Toripalimab

Toripalimab is a humanised IgG4 monoclonal antibody directed against the PD-1 receptor, produced in Chinese hamster ovary cells by recombinant DNA technology. The PD-1 pathway limits T-cell activity and maintains self-tolerance, and some tumours use it to escape immune surveillance. By blocking it, toripalimab restores T-cell activity against the tumour.

Mechanism of Action

• Target binding: binds the PD-1 receptor and blocks its interaction with the ligands PD-L1 and PD-L2.
• Immune effect: binding of these ligands to PD-1 on T cells inhibits T-cell proliferation, cytokine production and cytotoxic activity. Blocking the interaction releases this inhibition of the immune response, including the anti-tumour response.
• Preclinical evidence: in mouse tumour models, blocking PD-1 reduced tumour growth.
• Exposure and response: exposure-response relationships for efficacy are essentially flat over the exposures reached in the nasopharyngeal and oesophageal carcinoma studies.

Pharmacokinetics

• Absorption: given intravenously, so it is completely bioavailable.
• Distribution: mainly in the plasma; the volume of distribution at steady state is about 3.8 L.
• Metabolism: no dedicated metabolism studies were done. As a monoclonal antibody, toripalimab is expected to be broken down by catabolic pathways or receptor-mediated endocytosis into small peptides, amino acids and carbohydrates; it is not a substrate of cytochrome P450 enzymes or transporters.
• Elimination: the pharmacokinetics follow a two-compartment model with time-varying clearance, a mean 12.01 mL/h after the first dose and 8.49 mL/h at steady state. The terminal half-life at steady state with 240 mg every 3 weeks is about 14 days.
• Linearity: peak concentrations rose in proportion to dose between 80 and 480 mg every 2 weeks. At 240 mg every 3 weeks the steady-state trough is about 26.3 µg/mL, a 2.7-fold accumulation compared with the first dose.
• Special populations: no dose adjustment is needed for patients aged 65 or over, for mild or moderate renal impairment or for mild hepatic impairment. Data are insufficient in severe renal impairment and in moderate or severe hepatic impairment.

• Nasopharyngeal carcinoma: in combination with cisplatin and gemcitabine, first-line treatment of adults with recurrent nasopharyngeal carcinoma not amenable to surgery or radiotherapy, or with metastatic disease.
• Oesophageal squamous cell carcinoma: in combination with cisplatin and paclitaxel, first-line treatment of adults with unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma.

• Hypersensitivity to toripalimab or to any of the excipients.

In 403 patients given toripalimab 240 mg every 3 weeks with platinum-based chemotherapy, the most frequent reactions were anaemia (44.9%), leukopenia (41.7%), neutropenia (39.0%), thrombocytopenia (30.3%), nausea (29.8%), vomiting (27.3%), decreased appetite and rash (23.8% each), fatigue (23.6%), abnormal liver function tests (22.3%) and hypothyroidism (18.4%). Grade 3–5 reactions occurred in 81.5% of nasopharyngeal carcinoma patients on toripalimab plus chemotherapy (83.9% with chemotherapy alone) and in 24.9% of oesophageal carcinoma patients (13.6% with chemotherapy alone). The frequencies below come from 1,514 patients (1,100 on monotherapy, 514 with chemotherapy) in 15 studies.

Very common (≥1/10): upper respiratory tract infection; anaemia, leukopenia, neutropenia, thrombocytopenia; hypothyroidism; decreased appetite, hyponatraemia, weight decreased, hypoproteinaemia, hyperglycaemia, hypokalaemia, hyperuricaemia or gout; neuropathy; arrhythmia; cough; nausea, dyspepsia, eructation, vomiting, constipation, dyschezia, colitis or diarrhoea, abdominal pain; hyperbilirubinaemia or jaundice; rash, pruritus; musculoskeletal pain; proteinuria, haematuria; fatigue, pyrexia, pain; abnormal liver function and thyroid function tests, increased or decreased lipids, abnormal urine analysis.

Common (≥1/100 to <1/10), selected: pneumonia, urinary tract infection, ear infections, dental and oral soft tissue infections, herpes simplex or herpes zoster infection; tumour pain; leukocytosis, neutrophilia, lymphopenia; hyperthyroidism; hypochloraemia, hypomagnesaemia, hypocalcaemia, hypophosphataemia, hyperkalaemia, hypercalcaemia, hypoglycaemia, dehydration; hypersomnia or insomnia; dizziness, headache, neurotoxicity, dysgeusia; blurred vision; ear disorders; hypertension, hypotension, embolism and thrombosis; dyspnoea, pneumonitis (including immune-mediated and interstitial lung disease), haemoptysis, epistaxis, pleural effusion, hiccups, dysphonia, allergic rhinitis; stomatitis, abdominal distension, dry mouth, dysphagia, toothache, gastrointestinal haemorrhage, gastro-oesophageal reflux disease; hepatitis (including immune-mediated hepatitis), increased total bile acids; alopecia, vitiligo, pigmentation disorder; muscular weakness, arthritis; renal injury or nephropathy; oedema, influenza-like illness, face oedema, chills, eye disorders; decreased creatinine renal clearance, changes in blood creatine phosphokinase, increased lactate dehydrogenase, amylase, lipase, alkaline phosphatase, urea and C-reactive protein, weight increased, abnormal ECG.

Uncommon (≥1/1,000 to <1/100), selected: hypersensitivity or serum sickness; thyroiditis, adrenal insufficiency, hypophysitis; diabetes mellitus; myocarditis, cardiac failure, pericardial effusion; encephalopathy, epilepsy; eye inflammation (iritis, keratitis, uveitis); bronchospasm, respiratory failure, tracheo-oesophageal fistula; pancreatitis, gastric ulcer, intestinal obstruction; hepatic steatosis, cholecystitis; myositis; coagulopathy, bone marrow failure, myelosuppression; tumour haemorrhage, tumour rupture; bacteraemia, osteomyelitis, pulmonary tuberculosis; skin exfoliation, photosensitivity reaction; infusion-related reaction.

Rare (≥1/10,000 to <1/1,000), selected: hepatitis B reactivation, diverticulitis, urosepsis; myelodysplastic syndrome, pancytopenia; hyperparathyroidism, hypopituitarism; intracranial haemorrhage, paraplegia; retinal haemorrhage; aortic aneurysm, aortic valve disease; dermatomyositis, pemphigus; immune-mediated renal disorder, non-infective cystitis.

Immune-related reactions in the 403 patients given toripalimab with platinum chemotherapy included hypothyroidism (17.1%), immune-related skin reactions (9.4%), pneumonitis (3.2%), hepatitis (2.0%), thyroiditis (2.0%), hyperthyroidism (2.0%), colitis (0.7%), myocarditis (0.7%), myositis (0.5%) and, in 0.2% each, adrenal insufficiency, hypophysitis, diabetes mellitus and nephritis. Infusion-related reactions occurred in 2.7% of these patients (1.8% of all 1,514). Antibodies to toripalimab appeared during treatment in 8.7% of evaluable patients, without a clinically relevant effect on pharmacokinetics. No overall differences in safety were seen between patients aged 65 or over and younger patients.

• Pharmacokinetic interactions: no formal interaction studies have been performed. Toripalimab is cleared by catabolism and is not a substrate of cytochrome P450 enzymes or transporters, so metabolic interactions and pharmacokinetic interactions with small-molecule medicines are not expected. It is not a cytokine and is unlikely to modulate cytokines.
• Systemic corticosteroids and immunosuppressants before treatment: avoid before starting, because they may interfere with the activity and efficacy of toripalimab. Once treatment has started, they can be used to treat immune-related adverse reactions.
• Corticosteroids as premedication: may be used with chemotherapy combinations as antiemetic prophylaxis or to relieve chemotherapy-related adverse reactions.
• Combination partners: see the SmPCs of cisplatin, gemcitabine and paclitaxel for their own interactions.

Treatment must be initiated and supervised by physicians experienced in the treatment of cancer. Toripalimab is for intravenous use only and is given by infusion together with platinum-based chemotherapy.

Recommended Dose

• 240 mg every 3 weeks, as an intravenous infusion over 60 minutes for the first infusion. If no significant infusion-related reactions occurred, later infusions may be given over 30 minutes.
• Duration: until disease progression, unacceptable toxicity or a maximum of 24 months.
• Combination: with cisplatin and gemcitabine for nasopharyngeal carcinoma, or with cisplatin and paclitaxel for oesophageal squamous cell carcinoma. See the SmPCs of those products for their doses. When given on the same day as chemotherapy, toripalimab is given first.

Method of Administration

• The first infusion is given by infusion pump through an in-line filter with a pore size of 0.2 or 0.22 micron.
• Do not co-administer other medicinal products through the same infusion line.
• For dilution before administration, see section 6.6 of the SmPC.

Treatment Modifications for Adverse Reactions

The SmPC manages adverse reactions (graded by NCI CTCAE version 5.0) by withholding, interrupting or slowing the infusion, or permanently discontinuing treatment; it gives no dose-reduction step.

• Pneumonitis: withhold for grade 2; permanently discontinue for grade 3 or 4.
• Diarrhoea or colitis: withhold for grade 2 or 3; permanently discontinue for grade 4.
• Hepatitis: withhold if AST or ALT rises to more than 3 and up to 5 times the upper limit of normal (ULN) or total bilirubin to more than 1.5 and up to 3 times ULN; permanently discontinue if AST or ALT exceeds 5 times ULN or bilirubin exceeds 3 times ULN.
• Endocrinopathies: withhold grade 2–4 adrenal insufficiency or hypophysitis until clinically stable on hormone replacement; withhold grade 3 or 4 hyperthyroidism or thyroiditis, and grade 3–4 diabetes mellitus, until clinically stable on appropriate management (insulin for diabetes). Grade 1–4 hypothyroidism is managed with hormone replacement without interrupting toripalimab.
• Nephritis with renal dysfunction: withhold for grade 2–3 increased creatinine; permanently discontinue for grade 4.
• Exfoliative skin conditions: withhold for suspected Stevens-Johnson syndrome, toxic epidermal necrolysis or DRESS; permanently discontinue if confirmed.
• Myocarditis: permanently discontinue for grade 2, 3 or 4.
• Myositis: withhold or permanently discontinue according to severity for grade 2–3; permanently discontinue for grade 4.
• Other immune-related reactions (including neurological toxicity, pancreatitis, iritis, uveitis, immune-related cystitis and inflammatory arthritis): grade 2–3, withhold or permanently discontinue according to type and severity; grade 4, permanently discontinue.
• Infusion-related reactions: grade 1 or 2, interrupt or slow the infusion; grade 3 or 4, stop the infusion and permanently discontinue.
• Resuming: after a withheld immune-related reaction, treatment resumes once it has resolved to grade 0–1 after the corticosteroid taper. Treatment is permanently discontinued if the reaction is not below grade 1 within 12 weeks of starting steroids, if prednisone cannot be reduced to 10 mg per day or less (or equivalent) within 12 weeks, or if an endocrinopathy cannot be stabilised on hormone replacement.

Special Populations

• Elderly (65 years or over): no dose adjustment.
• Renal impairment: no adjustment for mild or moderate impairment; insufficient data in severe impairment.
• Hepatic impairment: no adjustment for mild impairment; insufficient data in moderate or severe impairment.
• Children and adolescents: safety and efficacy under 18 years have not been established, and no data are available.

Patient Card

Prescribers must inform every patient about the patient card, which explains what to do if any symptom of an immune-related adverse reaction occurs. The physician gives the card to each patient.

Immune-Related Adverse Reactions

• Immune-related reactions, which may be severe or fatal, can occur with antibodies that block the PD-1/PD-L1 pathway. They may affect any organ or tissue, more than one body system at once, and can appear after treatment has stopped. In patients with pre-existing autoimmune disease the risk may be higher, and flares of the underlying disease were frequent but mostly mild and manageable.
• Monitor patients closely. Liver enzymes, creatinine and thyroid function should be checked at baseline and periodically. For suspected reactions, exclude other causes, including infection, and start management promptly with specialist advice as appropriate.
• When treatment is withheld or permanently discontinued, systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) are given until improvement to grade 1 or less, then tapered. If myocarditis is suspected, high-dose steroids (for example methylprednisolone 1 g/day intravenously for 3–5 days) are started promptly. Other immunosuppressants can be considered if corticosteroids do not control the reaction, and hormone replacement is given for endocrinopathies as needed.
• Treatment may be restarted within 12 weeks of the last dose if the reaction has recovered to grade 1 or less and the corticosteroid dose is 10 mg prednisone equivalent per day or less. It must be permanently discontinued for any recurrent grade 3 and any grade 4 immune-related reaction, except endocrinopathies controlled with replacement hormones.

Organ-Specific Immune-Related Reactions

• Lungs, bowel and liver: pneumonitis (confirm with imaging and exclude other causes), colitis (which may present as diarrhoea; in corticosteroid-refractory colitis repeat the infectious work-up, as cytomegalovirus infection or reactivation has been reported with other PD-1/PD-L1 antibodies) and hepatitis.
• Endocrine: adrenal insufficiency, hypophysitis, thyroid disorders and type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Monitor for these signs before and during treatment, including thyroid function and hormone levels.
• Kidney, skin, heart and muscle: nephritis; rash or dermatitis, including exfoliative dermatitis (Stevens-Johnson syndrome, DRESS and toxic epidermal necrolysis); myocarditis, which needs prompt cardiology consultation and, if there is no improvement within 48 hours of corticosteroids, consideration of immunosuppressants; and myositis (monitor aldolase and creatine kinase).
• Other: encephalitis, demyelinating neuropathy (including Guillain-Barré syndrome), myasthenic syndrome, sarcoidosis, vasculitis and rhabdomyolysis may occur. Pancreatitis, iritis, uveitis, immune-related inflammatory arthritis and immune-related cystitis were reported in under 1% of patients.

Transplant-Related Reactions

Solid organ transplant rejection has been reported after marketing in patients treated with PD-1 inhibitors, so the benefit of treatment must be weighed against the risk of rejection. Fatal and other serious complications can occur in patients who had an allogeneic haematopoietic stem cell transplant before or after a PD-1/PD-L1 blocking antibody (graft-versus-host disease, hepatic veno-occlusive disease after reduced-intensity conditioning, steroid-requiring febrile syndrome). Follow these patients closely.

Infusion-Related Reactions

Severe and potentially life-threatening infusion-related reactions can occur. Manage them as described under treatment modifications; in patients who have had one, premedication with antipyretics and antihistamines may be considered.

Patients Excluded from Clinical Studies

Patients with active infections (active tuberculosis, hepatitis B or C, HIV), an immunocompromised state (systemic corticosteroids above 10 mg daily prednisone equivalent within 2 weeks of randomisation), active systemic autoimmune disease (except controlled hypothyroidism or diabetes mellitus), active or untreated central nervous system metastases, ECOG performance status of 2 or more, or a history of interstitial lung disease were not enrolled. Information is limited in severe renal impairment and in moderate to severe hepatic impairment, so toripalimab should be used with caution in these groups after careful assessment of benefit and risk.

Traceability

To improve traceability of this biological medicinal product, the name and batch number of the administered product must be clearly recorded.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 4 months after the last dose.
• Pregnancy: there are no data in pregnant women. Animal studies have not been conducted with toripalimab, but inhibition of the PD-1/PD-L1 pathway can increase the risk of immune-related rejection of the developing foetus and lead to foetal death, and human IgG4 crosses the placenta. 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.
• Breastfeeding: it is unknown whether toripalimab is secreted in human milk, but antibodies (including IgG4) are, so a risk to the breastfed infant cannot be excluded. A woman who chooses treatment should not breastfeed during treatment and for at least 4 months after the last dose.
• Fertility: studies of the effect on fertility have not been performed.

Excipients

Each vial contains less than 1 mmol (23 mg) sodium, that is to say it is essentially ‘sodium-free’, and 1.2 mg of polysorbate 80 (0.2 mg/mL). Polysorbates may cause allergic reactions.

Effect on Driving

Toripalimab has a minor influence on the ability to drive and use machines. Dizziness and fatigue have been reported in some patients.

Store the vial in a refrigerator (2–8 °C) in the original carton to protect it from light, and do not freeze. Keep the cold chain unbroken during transport and storage. Each carton holds one 6 mL type 1 glass vial with a chlorobutyl rubber stopper and an aluminium flip-off seal. For storage after dilution, see Shelf Life.

• Unopened vial: 3 years.
• After dilution: chemical and physical in-use stability has been shown for 24 hours at 2–8 °C or at 20–25 °C. From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the product should be used immediately; otherwise in-use storage times and conditions are the responsibility of the user.

Prescription only (Rx), on restricted medical prescription. Treatment must be started and supervised by physicians experienced in the treatment of cancer. Loqtorzi is given as an intravenous infusion, so it is supplied to the hospital or clinic that administers it, under refrigerated cold-chain handling (2–8 °C).