Loncastuximab Tesirine

Loncastuximab tesirine is an antibody-drug conjugate (ADC) directed at CD19. It combines a humanised IgG1 kappa monoclonal antibody, produced in Chinese Hamster Ovary cells, with SG3199, a pyrrolobenzodiazepine (PBD) dimer that acts as a cytotoxic alkylating agent. The two are joined by a protease-cleavable valine-alanine linker; SG3199 with its linker is called tesirine (SG3249).

Mechanism of Action

• Targeting CD19: the antibody binds human CD19, a transmembrane protein on the surface of cells of B-cell lineage and on most B-cell malignancies. CD19 is rapidly internalised and not shed into the circulation, which makes it a suitable ADC target (DrugBank).
• Internalisation and release: after binding, the conjugate is taken into the cell and proteases cut the linker, releasing SG3199.
• DNA damage: SG3199 binds in the minor groove of DNA and forms highly cytotoxic interstrand cross-links, which leads to cell death.
• Exposure and response: over 0.015–0.2 mg/kg, higher exposure in cycle 1 was linked with higher efficacy and with more grade 2 or higher adverse reactions, including skin and nail reactions, liver function test abnormalities and raised γ-glutamyltransferase.
• Cardiac electrophysiology: at 0.15 mg/kg in cycles 1 and 2 there were no large mean increases (more than 20 ms) in the QTc interval.

Pharmacokinetics

• Absorption: given as an intravenous infusion; other routes have not been studied. At the approved dose, geometric mean Cmax was 2,795 ng/mL and AUCtau 22,082 ng·day/mL in cycle 2, and 1,705 ng/mL and 16,265 ng·day/mL at steady state. Steady-state Cmax was 39.0% lower than after the second dose, and steady state is reached after about 15 weeks.
• Distribution: geometric mean volume of distribution 7.14 L. In vitro, SG3199 is a substrate of P-glycoprotein but not of BCRP, OATP1B1, OATP1B3 or OCT1, and it does not inhibit the transporters tested at clinically relevant concentrations.
• Metabolism: the antibody part is expected to be broken down into small peptides by normal catabolic pathways. SG3199 is metabolised by CYP3A4/5 in vitro and does not inhibit the main CYP enzymes at clinically relevant concentrations.
• Elimination: clearance fell from 0.34 L/day after a single dose to 0.26 L/day at steady state. Mean half-life was 15.8 days in cycle 1 and 20.5 days at steady state. The main excretion pathways of SG3199 have not been studied in humans; rat data show minimal renal excretion.
• Special populations: no clinically significant differences were seen by age (20–94 years) or sex. For renal and hepatic impairment see Administration and Dosage.

• Relapsed or refractory DLBCL and HGBL: Zynlonta as monotherapy for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL), after two or more lines of systemic therapy.

• Hypersensitivity to the active substance or to any of the excipients.

The frequencies below come from 215 patients with relapsed or refractory DLBCL who received Zynlonta alone at 0.15 mg/kg in two monotherapy studies. The most frequent adverse reactions were increased γ-glutamyltransferase (35.8%), neutropenia (34.9%), fatigue (30.2%), anaemia (28.8%), thrombocytopenia (28.4%), nausea (26.5%), peripheral oedema (23.3%) and rash (20.0%). The most frequent severe reactions (grade 3 or higher) were neutropenia (24.2%), increased γ-glutamyltransferase (17.2%), thrombocytopenia (15.8%), anaemia (11.6%) and infections (9.8%).

Very common (≥1/10): anaemia, neutropenia, thrombocytopenia; decreased appetite; pleural effusion, dyspnoea; abdominal pain, diarrhoea, nausea, vomiting, constipation; rash, pruritus, erythema; peripheral oedema, fatigue; increased γ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase and blood alkaline phosphatase.

Common (≥1/100 to <1/10): pneumonia (including lung infection), upper and lower respiratory tract infection, sepsis; febrile neutropenia; fluid retention; lethargy; pericardial effusion; ascites; bullous dermatitis, photosensitivity reaction, swelling of the face, maculopapular rash, pruritic rash, skin hyperpigmentation; neck pain, pain in extremity, back pain, musculoskeletal pain, myalgia, musculoskeletal chest pain; face oedema, asthenia, peripheral swelling, swelling, non-cardiac chest pain.

Uncommon (≥1/1,000 to <1/100): fluid overload; pericarditis; pustular rash; musculoskeletal discomfort, limb discomfort; generalised oedema, oedema.

Not known (identified after marketing): telangiectasia, blister, vesicular rash, cutaneous collagenous vasculopathy.

Serious reactions to watch for:

• Effusion and oedema: grade 3 or higher in 5.6% of patients; they led to discontinuation in 5.1%, and none were fatal.
• Myelosuppression: grade 3 or 4 neutropenia in 24.2%, thrombocytopenia in 15.8% and anaemia in 11.6%; febrile neutropenia in 3.3%.
• Infections: grade 3 or higher in 9.8%, with a fatal infection (lung infection) in 0.5%.
• Skin reactions: grade 3 in 3.7% (photosensitivity reaction 1.4%), none grade 4 or 5.
• Liver tests: abnormalities of grade 3 or higher in 19.5%, mostly raised γ-glutamyltransferase (17.2%), which caused dose delay in 17.7%, dose reduction in 3.3% and withdrawal in 8.8%.

Overall, 47.4% of patients needed a dose modification or interruption because of adverse reactions.

• No interaction studies have been performed in humans for loncastuximab tesirine, free tesirine, SG3199 or related metabolites, and no clinically important pharmacokinetic interactions are expected.
• In vitro data: SG3199 is metabolised by CYP3A4/5 and is a P-glycoprotein substrate. The SmPC gives no specific advice on CYP3A4 or P-glycoprotein modulators.
• Dexamethasone is part of the regimen as premedication (see Administration and Dosage).

Zynlonta must only be given under the supervision of a healthcare professional experienced in the diagnosis and treatment of cancer patients. It is for intravenous use only.

Recommended Dose

• 0.15 mg/kg every 21 days for 2 cycles, followed by 0.075 mg/kg every 21 days for the following cycles, until disease progression or unacceptable toxicity.

Premedication With Dexamethasone

Unless contraindicated, dexamethasone 4 mg is given orally or intravenously twice daily for 3 days, starting the day before Zynlonta, to reduce the toxicities related to the pyrrolobenzodiazepine. If it is not started the day before, oral or intravenous dexamethasone should begin at least 2 hours before Zynlonta.

Preparation and Infusion

• The infusion runs over 30 minutes through an intravenous line, using a dedicated infusion line with a sterile, non-pyrogenic, low-protein-binding in-line or add-on filter (0.2 or 0.22 micrometre pore size) and catheter.
• The medicine is reconstituted and diluted with aseptic technique under the supervision of a healthcare professional; see section 6.6 of the SmPC. It contains a cytotoxic component covalently attached to the antibody, so special handling and disposal procedures apply.
• Extravasation has been associated with irritation, swelling, pain and/or tissue damage, which may be severe, so the infusion site should be watched for subcutaneous infiltration during the infusion.

Dose Modification

• Neutropenia (absolute neutrophil count below 1 × 10⁹/L): withhold until the count returns to 1 × 10⁹/L or higher.
• Thrombocytopenia (platelets below 50,000/µL): withhold until the count returns to 50,000/µL or higher.
• Oedema or effusion of grade 2 or higher: withhold until the toxicity resolves to grade 1 or less.
• Other adverse reactions of grade 3 or higher: withhold until the toxicity resolves to grade 1 or less.
• If dosing is delayed by more than 3 weeks because of toxicity, subsequent doses are reduced by 50%. If toxicity requires a dose reduction after the second 0.15 mg/kg dose (cycle 2), cycle 3 is given at 0.075 mg/kg.
• If toxicity recurs after two dose reductions, permanent discontinuation should be considered.

Delayed or Missed Dose

A missed dose is given as soon as possible, and the schedule is adjusted to keep a 21-day interval between doses.

Special Populations

• Elderly: no dose adjustment for patients aged 65 years or over.
• Renal impairment: no adjustment for mild to moderate impairment. Zynlonta has not been studied in severe renal impairment (creatinine clearance 15 to 29 mL/min); its effect in severe impairment and end-stage renal disease, with or without haemodialysis, is unknown, and additional monitoring for adverse reactions may be warranted.
• Hepatic impairment: no adjustment for mild impairment (total bilirubin at or below the upper limit of normal with AST above it, or total bilirubin above 1 to 1.5 times the upper limit with any AST). It has not been studied in moderate or severe impairment (total bilirubin above 1.5 times the upper limit with any AST); monitoring for adverse reactions is recommended.
• Children and adolescents under 18: safety and efficacy have not been established; no data are available.

Traceability

Because Zynlonta is a biological medicinal product, its name and batch number should be clearly recorded for each patient.

Effusion and Oedema

Serious effusion and oedema have been reported. Patients should be monitored for new or worsening oedema or effusions, and Zynlonta withheld for grade 2 or higher until the toxicity resolves. Diagnostic imaging should be considered for symptoms of pleural or pericardial effusion, such as new or worse breathlessness, chest pain, or swelling and bloating of the abdomen (ascites), and appropriate medical management started. If effusion or oedema worsens with weight gain, severe hypotension, low albumin and/or haemoconcentration (raised haemoglobin or haematocrit), capillary leak syndrome should be considered.

Myelosuppression

Zynlonta can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia and anaemia. Complete blood counts should be checked before each dose; cytopenia may call for more frequent testing, interruption, dose reduction or discontinuation. Prophylactic granulocyte colony-stimulating factor should be considered, as applicable.

Infections

Fatal and serious infections, including opportunistic infections and sepsis, have been reported. Patients should be monitored for new or worsening signs of infection, and Zynlonta withheld for a grade 3 or 4 infection until it has resolved.

Photosensitivity and Skin Reactions

Serious skin reactions have been reported; in the studies they were treated with oral and topical corticosteroids and anti-pruritic therapy. Patients should be monitored for new or worsening skin reactions, including photosensitivity, and Zynlonta withheld for severe (grade 3) reactions until resolution. Patients should minimise or avoid direct natural or artificial sunlight, including through glass windows, and protect their skin with sun-protective clothing and/or sunscreen. Dermatological consultation should be considered if a skin reaction or rash develops.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy: there are no data in pregnant women and no animal reproduction studies were done. Zynlonta may cause embryo-foetal harm because it contains a genotoxic compound (SG3199) that affects actively dividing cells. It is not recommended during pregnancy unless the benefit to the woman outweighs the risk to the foetus, and not in women of childbearing potential who are not using contraception. A pregnancy test is advised before starting.
• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 10 months after the last dose. Men with partners of childbearing potential should use effective contraception during treatment and for at least 7 months after the last dose.
• Breastfeeding: a risk to the breast-fed child cannot be excluded. Breastfeeding should be discontinued during treatment and for at least 3 months after the last dose.
• Fertility: animal studies showed testicular toxicity, so loncastuximab tesirine may impair male fertility. Men should be advised to consider having sperm samples preserved and stored before starting.

Polysorbate

Each vial contains 0.4 mg of polysorbate 20 (0.2 mg/mL). Polysorbates may cause allergic reactions.

Effect on Driving

Zynlonta has no or negligible influence on the ability to drive and use machines. Fatigue has been reported, and this should be taken into account when driving or using machines.

Store unopened vials in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. As a refrigerated product, it should be transported and stored in an unbroken cold chain. Storage after reconstitution and dilution is described under Shelf Life. The vial (clear type 1 glass, 10 mg) is supplied in a pack of one.

• Unopened vial: 6 years.
• Reconstituted solution: use immediately. If it is not used immediately, in-use storage is the user’s responsibility and should not exceed 4 hours in a refrigerator (2–8 °C) or 4 hours at room temperature (20–25 °C), unless reconstitution took place under controlled and validated aseptic conditions. Chemical and physical in-use stability has been shown for up to 4 hours at either condition.
• Diluted solution for infusion: use immediately. If it is not used immediately, in-use storage should not exceed 24 hours in a refrigerator (2–8 °C) or 8 hours at room temperature (20–25 °C), unless dilution took place under controlled and validated aseptic conditions. Chemical and physical in-use stability has been shown for up to 24 hours at room temperature (20–25 °C).
• Do not use the medicine if storage conditions exceed the limits.

Prescription only (Rx), under restricted medical prescription (Annex II B of the marketing authorisation). Zynlonta is reconstituted, diluted and given as an intravenous infusion under the supervision of a healthcare professional experienced in cancer treatment, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.