Odronextamab

Odronextamab is a recombinant human immunoglobulin G4 (IgG4)-based bispecific antibody produced in Chinese hamster ovary cells. One arm binds CD20, a surface antigen present on normal and malignant B cells, and the other binds CD3, part of the T-cell receptor complex. It therefore redirects the patient’s own T cells against B-cell lymphoma.

Mechanism of Action

• T-cell engagement: binding both targets at once forms a synapse between a T cell and a CD20-expressing cell. The T cell is activated and a polyclonal cytotoxic T-cell response follows, which causes redirected lysis of the targeted cells, including malignant B cells.
• B-cell depletion: at the recommended doses, median circulating B cells in patients with detectable B cells at baseline fell to undetectable levels (below 1 cell/microlitre) by week 4, after the first 80 mg dose (follicular lymphoma) or 160 mg dose (DLBCL), and stayed depleted during treatment.
• Cytokine release: transient rises in IL-2, IL-6, IL-10, TNF-alpha and interferon-gamma were seen from 0.2 mg upwards. With the recommended step-up regimen, levels peaked within 24 hours of each cycle 1 infusion, usually in the first two weeks, and returned to baseline before the next infusion; later doses released little cytokine.
• Immunogenicity: anti-odronextamab antibodies were found in 1.5% (6 of 400) of patients; no neutralising antibodies were seen.

Pharmacokinetics

• Exposure: studied in B-cell non-Hodgkin lymphoma from 0.03 mg to 320 mg. During step-up dosing disposition depends on concentration and time; from 80 mg upwards the profile is linear and dose-proportional at steady state. Predicted median peak levels (Cmax) are 44.7 mg/L for follicular lymphoma at 80 mg weekly and 67.9 mg/L at 160 mg every 2 weeks, and 98.2 mg/L for DLBCL at 160 mg weekly and 147 mg/L at 320 mg every 2 weeks.
• Distribution: volume of distribution at steady state about 9.34 L (coefficient of variation 48.5%).
• Metabolism: expected to be broken down into small peptides by catabolic pathways.
• Elimination: two parallel processes, a linear, non-saturable catabolic one and a non-linear, saturable target-mediated one, with higher clearance at lower doses. After the last steady-state dose of 160 mg every 2 weeks, levels took 19 weeks to fall to the lower limit of quantification (12 weeks to 1% of median Cmax); after 320 mg every 2 weeks, 24 weeks (16 weeks to 1% of median Cmax).
• Special populations: no dose adjustment for elderly patients, renal impairment or mild to moderate hepatic impairment; severe hepatic impairment has not been studied.

Ordspono as monotherapy is indicated for adult patients with:

• Follicular lymphoma: relapsed or refractory follicular lymphoma (r/r FL) after two or more lines of systemic therapy.
• Diffuse large B-cell lymphoma: relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) after two or more lines of systemic therapy.

• Hypersensitivity to odronextamab or to any of the excipients.

The most common reactions were cytokine release syndrome (CRS, 54%), neutropenia (41%), pyrexia (39%), anaemia (38%), thrombocytopenia (27%), diarrhoea (24%) and COVID-19 (22%). The most common severe (grade 3 or higher) reactions were neutropenia (34%), anaemia (19%), thrombocytopenia (13%), lymphopenia (12%), pneumonia (10%), leukopenia (9%), COVID-19 (8%), hypokalaemia (6%) and hyperglycaemia (5%). The most common serious reactions were CRS (14%), pneumonia (9%), COVID-19 (9%) and pyrexia (6%). Infusions were interrupted because of a reaction in 16% of patients, and treatment was stopped in 14% (most often COVID-19 2.4%, pneumonia 1.3% and encephalopathy 0.8%). Frequencies come from 372 patients (153 with FL, 219 with DLBCL) given odronextamab alone; CRS and infusion-related reaction figures come from 197 patients given the recommended step-up regimen.

Very common (≥1/10): COVID-19, pneumonia, cytomegalovirus infection, upper respiratory tract infection, urinary tract infection, herpes virus infection, anaemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia, cytokine release syndrome, hypokalaemia, decreased appetite, hyperglycaemia, hyponatraemia, hypophosphataemia, insomnia, headache, hypotension, cough, dyspnoea, diarrhoea, nausea, abdominal pain, constipation, vomiting, rash, musculoskeletal pain, pyrexia, fatigue, oedema, increased ALT, increased AST, infusion-related reaction.

Common (≥1/100 to <1/10): respiratory tract infection, fungal infection, sinusitis, sepsis, bacteraemia, tumour flare, febrile neutropenia, hypomagnesaemia, hypoalbuminaemia, mental status changes, peripheral neuropathy, tachycardia, interstitial lung disease, increased gamma-glutamyltransferase, increased blood bilirubin.

Uncommon (≥1/1,000 to <1/100): tumour lysis syndrome, aphasia, neurotoxicity, immune effector cell-associated neurotoxicity syndrome (ICANS).

Important serious reactions:

• CRS: with the recommended step-up regimen it occurred in 58% of patients with FL (grade 1 47%, grade 2 10%, grade 3 1.3%) and 52% with DLBCL (grade 1 35%, grade 2 16%, grade 3 0.8%). Median onset was about 20 hours after the end of an infusion and median duration 2 days; 96% of patients with CRS had their first event during step-up dosing or the first full dose. Incidence and severity fell with continued dosing.
• Serious infections: 44% in FL and 33% in DLBCL; infections fatal within 90 days of the last dose occurred in 8% and 9%, many due to COVID-19.
• Neurologic toxicity: headache (13%), dizziness (8%), anxiety (4.3%), confusional state (3.5%) and encephalopathy (3%) were most frequent; grade 3 or 4 neurologic reactions occurred in 7%, and one patient (0.3%) had grade 2 ICANS.
• Tumour lysis syndrome in 0.5% (2 patients, both grade 3) and tumour flare in 3.5%.

No interaction studies have been performed.

• CYP450 substrates: starting Ordspono causes a transient rise in cytokines, which may suppress CYP450 enzyme activity. The risk is highest in cycle 1 in patients taking CYP450 substrates, especially those with a narrow therapeutic index (for example warfarin, ciclosporin or theophylline). Therapeutic monitoring should be considered when Ordspono is started.
• Live vaccines: live and live-attenuated vaccines should not be given together with Ordspono.

Ordspono must be given only under the supervision of a healthcare professional experienced in diagnosing and treating cancer who has access to appropriate medical support to manage severe CRS. At least one dose of tocilizumab for CRS must be available before the cycle 1 administration, with access to a further dose within 8 hours of using the previous one. Patients should be well hydrated.

Premedication and Supportive Medicines

• Premedication is required for every dose in cycle 1 and on days 1 and 8 of cycle 2, and post-medication on cycle 1 days 3, 10 and 17 and cycle 2 day 2. It may continue beyond cycle 2, day 8 until a dose is tolerated without CRS or infusion-related reactions.
• Table 1 of the SmPC sets the doses. In cycle 1, before each infusion: dexamethasone 10 mg orally 12 to 24 hours before (omitted on days 2, 9 and 16 if infusions are given on consecutive days) and 20 mg intravenously 1 to 3 hours before, plus diphenhydramine 25 mg (or an equivalent antihistamine) and paracetamol 650 to 1,000 mg, both 30 to 60 minutes before; on days 3, 10 and 17, dexamethasone 10 mg orally 24 hours after the infusion. In cycle 2: dexamethasone 20 mg intravenously 1 to 3 hours before the day 1 dose and 10 mg intravenously before the day 8 dose (20 mg if CRS or an infusion-related reaction occurred with the day 1 dose), with the same antihistamine and paracetamol, and dexamethasone 10 mg orally 24 hours after the day 1 infusion. The SmPC table gives the full day-by-day schedule.
• Prophylaxis against infection, tumour lysis syndrome and corticosteroid-induced gastrointestinal reactions is also recommended.

Recommended Dose

Cycles 1 to 4 last 21 days. Each dose is given only if the previous dose was tolerated, and treatment continues until disease progression or unacceptable toxicity.

• Cycle 1, step-up dosing (4-hour infusions, both indications): 0.2 mg on day 1, 0.5 mg on day 2, 2 mg on days 8 and 9, and 10 mg on days 15 and 16.
• Cycles 2 to 4 (days 1, 8 and 15): 80 mg for r/r FL or 160 mg for r/r DLBCL. The cycle 2, day 1 infusion lasts 4 hours; if tolerated, infusions from cycle 2, day 8 can be shortened to 1 hour.
• Maintenance every 2 weeks: starting 1 week after the end of cycle 4, 160 mg (r/r FL) or 320 mg (r/r DLBCL) as a 1-hour infusion.
• Maintenance every 4 weeks: patients in complete response for 9 months move to the same maintenance dose every 4 weeks.

Restarting After a Dose Delay

Table 3 of the SmPC sets restart rules by cycle and length of delay. In general, if the delay is short the next scheduled dose is given; for longer delays an earlier step is repeated; and treatment restarts from 0.2 mg if more than 3 days pass after the 0.2 mg dose, 2 weeks or more after the 0.5 mg dose, more than 4 weeks after the 2 mg doses, more than 5 weeks after the 10 mg doses, or more than 10 weeks in cycles 2 onwards (including maintenance). Premedication is given again as in Table 1 of the SmPC.

Managing Cytokine Release Syndrome

CRS is identified from the clinical picture, and other causes of fever, hypoxia and hypotension are evaluated and treated. If CRS is suspected, Ordspono is withheld until it resolves, with supportive therapy (intensive care for severe or life-threatening CRS). After grade 1, 2 or 3 CRS, premedication is given before the next dose and the patient is monitored more often.

• Grade 1 (fever ≥38 °C): withhold the infusion and manage per current practice guidelines; in advanced age, with co-morbidities or fever not responding to antipyretics, consider dexamethasone and/or tocilizumab. Resume when symptoms resolve.
• Grade 2 (fever with hypotension not needing vasopressors and/or hypoxia needing low-flow oxygen): withhold and give dexamethasone and/or tocilizumab. Resume when symptoms resolve; for the next dose monitor more frequently and consider hospitalisation. Recurrent grade 2 CRS is managed as grade 3.
• Grade 3 (fever with hypotension needing a vasopressor and/or hypoxia needing high-flow oxygen): withhold, give dexamethasone and/or tocilizumab and supportive therapy, which may include intensive care. When symptoms resolve, give the next dose at least 5 days after the previous one, in hospital. If CRS occurred on cycle 1, day 1 or 2, repeat the 0.2 mg or 0.5 mg dose respectively; if on cycle 1, day 8 or later, reduce to 50% of the last dose received. If it does not recur, complete the step-up dosing and continue on schedule. If CRS is refractory, consider alternative anti-cytokine or immunosuppressant therapy.
• Grade 4 (fever with hypotension needing multiple vasopressors and/or hypoxia needing positive-pressure oxygen): discontinue permanently; manage with dexamethasone and/or tocilizumab and supportive therapy, which may include intensive care.
• Doses: dexamethasone 10 to 20 mg per day intravenously (grades 1 and 2) or 10 to 20 mg intravenously every 6 hours (grades 3 and 4); tocilizumab 8 mg/kg intravenously over 1 hour, not above 800 mg per dose.

Managing Neurologic Toxicity

At the first sign of neurologic toxicity, including ICANS, consider a neurology evaluation, rule out other causes and give supportive therapy, which may include intensive care.

• ICANS grade 1 (ICE score 7 to 9, or awakens spontaneously): withhold until it resolves; supportive care (monitoring, consider neurology consultation and imaging, consider seizure prophylaxis with a non-sedating antiseizure medicine such as levetiracetam); consider dexamethasone, and tocilizumab if CRS is also present.
• ICANS grade 2 (ICE score 3 to 6, or awakens to voice): withhold until it resolves; supportive care as for grade 1; dexamethasone 10 mg intravenously, reassessed and repeated every 6 to 12 hours until resolution or baseline; tocilizumab if CRS is also present.
• ICANS grade 3 (ICE score 0 to 2, awakens only to touch, seizures, or raised intracranial pressure with focal oedema on imaging): discontinue permanently; supportive care; dexamethasone 10 mg intravenously every 6 hours or methylprednisolone 1 mg/kg intravenously every 12 hours; tocilizumab if CRS is also present.
• ICANS grade 4 (ICE score 0, unarousable, stupor or coma, life-threatening or repetitive seizures, deep focal motor weakness or signs of raised intracranial pressure or cerebral oedema): discontinue permanently; consider intensive care and mechanical ventilation for airway protection; high-dose corticosteroids; standard measures for raised intracranial pressure with neurosurgical consultation; tocilizumab if CRS is also present.
• Neurologic toxicity other than ICANS: for grade 2 or 3, withhold until symptoms improve to grade 1 or baseline, give supportive therapy and consider neurologic evaluation; for grade 4, discontinue permanently.
• Antifungal prophylaxis is recommended, as clinically indicated, in patients given corticosteroids for CRS or neurologic toxicity.

Other Adverse Reactions

• Infusion-related reactions: grade 2, interrupt and manage, then resume at 50% of the infusion rate and increase as tolerated; grade 3, interrupt, and after resolution wait 24 hours and repeat the dose (reduced by 50% for doses of 2 mg or more); grade 4, discontinue permanently.
• Infections: withhold Ordspono in patients with active infection until it resolves; for grade 4 consider permanent discontinuation.
• Tumour lysis syndrome (grade 3 or 4): withhold and manage per standard practice. After complete resolution, restart from 0.2 mg if the dose was 0.5 mg or less; resume at 50% of the last dose if it was 2 mg or more. Keep at least 2 days between consecutive doses until the end of cycle 1.
• Neutropenia (neutrophils below 0.5 × 10⁹/L) and thrombocytopenia (platelets below 50 × 10⁹/L): withhold until neutrophils are 0.5 × 10⁹/L or higher and platelets 50 × 10⁹/L or higher.
• Other adverse reactions: grade 3, withhold until resolution to grade 1 or baseline, then continue; grade 4, discontinue permanently (transient grade 4 laboratory abnormalities may resume treatment on recovery to grade 1 or baseline).

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no dose adjustment.
• Hepatic impairment: no adjustment in mild to moderate impairment. Not studied in severe impairment (total bilirubin above 3 and up to 10 times the upper limit of normal with any AST), so no dose recommendation can be made.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Method of Administration

Intravenous use after dilution only. The first cycle is a 4-hour infusion; if cycle 2, day 1 is tolerated, later infusions can be shortened to 1 hour. Give through a dedicated infusion line, never as an intravenous push or bolus. Dilute using aseptic technique (section 6.6 of the SmPC gives the instructions and compatible tubing); a 0.2-micron or 5-micron polyethersulfone filter is recommended.

Cytokine Release Syndrome and Infusion-Related Reactions

CRS can be serious or life-threatening. Signs include fever, hypotension, hypoxia, tachycardia, chills, dyspnoea and headache; most events occur in cycle 1, and a transient rise in liver enzymes has been seen during CRS. The step-up schedule and premedication were set up to reduce the risk and must be followed. Patients are monitored during and after each administration and must stay within reach of a qualified healthcare facility for at least 24 hours after each dose of the step-up regimen and after the first full dose. At the first sign of CRS they are assessed for hospitalisation, and they should seek immediate medical attention if symptoms appear at any time. Some infusion-related reactions cannot be told apart from CRS; for these, withhold, slow or permanently stop the infusion according to severity. Patients with CRS, or other reactions that impair consciousness, should not drive or operate heavy or dangerous machinery until they resolve.

Serious Infections

Serious or fatal infections can occur. Patients are monitored before and during treatment for bacterial, fungal and new or reactivated viral infections. Ordspono is not given in the presence of active infection, and caution applies with a history of recurring or chronic infections. Prophylactic antimicrobials are given as appropriate: prophylaxis against Pneumocystis jirovecii pneumonia is recommended for all patients, and prophylaxis for those with a history of herpes virus or cytomegalovirus infection. Antiviral treatment is recommended for patients with hepatitis B surface antigen, hepatitis B core antibody and/or a measurable viral load, and intravenous immunoglobulin should be considered per guidelines. Febrile neutropenia calls for evaluation for infection and management with antibiotics, fluids and supportive care; withhold or consider permanent discontinuation by severity.

Neurologic Toxicity

Neurologic toxicities, including ICANS, aphasia and encephalopathy, may be severe. Patients should be monitored for signs and symptoms, evaluated and given supportive care, and Ordspono is withheld or stopped permanently according to severity. Patients are told to seek medical attention if symptoms occur.

Tumour Lysis Syndrome

Tumour lysis syndrome is more likely with a high tumour burden, rapidly proliferating tumours or renal dysfunction. Patients at increased risk need adequate hydration and prophylactic anti-hyperuricaemic treatment (for example allopurinol or rasburicase) before Ordspono. Blood chemistry is monitored and abnormalities treated promptly.

Pneumonitis and Interstitial Lung Disease

Pneumonitis or interstitial lung disease, which may be life-threatening or fatal, has been reported. It should be considered in respiratory symptoms with no causative pathogen.

Tumour Flare

Tumour flare has been reported; it can cause localised pain and swelling. Patients are monitored and assessed for tumour flare at critical anatomical sites.

Patient Card

The Patient Card describes the common signs and symptoms of CRS and neurologic toxicity, including ICANS, and when to seek immediate medical attention. The prescriber must discuss the risks with the patient and give them the card, which they should carry at all times and show to every healthcare provider.

Vaccination

Live and live-attenuated vaccines should not be given together with Ordspono. Studies have not been done in patients who recently received live vaccines.

Traceability and Excipients

The name and batch number of the product given must be clearly recorded (and of the human albumin solution, if used as suggested in section 6.6). Ordspono contains polysorbate 80, which may cause allergic reactions.

Pregnancy, Breastfeeding and Fertility

• Contraception: females of reproductive potential should use effective contraception during treatment and for at least 6 months after the last dose.
• Pregnancy: there are no data in pregnant women and no animal reproductive studies. Human IgG crosses the placenta, and odronextamab may cause foetal harm, including B-cell lymphocytopenia. It is not recommended in pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: there is no information on milk transfer, but human IgG can be secreted in milk. Women should not breastfeed during treatment and for at least 6 months after the last dose.
• Fertility: no human data. Animal studies do not indicate harmful effects on male or female reproductive organs or fertility parameters.

Effect on Driving

Ordspono has a minor influence on the ability to drive and use machines. Patients with CRS or other reactions that impair consciousness should be evaluated and advised not to drive or operate heavy or potentially dangerous machinery until they resolve.

Store in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. The product travels in the cold chain from supply to the hospital. Storage after dilution is described under Shelf Life.

• Unopened vial: 3 years.
• Diluted infusion solution: chemical and physical in-use stability has been shown for up to 24 hours at 2–8 °C for all doses; at room temperature (20–25 °C) for up to 6 hours for the 0.2 mg dose prepared with human albumin, and up to 12 hours for doses of 0.5 mg or more. Discard the diluted solution if these limits are exceeded. From a microbiological point of view the product should be used immediately.

Prescription only (Rx), subject to restricted medical prescription. Ordspono may be given only under the supervision of a healthcare professional experienced in diagnosing and treating cancer, with medical support and tocilizumab available for severe CRS. It is an intravenous infusion given in hospital, so it is supplied to the hospital that administers it, with cold-chain delivery at 2–8 °C.