3) of these patients.

Immune‑related myositis

Immune‑related myositis occurred in 0.5% (2/403) of patients receiving toripalimab in in JUPITER‑02 and JUPITER‑06, including 2 (0.5%) Grade 3 and no Grade 2 adverse events. The median time to onset of immune‑related myositis was 2.5 month (range 1.2 to 3.9 months). The two patients with immune‑related myositis received corticosteroids and both permanently discontinued toripalimab.

Immune‑related nephritis

Immune‑related nephritis occurred in 0.2% (1/403) of patients receiving toripalimab in JUPITER‑02 and JUPITER‑06. The time to onset of immune‑related nephritis was 18.2 months and the duration was 3.3 months. The patient with immune‑related nephritis (Grade 4) required systemic corticosteroids and nephritis led to discontinuation of toripalimab. Nephritis resolved in this patient.

Other immune‑related adverse reactions

Immune‑related cystitis occurred in 0.5% (2/403) of patients receiving toripalimab in JUPITER‑02 and JUPITER‑06, including 1 Grade 3 (0.2%) and 1 Grade 1 (0.2%) adverse reactions. The median time to onset of immune‑related cystitis was 5.0 months (range 3.4 to 6.6 months). Corticosteroid therapy was required in the one patient with Grade 3 cystitis who also permanently discontinued toripalimab. The other patient did not interrupted dosing. Immune‑related cystitis resolved in the single patient with a Grade 3 cystitis who received corticosteroid treatment.

Infusion related reactions

Of the 403 patients who received toripalimab in combination with platinum containing chemotherapy in JUPITER‑02 or JUPITER‑06, infusion‑related reactions occurred in 11 patients (2.7%), including Grade 4 (0.2%), Grade 3 (0.2%) and Grade 2 (0.5%) adverse reactions.

Overall, infusion related reactions occurred in 28 (1.8%) of 1514 patients treated with toripalimab, including Grade 4 (0.07%) and Grade 3 (0.13%) reactions. Infusion‑related reaction led to permanent discontinuation of toripalimab in 3 (0.2%) patients. Common symptoms of infusion‑related reaction include fever, chills, rash, pruritus, nausea and hypotension.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. In patients who received toripalimab, treatment‑emergent antibodies to toripalimab were detected in 8.7% (128/1479) of the evaluable patients tested. There was no evidence of any clinically relevant effect of anti‑toripalimab antibody development on its pharmacokinetics. Across all studies, the median time to onset of ADA was 46 days (range to 14 to 506 days). There are insufficient numbers of patients to adequately assess the effect of ADA on efficacy.

Elderly

Of the 403 patients treated with toripalimab in combination with platinum‑based chemotherapy in clinical studies, 73.2% (295/403) were less than 65 years and 26.8% (108/403) were 65 years or older.

No overall differences in safety were observed between patients ≥ 65 years of age and younger patients receiving toripalimab.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

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