Zolbetuximab

Zolbetuximab is a chimeric (mouse/human) IgG1 monoclonal antibody directed against claudin 18.2 (CLDN18.2), a tight-junction molecule. In healthy tissue the claudin 18 isoform 2 is found only in the lining of the stomach. When stomach cells turn malignant its expression is retained, and the loss of normal cell polarity leaves the protein exposed on the cell surface, which makes it a target for an antibody. Zolbetuximab is produced in Chinese hamster ovary cells by recombinant DNA technology.

Mechanism of Action

• Target binding: zolbetuximab binds selectively to cells that carry CLDN18.2, whether transfected or expressing it naturally.
• Immune-mediated killing: it depletes CLDN18.2-positive cells through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), recruiting cellular and soluble immune effectors.
• Effect of chemotherapy: in non-clinical data, cytotoxic medicines increased CLDN18.2 expression on human cancer cells and improved zolbetuximab-induced ADCC and CDC.
• Dosing schedules: exposure-response analyses predict no clinically significant difference in efficacy or safety between 800/400 mg/m² every 2 weeks and 800/600 mg/m² every 3 weeks.

Pharmacokinetics

• Dose proportionality: after intravenous infusion, pharmacokinetics are dose-proportional from 33 to 1,000 mg/m². At 800/600 mg/m² every 3 weeks, steady state is reached by about 24 weeks, with a mean Cmax of 453 μg/mL and AUCtau of 4,125 day·μg/mL. At 800/400 mg/m² every 2 weeks, steady state is expected by about 22 weeks, with a mean Cmax of 359 μg/mL and AUCtau of 2,758 day·μg/mL.
• Distribution: the mean steady-state volume of distribution is about 5.5 L.
• Metabolism: like other antibodies, zolbetuximab is expected to be broken down into small peptides and amino acids by non-specific catabolism, so no metabolic drug interactions are expected.
• Elimination: clearance decreases over time, by up to 57.6% from baseline, to a population mean steady-state clearance of 0.0117 L/h. The half-life ranged from 7.6 to 15.2 days during treatment.
• Special populations: a population analysis found no clinically meaningful effect of age (22–83 years), sex or race. Mild (n=298) and moderate (n=109) renal impairment did not change pharmacokinetics; the effect of severe renal impairment is unknown (n=1).
• Immunogenicity: in a pooled analysis of two phase 3 studies, 9.5% of patients (46 of 485) tested positive for anti-drug antibodies and 3.3% (16 of 485) for neutralising antibodies. Because of this low rate, the effect of the antibodies on pharmacokinetics, safety or effectiveness is uncertain.

Zolbetuximab is used only in combination with chemotherapy.

• Gastric or gastro-oesophageal junction (GEJ) adenocarcinoma: first-line treatment, in combination with fluoropyrimidine- and platinum-containing chemotherapy, of adults with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2 positive.
• Biomarker requirement: CLDN18.2-positive status means that at least 75% of tumour cells show moderate to strong membranous CLDN18 staining on immunohistochemistry, assessed with a CE-marked in vitro diagnostic test for this purpose or, if none is available, an alternative validated test.

• Hypersensitivity to zolbetuximab or to any of the excipients.

The frequencies come from two phase 2 and two phase 3 studies in 631 patients who received a loading dose of 800 mg/m² followed by 600 mg/m² every 3 weeks with fluoropyrimidine- and platinum-containing chemotherapy (median exposure 174 days). The most common reactions were nausea (77.2%), vomiting (66.9%), decreased appetite (42%), neutropenia (30.7%), decreased neutrophil count (28.4%), weight decrease (21.9%), pyrexia (17.4%), hypoalbuminaemia (17.1%), peripheral oedema (13.9%), hypertension (9%), dyspepsia (7.8%), chills (5.2%), salivary hypersecretion (3.8%), infusion-related reaction (3.2%) and drug hypersensitivity (1.6%).

Very common (≥1/10): neutropenia, decreased neutrophil count, hypoalbuminaemia, decreased appetite, vomiting, nausea, pyrexia, peripheral oedema, weight decrease.

Common (≥1/100 to <1/10): drug hypersensitivity, hypertension, dyspepsia, salivary hypersecretion, chills, infusion-related reaction.

Uncommon (≥1/1,000 to <1/100): anaphylactic reaction.

Serious adverse reactions occurred in 45% of patients; the most common were vomiting (6.8%), nausea (4.9%) and decreased appetite (1.9%). Twenty percent of patients stopped zolbetuximab permanently because of adverse reactions, most often vomiting (3.8%) and nausea (3.3%). Reactions led to dose interruption in 60.9% of patients, mainly vomiting (26.6%), nausea (25.5%), neutropenia (9.8%), decreased neutrophil count (5.9%) and hypertension (3.2%).

• No formal studies: no pharmacokinetic drug interaction studies have been done with zolbetuximab. Because it is cleared from the circulation by catabolism, no metabolic drug–drug interactions are expected.
• Chemotherapy partners: zolbetuximab is given with fluoropyrimidine- and platinum-containing chemotherapy, whose own SmPCs describe their interactions. When both are given on the same day, zolbetuximab is infused first.
• Antiemetic pre-medication: a combination of antiemetics (for example NK-1 receptor blockers and 5-HT3 receptor blockers) is given before each infusion as part of the regimen; this is a planned measure to prevent nausea and vomiting, not an interaction.

Treatment must be prescribed, started and supervised by a physician experienced in the use of anti-cancer therapies, and resources for managing hypersensitivity and anaphylactic reactions must be available. Zolbetuximab is given as an intravenous infusion over a minimum of 2 hours and must never be given as an intravenous push or bolus injection. Reconstitution and dilution follow section 6.6 of the SmPC; after reconstitution each mL contains 20 mg of zolbetuximab.

Patient Selection

Only patients whose tumours are CLDN18.2 positive (at least 75% of tumour cells with moderate to strong membranous CLDN18 staining) are eligible, as assessed with a CE-marked in vitro diagnostic test for this purpose or an alternative validated test.

Before Each Infusion

• If a patient has nausea and/or vomiting before the first infusion, the symptoms should have resolved to grade 1 or below.
• Before every infusion, patients receive a combination of antiemetics (for example NK-1 receptor blockers and 5-HT3 receptor blockers, and other medicines as indicated). This is important to prevent early discontinuation. Systemic corticosteroids according to local guidelines may also be considered, particularly before the first infusion.

Recommended Dose

The dose is calculated from body surface area and given together with fluoropyrimidine- and platinum-containing chemotherapy (dosed according to its own SmPC). The cycle length follows the chemotherapy backbone.

• Loading dose: 800 mg/m² intravenously once, on cycle 1, day 1.
• Maintenance dose: either 600 mg/m² intravenously every 3 weeks, starting 3 weeks after the loading dose, or 400 mg/m² intravenously every 2 weeks, starting 2 weeks after the loading dose.
• Duration: until disease progression or unacceptable toxicity.

Infusion Rate

To limit adverse reactions, each infusion starts slowly for 30–60 minutes and the rate is then increased as tolerated.

• 800 mg/m² loading dose and 600 mg/m² every 3 weeks: 75 mg/m² per hour for the first 30–60 minutes, then 150–300 mg/m² per hour for the rest of the infusion.
• 400 mg/m² every 2 weeks: 50 mg/m² per hour for the first 30–60 minutes, then 100–200 mg/m² per hour for the rest of the infusion.
• If the infusion would run beyond the permitted room-temperature storage time of the prepared bag, the bag is discarded and a new one prepared to continue the infusion.

Dose Modifications for Adverse Reactions

No dose reduction is recommended. Reactions are managed by slowing, interrupting or stopping the infusion (severity graded by NCI-CTCAE version 4.03).

• Hypersensitivity reaction: anaphylactic reaction, suspected anaphylaxis, or grade 3 or 4: stop the infusion immediately and discontinue permanently. Grade 2: interrupt until grade 1 or below, then resume at a reduced rate for the rest of the infusion; at the next infusion give antihistamine pre-medication and follow the standard infusion rates.
• Infusion-related reaction: grade 3 or 4: stop immediately and discontinue permanently. Grade 2: manage as for a grade 2 hypersensitivity reaction.
• Nausea, grade 2 or 3: interrupt until grade 1 or below, then resume at a reduced rate; follow the standard infusion rates at the next infusion.
• Vomiting: grade 4, discontinue permanently; grade 2 or 3, manage as for nausea.
• The reduced rate is set by the physician according to tolerability, severity of the reaction and the rate previously tolerated.

Special Populations

• Elderly: no dose adjustment at 65 years or over; data in patients aged 75 or over are limited.
• Renal impairment: no adjustment in mild (creatinine clearance 60 to under 90 mL/min) or moderate (30 to under 60 mL/min) impairment; no recommendation can be made in severe impairment (15 to under 30 mL/min).
• Hepatic impairment: no adjustment in mild impairment; no recommendation can be made in moderate or severe impairment.
• Children and adolescents: there is no relevant use in the paediatric population for gastric or gastro-oesophageal junction adenocarcinoma.

Traceability

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

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactic reaction and drug hypersensitivity, occurred in clinical studies. Patients are monitored during the infusion and afterwards for at least 2 hours, or longer if clinically indicated, for signs highly suggestive of anaphylaxis: urticaria, repeated cough, wheeze, and throat tightness or change in voice. Reactions are managed with the dose modifications above.

Infusion-Related Reactions

Patients are monitored for signs and symptoms such as nausea, vomiting, abdominal pain, salivary hypersecretion, pyrexia, chest discomfort, chills, back pain, cough and hypertension. These are usually reversible when the infusion is interrupted.

Nausea and Vomiting

Nausea and vomiting were the most frequent gastrointestinal reactions. Before treatment, prescribers should assess the individual patient’s risk of gastrointestinal toxicity and manage nausea and vomiting proactively, to avoid reduced exposure to zolbetuximab and/or the chemotherapy. Pre-treatment with a combination of antiemetics is recommended before every infusion. During the infusion, patients are monitored closely and gastrointestinal toxicity is managed by interrupting the infusion and/or reducing the rate. During and after the infusion, standard care applies, including antiemetics or fluid replacement as clinically indicated.

Pregnancy, Breastfeeding and Fertility

• Contraception: as a precaution, women of childbearing potential should use effective contraception during treatment.
• Pregnancy: there are no data in pregnant women. An animal reproductive and developmental study in pregnant mice showed no adverse effects. Zolbetuximab should be given in pregnancy only if the benefit outweighs the potential risk.
• Breastfeeding: there are no data on its presence in human milk or its effects on the breast-fed child. Because antibodies can pass into milk and serious reactions in the infant cannot be excluded, breastfeeding is not recommended during treatment.
• Fertility: no studies have been done, so the effect on male and female fertility is unknown.

Excipient With Known Effect

Each mL of concentrate contains 0.21 mg of polysorbate 80.

Effect on Driving

Zolbetuximab has no or negligible influence on the ability to drive and use machines.

Store the vials in a refrigerator at 2–8 °C, in the original carton to protect from light. Do not freeze. This is a cold-chain product and is transported and held at 2–8 °C until it is reconstituted.

• Reconstituted vial: may be kept at room temperature (25 °C or below) for up to 6 hours. Do not freeze it or expose it to direct sunlight; discard unused reconstituted vials beyond this time.
• Diluted solution in the infusion bag: from a microbiological point of view it should be given immediately. If not, store the prepared bag either under refrigeration (2–8 °C) for no longer than 24 hours including infusion time, counted from the end of preparation (do not freeze), or at room temperature (25 °C or below) for no longer than 8 hours including infusion time, counted from when the bag is taken out of the refrigerator. Protect from direct sunlight and discard any unused bag beyond the storage time.

The 100 mg powder is supplied in a 20 mL type I glass vial (green cap) in cartons of 1 or 3 vials, and the 300 mg powder in a 50 mL type I glass vial (violet cap) in cartons of 1 vial; not all pack sizes may be marketed.

• Unopened vial: 4 years.
• Reconstituted vial: up to 6 hours at room temperature (25 °C or below).
• Diluted solution in the infusion bag: administer immediately where possible; otherwise up to 24 hours at 2–8 °C including infusion time, and up to 8 hours at room temperature including infusion time from removal from the refrigerator.

Prescription only (Rx), on restricted medical prescription (Annex II B) from a physician experienced in the use of anti-cancer therapies, after the tumour has been shown to be CLDN18.2 positive. Zolbetuximab is infused in hospital, where resources to manage hypersensitivity reactions must be available, so it is supplied to the hospital or clinic that administers it, as a refrigerated cold-chain product at 2–8 °C.