Tafasitamab

The safety of immunisation with live vaccines following tafasitamab therapy has not been investigated and vaccination with live vaccines is not recommended concurrently with tafasitamab therapy.

There are no data in patients with severe renal impairment for dosing recommendations.

There are no data in patients with moderate or severe hepatic impairment for dosing recommendations.

Tafasitamab should be administered to patients with an active infection only if the infection is treated appropriately and well controlled. Patients with a history of recurring or chronic infections may be at increased risk of infection and should be monitored appropriately.

Treatment with tafasitamab in combination with lenalidomide should not be initiated in female patients unless pregnancy has been excluded. Please also refer to the SmPC of lenalidomide.

Reproductive and developmental toxicity studies have not been conducted with tafasitamab.

There are no data on the use of tafasitamab in pregnant women. However, IgG is known to cross the placenta and tafasitamab may cause foetal B-cell depletion based on the pharmacological properties. In case of exposure during pregnancy, newborns should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant's B-cell count has recovered.

Tafasitamab is not recommended during pregnancy and in women of childbearing potential not using contraception.

Lenalidomide can cause embryo-foetal harm and is contraindicated for use in pregnancy and in women of childbearing potential unless all of the conditions of the lenalidomide pregnancy prevention programme are met.

It is not known whether tafasitamab is excreted in human milk. However, maternal IgG is known to be excreted in human milk. There are no data on the use of tafasitamab in breast-feeding women and a risk for breast-feeding children cannot be excluded. Women should be advised not to breast-feed during and for at least 3 months after the last dose of tafasitamab.

Women of childbearing potential / Contraception in females

Women of childbearing potential should be advised to use effective contraception during and for at least 3 months after end of treatment with tafasitamab.

Fertility

No specific studies have been conducted to evaluate potential effects of tafasitamab on fertility. No adverse effects on male and female reproductive organs were observed in a repeat-dose toxicity study in animals.

Tafasitamab has no or negligible influence on the ability to drive and use machines. However, fatigue has been reported in patients taking tafasitamab and this should be taken into account when driving or using machines.

Summary of the safety profile

Patients with relapsed or refractory DLBCL

The safety of tafasitamab in patients with DLBCL was evaluated in the open-label, multicentre, single- arm phase 2 study L-MIND in 81 patients with relapsed or refractory DLBCL. Patients received tafasitamab 12 mg/kg intravenously in combination with lenalidomide for a maximum of 12 cycles, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. The median duration of exposure to tafasitamab was 7.7 months.

The most common adverse reactions were: infections (73%), neutropenia (51%), asthenia (40%), anaemia (36%), diarrhoea (36%), thrombocytopenia (31%), cough (26%), oedema peripheral (24%), pyrexia (24%), decreased appetite (22%).

The most common serious adverse reactions were infection (26%) including pneumonia (7%), and febrile neutropenia (6%).

Permanent discontinuation of tafasitamab due to an adverse reaction occurred in 15% of patients. The most common adverse reactions leading to permanent discontinuation of tafasitamab were infections and infestations (5%), nervous system disorders (2.5%), and respiratory, thoracic and mediastinal disorders (2.5%).

The frequency of dose modification or interruption due to adverse reactions was 65%. The most common adverse reactions leading to tafasitamab treatment interruption were blood and lymphatic system disorders (41%).

Patients with relapsed or refractory FL after at least one line of systemic therapy

The safety of tafasitamab in patients with FL was evaluated in the randomised, double-blind, placebo- controlled multicenter phase 3 study inMIND in 652 patients, including 546 participants with relapsed or refractory (R/R) follicular lymphoma and 106 participants with R/R marginal zone lymphoma. Patients received tafasitamab 12 mg/kg (n = 327) or placebo (n = 325) intravenously in combination with rituximab 375 mg/m 2 intravenously (for a maximum of 5 cycles) and lenalidomide 20 mg orally (for a maximum of 12 cycles). Tafasitamab treatment was stopped after 12 cycles. Among patients who received tafasitamab, 83% were exposed for 6 months or longer. The median duration of exposure to tafasitamab was 322 days.

In the inMIND study, the most common adverse reactions were infections (68%), including viral infections (41%) and bacterial infections (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%).

The most common serious adverse reactions were infections (26%), including viral infections (13%), and bacterial infections (6%); febrile neutropenia (2.8%), acute kidney injury (2.8%) and pyrexia (1.8%).

Permanent discontinuation of tafasitamab due to an adverse reaction occurred in 11.6% of patients. The most common adverse reactions leading to permanent discontinuation of tafasitamab were viral infections (2.4%), including COVID-19 (1.5%) and COVID-19 pneumonia (1.2%), infusion-related reaction (0.9%) and pyrexia (0.9%).

The frequency of tafasitamab dose modification or interruption due to adverse reactions was 74.9%. The most common adverse reactions leading to tafasitamab dose modification and interruption were neutropenia (38.8%) and viral infections (23.9%) including COVID-19 (21.1%) and COVID-19 pneumonia (3.7%).

Tabulated list of adverse reactions

Adverse reactions reported for tafasitamab in clinical trials are listed by MedDRA System Organ Class and by frequency.

The adverse reaction frequencies from clinical trials are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes than the medicinal product, such as the disease, other medicines or unrelated causes. Frequencies are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2. Adverse reactions in patients with relapsed or refractory DLBCL who received tafasitamab in combination with lenalidomide in the clinical trial MOR208C203 (L-MIND):

⁺ Further information on this adverse reaction is provided in the text below.
⁺⁺ Asthenia includes asthenia, fatigue and malaise.
Compared with the incidences on combination therapy with lenalidomide, the incidences of non-haematological adverse reactions on tafasitamab monotherapy decreased by at least 10% for decreased appetite, asthenia, hypokalaemia, constipation, nausea, muscle spasms, dyspnoea and C-reactive protein increased.

Table 3. Adverse reactions in patients with relapsed or refractory FL who received tafasitamab in combination with rituximab and lenalidomide in INCMOR 0208-301 (inMIND:

^a The severity of adverse drug reactions was assessed based on the CTCAE, defining grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, and 5 = death.
^b Includes viral infection, COVID-19, COVID-19 pneumonia, coronavirus infection, coronavirus test positive, cytomegalovirus chorioretinitis, cytomegalovirus infection reactivation, gastroenteritis rotavirus, genital herpes, Hepatitis B, herpes ophthalmic, herpes simplex, herpes simplex reactivation, herpes virus infection, herpes zoster, herpes zoster reactivation, influenza, laryngitis viral, nasal herpes, norovirus infection, oral herpes, parainfluenzae virus infection, pneumonia viral, progressive multifocal leukoencephalopathy, respiratory syncytial virus infection, respirovirus test positive, rhinovirus infection, skin papilloma, varicella zoster pneumonia, varicella zoster virus infection, and viral upper respiratory tract infection.
^c Includes bacterial infection, abdominal infection, abscess, appendicitis, asymptomatic bacteriuria, atypical pneumonia, bacteraemia, bacterial sepsis, breast abscess, bronchopulmonary aspergillosis, campylobacter gastroenteritis, campylobacter infection, carbuncle, catheter site infection, cellulitis, cholecystitis, chronic sinusitis, clostridium difficile colitis, clostridium difficile infection, corynebacterium infection, device related infection, diverticulitis, ear infection, ear lobe infection, empyema, enterobacter bacteraemia, erysipelas, erythrasma, escherichia infection, escherichia sepsis, eye infection, folliculitis, furuncle, hemophilus bacteraemia, hemophilus infection, helicobacter gastritis, helicobacter infection, infected cyst, infected dermal cyst, lower respiratory tract infection, moraxella infection, mycobacterium chelonae infection, myopericarditis, myringitis, otitis externa, otitis media, perineal infection, periodontitis, peritonitis bacterial, pneumocystis jirovecii pneumonia, pneumonia moraxella, pneumonia pneumococcal, pneumonia streptococcal, postoperative wound infection, proctitis, prostatitis, pseudomonal sepsis, pseudomonal skin infection, pseudomonas infection, pulmonary sepsis, pulpitis dental, pyelonephritis, salmonellosis, septic shock, sinusitis, skin infection, soft tissue infection, staphylococcal bacteraemia, staphylococcal infection, tooth abscess, tooth infection, urinary tract infection, urosepsis, vaginal infection, and wound infection.
^d Includes neutropenia and neutrophil count decreased.
^e Includes thrombocytopenia and platelet count decreased.
^f Includes anaemia and haematocrit decreased.
^g Includes abdominal pain, abdominal discomfort, abdominal pain lower, abdominal pain upper, and gastrointestinal pain.
^h Includes rash, rash erythematous, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, and urticaria.
ⁱ Includes asthenia, malaise, and fatigue.

Description of selected adverse reactions

Myelosuppression

Treatment with tafasitamab can cause serious or severe myelosuppression including neutropenia, thrombocytopenia and anaemia.

In the L-MIND study, myelosuppression (i.e. neutropenia, febrile neutropenia, thrombocytopenia, leukopenia, lymphopenia or anaemia) occurred in 65.4% of patients treated with tafasitamab.

Myelosuppression led to interruption of tafasitamab in 41% and to tafasitamab discontinuation in 1.2%.

In the inMIND study, myelosuppression (i.e. neutropenia, febrile neutropenia, thrombocytopenia, leukopenia, lymphopenia or anaemia) occurred in 63.3% of patients treated with tafasitamab, lenalidomide, and rituximab (tafasitamab group) and 63.1% of patients treated with lenalidomide and rituximab (placebo group). Grade 4 haematological adverse reactions included neutropenia, thrombocytopenia and febrile neutropenia. Myelosuppression led to interruption of tafasitamab in 42.8% and to tafasitamab discontinuation in 1.5%.

Myelosuppression was managed by reduction or interruption of lenalidomide, interruption of tafasitamab and/or rituximab. In addition, severe neutropenia was managed by the administration of GCSF.

Neutropenia/febrile neutropenia

In the L-MIND study, incidence of neutropenia was 51%. Incidence of Grade 3 or 4 neutropenia was 49% and of Grade 3 or 4 febrile neutropenia was 12%. Median duration of any adverse reaction of neutropenia was 8 days (range 1 – 222 days); median time to onset to first occurrence of neutropenia was 49 days (range 1 – 994 days).

In the inMIND study, incidence of neutropenia was 56.9% in the tafasitamab group (tafasitamab, lenalidomide and rituximab) and 54.2% in the placebo group (lenalidomide and rituximab). Incidence of Grade 3 or 4 neutropenia was 46.8% in the tafasitamab group and 45.5% in the placebo group. Incidence of Grade 3 or Grade 4 febrile neutropenia was 4.3% in the tafasitamab group and 3.4% in the placebo group. Median duration of any adverse reaction of neutropenia was 11 days (range 1 – 433 days). Median duration of febrile neutropenia was 5 days (range 1 – 57 days); median time to onset to first occurrence of neutropenia was 57 days (range 1 – 338 days); median time to onset to first occurrence of febrile neutropenia was 77 days (range 3 – 304 days).

Thrombocytopenia

In the L-MIND study, incidence of thrombocytopenia was 31%. Incidence of Grade 3 or 4 thrombocytopenia was 17%. Median duration of any adverse reaction thrombocytopenia was 11 days (range 1 – 470 days); median time to onset to first occurrence of thrombocytopenia was 71 days (range 1 – 358 days).

In the inMIND study, incidence of thrombocytopenia was 17.1% in the tafasitamab group (tafasitamab, lenalidomide and rituximab) and 20.6% in the placebo group (lenalidomide and rituximab). Incidence of Grade 3 or Grade 4 thrombocytopenia was 6.4% in the tafasitamab group and 9.8% in the placebo group. Median duration of thrombocytopenia was 16 days (range 2 – 434 days); median time to onset to first occurrence of thrombocytopenia was 33 days (range 1 – 324 days).

Anaemia

In the L-MIND study, incidence of anaemia was 36%. Incidence of Grade 3 or 4 anaemia was 7%. Median duration of any adverse reaction of anaemia was 15 days (range 1 – 535 days); median time to onset to first occurrence of anaemia was 49 days (range 1 – 1129 days).

When patients in the L-MIND study were switched from tafasitamab and lenalidomide in the combination therapy phase to tafasitamab alone in the extended monotherapy phase, the incidences of haematological events decreased by at least 20% for neutropenia, thrombocytopenia and anaemia; no incidences of febrile neutropenia were reported with tafasitamab monotherapy.

In the inMIND study, incidence of anaemia was 17.1% in the tafasitamab group (tafasitamab, lenalidomide and rituximab) and 14.5% in the placebo group (lenalidomide and rituximab). Incidence of Grade 3 or 4 anaemia was 6.4% in the tafasitamab group and 6.5% in the placebo group. Median duration of any adverse reaction of anaemia was 23 days (range 1 – 432 days); median time to onset to first occurrence of anaemia was 49 days (range 1 – 274 days).

Infections

In the L-MIND study, infections occurred in 73% of patients. Incidence of Grade 3 or 4 infections was 28%. The most frequently reported Grade 3 or higher infections were pneumonia (7%), respiratory tract infections (4.9%), urinary tract infections (4.9%) and sepsis (4.9%). Infection was fatal in < 1% of patients (pneumonia) within 30 days of last treatment. Median time to first onset of Grade 3 or 4 infection was 62.5 days (4 – 1014 days). Median duration of any infection was 11 days (1 – 392 days).

Infection led to dose interruption of tafasitamab in 27% and tafasitamab discontinuation in 4.9%. In the inMIND study, infections occurred in 52.3% of patients in the tafasitamab group (tafasitamab, lenalidomide and rituximab) and in 45.2% of patients in the placebo group (lenalidomide and rituximab). Viral infections occurred in 41.3% of patients in the tafasitamab group and 32% in the placebo group. Bacterial infections occurred in 27.2% of patients in the tafasitamab group and 25.2% in the placebo group. Incidence of Grade 3 or 4 viral infections was 11.6% in the tafasitamab group and 4.6% in the placebo group. Incidence of Grade 3 or 4 bacterial infections was 7.6% in the tafasitamab group and 7.7% in the placebo group. Infections were fatal in 3 patients in the tafasitamab group (two cases of COVID-19 and one of sepsis).

Median time to first onset of any infection ≥ Grade 3 was 10 days (2 – 311 days).

Infusion-related reactions

In the L-MIND study, infusion-related reactions occurred in 6% of patients. All infusion related reactions were Grade 1 and resolved on the day of occurrence. Eighty percent of these reactions occurred during cycle 1 or 2.

In study inMIND, infusion-related reactions occurred in 15.9% of patients in the tafasitamab group (tafasitamab, lenalidomide and rituximab) and 15.1% in the placebo group (lenalidomide and rituximab). Grade 3 infusion-related reactions occurred in 6.1% of patients in the tafasitamab group. In the tafasitamab group infusion-related reactions occurred in 15.3% of patients during cycle 1, in 1.3% of patients during cycle 2 and in 0.3% of patients during cycle 3.

Symptoms included chills, flushing, dyspnoea, hypertension and rash.

Immunogenicity

In 245 patients treated with tafasitamab in the initial clinical studies, no treatment-emergent or treatment-boosted anti-tafasitamab antibodies were observed. Pre-existing anti-tafasitamab antibodies were detected in 17/245 patients (6.9%) with no impact on pharmacokinetics, efficacy or safety of tafasitamab.

Anti-drug antibodies (ADAs) were tested in 327 patients with relapsed or refractory follicular lymphoma or relapsed or refractory marginal zone lymphoma who received tafasitamab in study inMIND. The incidence of tafasitamab treatment-emergent ADAs was 0.9% (3/327) using a bridging enzyme-linked immunosorbent assay.

No neutralizing antibodies were detected. There was no apparent clinically meaningful effect of ADAs on the pharmacokinetics, pharmacodynamics, safety, or effectiveness of tafasitamab over the median treatment duration of 322.5 days.

Special populations

Elderly

Among 81 patients treated in the L-MIND study, 56 (69%) patients were >65 years of age. Patients >65 years of age had a numerically higher incidence of serious treatment emergent adverse events (TEAEs) (55%) than patients ≤65 years (44%).

Among the 274 patients with FL treated with tafasitamab in study inMIND, 50% were ≥65 years of age and 20% were ≥75 years of age. No clinically meaningful differences in safety or effectiveness were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.