Tafasitamab

Tafasitamab is a humanised CD19-specific monoclonal antibody of the immunoglobulin G (IgG) subclass, produced in Chinese hamster ovary cells by recombinant DNA technology. Its Fc region is modified to strengthen immune effector activity against B cells.

Mechanism of Action

• Target: CD19, an antigen expressed on the surface of pre-B and mature B lymphocytes.
• B-cell lysis: after binding CD19, tafasitamab causes B-cell lysis by engaging immune effector cells such as natural killer cells, γδ T cells and phagocytes, and by inducing direct cell death (apoptosis).
• Fc enhancement: the Fc modification increases antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.
• B-cell depletion: circulating B cells fall quickly. In relapsed or refractory DLBCL the reduction from baseline reached 97% after eight days and about 100% (median) within 16 weeks. In follicular lymphoma, circulating B cells became undetectable by day 8 in patients who had detectable cells at the start, and stayed depleted during treatment. Depletion in the blood does not directly correlate with depletion in solid organs or malignant deposits.

Pharmacokinetics

The pharmacokinetics were described by a population analysis.

• Exposure: average serum trough concentrations were 178.4 (± 66) μg/mL during weekly 12 mg/kg infusions in cycles 1 to 3 and 163.2 (± 74.3) μg/mL during dosing every 14 days in cycles 4 to 6. The mean maximum serum concentration was 488.4 (± 126.6) μg/mL.
• Distribution: the total volume of distribution at steady state is 7.11 L.
• Metabolism: the exact pathway has not been characterised. As a human IgG antibody, tafasitamab is expected to be broken down into small peptides and amino acids by the same catabolic pathways as endogenous IgG.
• Elimination: clearance was 0.44 L/day and the terminal half-life 13.4 days. Over long-term observation clearance fell to 0.29 L/day after two years.
• Special populations: age, body weight, sex, tumour size, disease type, B-cell or lymphocyte counts, anti-drug antibodies, lactate dehydrogenase and serum albumin had no relevant effect on pharmacokinetics. The influence of race and ethnicity is unknown.

• Relapsed or refractory DLBCL: in combination with lenalidomide, followed by tafasitamab monotherapy, for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT).
• Relapsed or refractory follicular lymphoma (FL): in combination with lenalidomide and rituximab, for adults with relapsed or refractory follicular lymphoma (grade 1–3a) after at least one line of systemic therapy.

• Hypersensitivity to tafasitamab or to any of the excipients.

In DLBCL (study L-MIND, 81 patients given tafasitamab with lenalidomide), the most common reactions were infections (73%), neutropenia (51%), asthenia (40%), anaemia (36%), diarrhoea (36%), thrombocytopenia (31%), cough (26%), peripheral oedema (24%), pyrexia (24%) and decreased appetite (22%). Serious reactions were mainly infection (26%, including pneumonia 7%) and febrile neutropenia (6%). Tafasitamab was permanently stopped for an adverse reaction in 15% of patients.

In follicular lymphoma (study inMIND, 327 patients given tafasitamab with rituximab and lenalidomide), the most common reactions were infections (68%, including viral 41% and bacterial 27%), neutropenia (57%), rash (36.4%), asthenia (34.9%), pyrexia (19%), thrombocytopenia (17%), anaemia (17%), infusion-related reaction (15.9%), pruritus (15.6%) and headache (10.4%). Serious reactions were mainly infections (26%), febrile neutropenia (2.8%), acute kidney injury (2.8%) and pyrexia (1.8%). Tafasitamab was permanently stopped in 11.6% of patients.

The frequencies below are based on all-cause adverse event rates, so some events may have other causes such as the disease or other medicines.

Very common (≥1/10): infections (bacterial, viral and fungal, including pneumonia, bronchitis and urinary tract infection, and opportunistic infections with fatal outcome), neutropenia, thrombocytopenia, anaemia, diarrhoea, constipation, abdominal pain, rash, asthenia, pyrexia. In DLBCL also febrile neutropenia, leukopenia, hypokalaemia, decreased appetite, dyspnoea, cough, vomiting, nausea, back pain, muscle spasms and peripheral oedema. In follicular lymphoma also headache, pruritus and infusion-related reaction.

Common (≥1/100 to <1/10): sepsis (including neutropenic sepsis), increased transaminases. In DLBCL also basal cell carcinoma, lymphopenia, hypogammaglobulinaemia, hypocalcaemia, hypomagnesaemia, headache, paraesthesia, dysgeusia, exacerbation of chronic obstructive pulmonary disease, nasal congestion, hyperbilirubinaemia, increased gamma-glutamyltransferase, pruritus, alopecia, erythema, hyperhidrosis, arthralgia, pain in extremity, musculoskeletal pain, increased blood creatinine, mucosal inflammation, weight decrease, increased C-reactive protein and infusion-related reaction. In follicular lymphoma also bronchitis, febrile neutropenia, leukopenia and chills.

Uncommon (≥1/1,000 to <1/100): tumour lysis syndrome (follicular lymphoma).

Myelosuppression (neutropenia, febrile neutropenia, thrombocytopenia, leukopenia, lymphopenia or anaemia) occurred in about 63–65% of patients and led to interruption of tafasitamab in about 41–43%. Infusion-related reactions are most frequent in the first cycle (symptoms include chills, flushing, dyspnoea, hypertension and rash). Fatal infections occurred, including COVID-19 and sepsis in the follicular lymphoma study. Progressive multifocal leukoencephalopathy has been reported with combination therapy.

• Interaction studies: none have been performed with tafasitamab.
• Combination partners: for lenalidomide and rituximab, including prophylactic antithrombotic medicines with lenalidomide, see their own SmPCs.
• Medicines that raise bleeding risk (platelet inhibitors, anticoagulants): withholding them should be considered because of thrombocytopenia.
• Live vaccines: not recommended during tafasitamab therapy; their safety after therapy has not been investigated.

Minjuvi must be given by a healthcare professional experienced in treating cancer patients. It is infused intravenously after reconstitution and dilution. It must not be given as an intravenous push or bolus, and not through the same infusion line as other medicines.

Premedication

A premedication to reduce the risk of infusion-related reactions is given 30 minutes to 2 hours before the infusion. It is optional for later infusions if no infusion-related reactions occurred during the first 3 infusions. It may include an antipyretic (for example paracetamol), an H1 blocker (for example diphenhydramine), an H2 blocker (for example cimetidine) and/or a glucocorticosteroid (for example methylprednisolone). After a grade 1 to 3 infusion-related reaction, premedication is given before every later infusion.

Recommended Dose

The dose is 12 mg per kg body weight as an intravenous infusion, in 28-day cycles.

• Relapsed or refractory DLBCL: cycle 1, infusions on days 1, 4, 8, 15 and 22; cycles 2 and 3, days 1, 8, 15 and 22; from cycle 4 until disease progression, days 1 and 15. Patients take lenalidomide capsules themselves, starting at 25 mg daily on days 1 to 21 of each cycle (adjusted per the lenalidomide SmPC). The combination is given for up to twelve cycles; lenalidomide then stops and tafasitamab continues alone on days 1 and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
• Relapsed or refractory follicular lymphoma: cycles 1 to 3, infusions on days 1, 8, 15 and 22; cycles 4 to 12, days 1 and 15. Rituximab 375 mg/m² is given intravenously on days 1, 8, 15 and 22 of cycle 1 and on day 1 of cycles 2 to 5, and stops after five cycles. Lenalidomide is taken at 20 mg daily on days 1 to 21 of each 28-day cycle (adjusted per the lenalidomide SmPC). Tafasitamab and lenalidomide stop after a maximum of twelve cycles.

Infusion Rate

For the first infusion of cycle 1, the rate is 70 mL/h for the first 30 minutes and is then increased so that the infusion is complete within 2.5 hours. All later infusions are given over 1.5 to 2 hours.

Dose Modifications

• Infusion-related reaction, grade 2: interrupt the infusion and treat the symptoms. Once they resolve or fall to grade 1, resume at no more than 50% of the rate at which the reaction occurred; if there is no further reaction within 1 hour and vital signs are stable, the rate can be raised every 30 minutes as tolerated, up to the rate at which the reaction occurred.
• Grade 3: interrupt and treat. Once the reaction is grade 1 or resolved, resume at no more than 25% of that rate; if no further reaction occurs within 1 hour and vital signs are stable, the rate can be raised every 30 minutes up to a maximum of 50% of that rate. If the reaction returns, stop the infusion immediately.
• Grade 4: stop the infusion immediately and permanently discontinue tafasitamab.
• Platelets below 50,000/µL: withhold tafasitamab and lenalidomide and check blood counts weekly until platelets are 50,000/µL or higher. Resume tafasitamab at the same dose and lenalidomide at a reduced dose.
• Neutrophils below 1,000/µL for at least 7 days, below 1,000/µL with a temperature of 38 °C or higher, or below 500/µL: withhold both and check blood counts weekly until neutrophils are 1,000/µL or higher. Resume tafasitamab at the same dose and lenalidomide at a reduced dose.

For lenalidomide dose changes, the lenalidomide SmPC applies.

Special Populations

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

Traceability

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

Infusion-Related Reactions

These are reported more often with the first infusion. Patients are monitored closely during the infusion and should contact their healthcare professional if fever, chills, rash or breathing problems occur within 24 hours. Premedication is given before starting, and the infusion is interrupted or discontinued according to severity.

Myelosuppression, Neutropenia and Thrombocytopenia

Serious or severe neutropenia, thrombocytopenia and anaemia can occur. Complete blood counts are monitored throughout treatment and before each cycle, and infusions are withheld as in the dose modification rules. Granulocyte colony-stimulating factors should be considered, especially in grade 3 or 4 neutropenia. Patients should report bruising or bleeding immediately.

Infections

Fatal and serious infections, including opportunistic infections, have occurred. Tafasitamab should be given to a patient with an active infection only if the infection is treated appropriately and well controlled. Patients with recurring or chronic infections may be at higher risk. Patients should contact their healthcare professional if fever or other signs of infection (chills, cough, pain on urination) develop.

Progressive Multifocal Leukoencephalopathy

PML has been reported with combination therapy. Patients are monitored for new or worsening neurological signs, such as altered mental status, memory loss, speech impairment, motor deficits (weakness of one side of the body or of one limb), limb or gait ataxia, and visual problems such as hemianopia and diplopia. If PML is suspected, dosing is suspended immediately and referral to a neurologist considered; diagnosis may involve MRI and cerebrospinal fluid testing for JC viral DNA. If PML is confirmed, tafasitamab must be permanently discontinued.

Tumour Lysis Syndrome

Patients with a high tumour burden and rapidly proliferating tumour are at higher risk. Appropriate measures or prophylaxis according to local guidelines are taken before treatment, and patients are monitored closely.

CD19-Negative or CD20-Negative Disease

There are no data in patients with CD19-negative or CD20-negative follicular lymphoma treated with tafasitamab, lenalidomide and rituximab, and they may benefit less. The potential risks and benefits should be considered.

Immunisations

The safety of immunisation with live vaccines after tafasitamab has not been investigated, and live vaccines are not recommended during treatment.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test: tafasitamab with lenalidomide must not be started in female patients unless pregnancy has been excluded.
• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 3 months after it ends.
• Pregnancy: no reproductive or developmental toxicity studies and no data in pregnant women. IgG crosses the placenta, so tafasitamab may cause B-cell depletion in the foetus. After exposure in pregnancy, newborns should be monitored for B-cell depletion, and live-virus vaccination should wait until the infant’s B-cell count has recovered. Tafasitamab is not recommended in pregnancy or in women of childbearing potential not using contraception. Lenalidomide can cause embryo-foetal harm and is contraindicated in pregnancy and in women of childbearing potential unless all conditions of its pregnancy prevention programme are met.
• Breastfeeding: it is not known whether tafasitamab passes into human milk, but maternal IgG does, so a risk cannot be excluded. Women should not breastfeed during treatment and for at least 3 months after the last dose.
• Fertility: no specific studies have been done; see the SmPC.

Sodium and Polysorbate 20

Each vial contains 7.4 mg of sodium and 1.0 mg of polysorbate 20. Five vials (the dose of a patient weighing 83 kg) contain 37.0 mg of sodium, equal to 1.85% of the WHO recommended maximum daily intake of 2 g for an adult, and 5.0 mg of polysorbate 20, which may cause allergic reactions.

Effect on Driving

Minjuvi has no or negligible influence on the ability to drive and use machines. Fatigue has been reported and should be taken into account.

Store vials in a refrigerator at 2–8 °C, in the outer carton to protect from light. Minjuvi is a refrigerated product and needs an unbroken cold chain at 2–8 °C until it is prepared for infusion at the hospital.

After reconstitution (before dilution), chemical and physical in-use stability has been shown for up to 30 days at 2–8 °C or up to 24 hours at 25 °C; do not freeze or shake. The diluted solution for infusion has shown stability for a maximum of 14 days at 2–8 °C followed by up to 24 hours at up to 25 °C. From a microbiological point of view the reconstituted solution should be used immediately; if not, in-use times and conditions are the responsibility of the user and would normally not exceed 24 hours at 2–8 °C, unless reconstitution took place under controlled and validated aseptic conditions. See SmPC section 6.3 for details.

It is supplied as a 200 mg powder in a clear type I glass vial with a butyl rubber stopper, aluminium seal and plastic flip-off cap, in packs of one vial.

5 years for the unopened vial. For reconstituted and diluted solutions see Storage Conditions.

Prescription only (Rx), subject to restricted medical prescription (Annex II B); it must be administered by a healthcare professional experienced in treating cancer patients. Tafasitamab is a hospital infusion, so it is supplied to the hospital or clinic that administers it, as a cold-chain delivery at 2–8 °C.