Tarlatamab: prescribing information – dosing, contraindications, interactions, side effects

IMDYLLTRA is indicated as monotherapy for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC), who require systemic therapy following disease progression on or after first-line treatment with platinum-based chemotherapy.

IMDYLLTRA treatment should be initiated under the direction of and supervised by physicians experienced in the use of cancer therapy. It should be administered in an appropriate healthcare facility. See table 2 for recommended concomitant medicinal products.

Patients should be monitored from the start of the infusion for 6 to 8 hours on day 1 and day 8.
Additional monitoring and monitoring on subsequent infusions is at the discretion of the physician.

On day 1 and day 8, patients should be instructed to remain within proximity of an appropriate healthcare facility for 24 hours starting from each infusion, accompanied by a caregiver.

Both patients and caregivers should be informed on signs and symptoms of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) prior to discharge.

Posology

The recommended dosing schedule of IMDYLLTRA is an initial dose of 1 mg on day 1 followed by 10 mg on days 8, 15, and every 2 weeks thereafter as shown in table 1.

Patients should be treated until disease progression or unacceptable toxicity.

Table 1. Recommended dosing schedule of IMDYLLTRA

Dose of IMDYLLTRA
Day 1
1 mg
Day 8
10 mg
Day 15 and every 2 weeks thereafter
10 mg

Recommended concomitant medicinal products

Concomitant medicinal products for IMDYLLTRA administration should be administered as presented in table 2 to reduce the risk of cytokine release syndrome (see section 4.4).

Table 2. Concomitant medicinal products for day 1 and day 8

Treatment day
Medicinal products
Administration
Day 1 and day 8
Administer 8 mg of dexamethasone intravenously (or equivalent)
Within 1 hour prior to IMDYLLTRA infusion
Intravenous administration of 1 litre of sodium chloride 9 mg/mL (0.9%) solution for injection is recommended per standard of care guidelines Immediately after completion of IMDYLLTRA infusion

Restarting IMDYLLTRA after dose delay

If a dose of IMDYLLTRA is delayed, therapy should be restarted based on the recommendations listed in table 3, and the dosing schedule should be resumed accordingly. Recommended concomitant medicinal products should be administered as indicated in table 2.

Table 3. Recommendations for restarting therapy with IMDYLLTRA after dose delay

Last dose administered
Time since the last dose administered
Actiona
1 mg on day 1
2 weeks or less
(≤ 14 days)
Administer IMDYLLTRA 10 mg, then resume with the planned dosing schedule.
Greater than 2 weeks
(> 14 days)
Administer IMDYLLTRA 1 mg. If tolerated, increase to 10 mg 1 week later. Then resume with the planned dosing schedule.

Last dose administered
Time since the last dose administered
Actiona
10 mg on day 8
3 weeks or less
(≤ 21 days)
Administer IMDYLLTRA 10 mg, then resume with the planned dosing schedule.
Greater than 3 weeks
(> 21 days)
Administer IMDYLLTRA 1 mg. If tolerated, increase to 10 mg 1 week later. Then resume with the planned dosing schedule.
10 mg on day 15 and every 2 weeks thereafter
4 weeks or less
(≤ 28 days)
Administer IMDYLLTRA 10 mg, then resume with the planned dosing schedule.
Greater than 4 weeks
(> 28 days)
Administer IMDYLLTRA 1 mg. If tolerated, increase to 10 mg 1 week later. Then resume with the planned dosing schedule.
a Administer recommended concomitant medicinal products before and after IMDYLLTRA infusions on day 1 and day 8 and monitor patients accordingly (see table 2).

Dose modifications and management of adverse reactions

No dose reduction for IMDYLLTRA is recommended.

See table 4 for recommended actions for the management of CRS, table 5 for recommended actions for the management of ICANS, and table 6 for the management of other adverse reactions.

Cytokine release syndrome (CRS)

CRS should be diagnosed based on clinical presentation (see section 4.4). Patients should be evaluated and treated for other causes of fever, hypoxia, and hypotension. If CRS is suspected, it should be managed according to the recommendations in table 4. Patients who experience grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygen) should be monitored for CRS signs and symptoms including fever, hypotension and hypoxia using pulse oximetry or cardiac telemetry as indicated. For severe or life-threatening CRS, anti-IL-6 therapy is recommended, for example, tocilizumab and admission in an intensive-care unit (ICU) for supportive therapy.

Table 4. Guidelines for grading, dose modification and management of cytokine release syndromea

CRS grade
Defining symptoms
IMDYLLTRA dose modification
Management
Grade 1
Symptoms require symptomatic treatment only (e.g., fever ≥ 38°C without hypotension or hypoxia).
- Withhold
IMDYLLTRA until event resolves, then resume IMDYLLTRA at the next scheduled doseb.
- Administer symptomatic antipyretic treatment
(e.g., paracetamol) for fever.
- Consider dexamethasonec (or equivalent) 4 mg to
10 mg orally or intravenously.

CRS grade
Defining symptoms
IMDYLLTRA dose modification
Management
Grade 2
Symptoms require and respond to moderate intervention.
- Fever ≥ 38°C,
- Hypotension responsive to fluids not requiring vasopressors, and/or
- Hypoxia requiring low flow nasal cannula or blow-by.
- Withhold
IMDYLLTRA until event resolves, then resume IMDYLLTRA at the next scheduled doseb.
- Hospitalisation with monitoring for fever, hypotension and hypoxia using pulse oximetry or, as indicated, cardiac telemetry, is recommended.
- Administer symptomatic antipyretic treatment
(e.g., paracetamol) for fever.
- Administer supplemental oxygen and intravenous fluids when indicated.
- Consider dexamethasonec (or equivalent) 8 mg orally or intravenously.
- Consider tocilizumab (or equivalent).

When resuming treatment at the next planned dose, monitor patients at the physician’s discretion in an appropriate healthcare facilityb.
Grade 3
Severe symptoms defined as temperature
≥ 38°C with:
- Haemodynamic instability requiring a vasopressor (with or without vasopressin) and/or
- Worsening hypoxia or respiratory distress requiring high flow nasal canula (> 6 L/min oxygen) or face mask.
- Withhold
IMDYLLTRA until the event resolves, then resume
IMDYLLTRA at the next scheduled doseb.
- For recurrent grade 3 events, permanently discontinue
IMDYLLTRA.
In addition to grade 2 treatment:
- Intensive monitoring, e.g., ICU care is recommended.
- Administer dexamethasonec (or equivalent) 8 mg intravenously every
8 hours up to 3 doses.
- Vasopressor support as needed.
- High flow oxygen support as needed.
- Tocilizumab (or equivalent) is recommended.
- Prior to the next dose, administer concomitant medicinal products as recommended for day 1 and day 8 (see table 2).

When resuming treatment at the next planned dose, monitor patients at the physician’s discretion in an appropriate healthcare facilityb.

CRS grade
Defining symptoms
IMDYLLTRA dose modification
Management
Grade 4
Life-threatening symptoms defined as temperature ≥ 38°C with:
- Haemodynamic instability requiring multiple vasopressors
(excluding vasopressin) and/or
- Worsening hypoxia or respiratory distress despite oxygen administration requiring positive pressure.
Permanently discontinue
IMDYLLTRA.
- ICU care.
- Per grade 3 treatment.
a CRS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (2019).
b See table 3 for recommendations on restarting IMDYLLTRA after dose delays.
c Taper steroids per standard of care guidelines.
ICU = Intensive Care Unit

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Patients should be monitored for signs and symptoms of ICANS. Other causes of neurologic symptoms should be ruled out. Intensive care should be provided for severe or life-threatening neurologic toxicities. If ICANS is suspected, it should be managed according to the recommendations in table 5.

Table 5. Guidelines for grading, dose modification and management of immune effector cell-associated neurotoxicity syndromea

ICANS gradea
Defining symptoms
IMDYLLTRA dose modification
Management
Grade 1
ICE score 7-9b with no depressed level of consciousness.
- Withhold IMDYLLTRA until ICANS resolves, then resume
IMDYLLTRA at the next scheduled dosec.
- Supportive care.

ICANS gradea
Defining symptoms
IMDYLLTRA dose modification
Management
Grade 2
ICE score 3-6b and/or mild somnolence awaking to voice.
- Withhold IMDYLLTRA until ICANS resolves, then resume
IMDYLLTRA at the next scheduled dosec.
- Supportive care.
- Dexamethasoned (or equivalent) 8 mg to 10 mg orally or intravenously.
- If symptoms worsen, repeat dexamethasone every
12 hours or methylprednisoloned (or equivalent) 1 mg/kg intravenously every
12 hours.
- Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management.
- Monitor patients at the physician’s discretion following the next dose of
IMDYLLTRAc.
Grade 3
ICE score 0-2b and/or depressed level of consciousness awakening only to tactile stimulus and/or any clinical seizure focal or generalised that resolves rapidly

Or

Nonconvulsive seizures on EEG that resolve with intervention and/or focal or local oedema seen on neuroimaging.

- Withhold IMDYLLTRA until the ICANS resolves, then resume
IMDYLLTRA at the next scheduled dosec.
- If there is no improvement to grade ≤ 1 within 7 days, permanently discontinue IMDYLLTRA.
- For recurrent grade 3 events, permanently discontinue.
- Intensive monitoring, e.g.,
ICU care is recommended.
- Consider mechanical ventilation for airway protection. Dexamethasoned
(or equivalent) 10 mg intravenously every 6 hours or methylprednisoloned (or equivalent) 1 mg/kg intravenously every 12 hours.
- Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent grade ≥ 3 neurotoxicity.
- Monitor patients at the physician’s discretion following the next dose of
IMDYLLTRAc.

ICANS gradea
Defining symptoms
IMDYLLTRA dose modification
Management
Grade 4
ICE score 0b
(patient is unarousable and unable to perform ICE) and/or stupor or coma and/or life-threatening prolonged seizure (> 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between and/or diffuse cerebral oedema on neuroimaging, decerebrate or decorticate posturing or papilloedema, cranial nerve VI palsy, or Cushing’s triad.
- Permanently discontinue
IMDYLLTRA.
- ICU care.
- Consider mechanical ventilation for airway protection.
- High-dose corticosteroids such as methylprednisoloned
1 000 mg/day in divided doses intravenously for
3 days.
- Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent grade ≥ 3 neurotoxicity.
- Treat convulsive status epilepticus per institutional guidelines.
a ICANS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (2019).
b If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (names 3 objects, e.g., point to clock, pen, button = 3 points); Following commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (grade 4 ICANS) = 0 points.
c See table 3 for recommendations on restarting IMDYLLTRA after dose delays.
d Taper steroids per standard of care guidelines.
CT = Computed Tomography; EEG = Electroencephalogram; ICU = Intensive Care Unit; MRI = Magnetic resonance imaging

Neutropenia and other adverse reactions

Neutropenia and other adverse reactions should be managed in accordance with table 6.

Table 6. Recommended treatment interruptions of IMDYLLTRA for the management of other adverse reactionsa,b

Adverse reactions
Severitya
Dose modificationb
Neutropenia
(see section 4.4)
Grades 1 and 2
No treatment interruption needed.
Grade 3
- Interrupt IMDYLLTRA for at least 3 days and until the event improves to grade ≤ 2, then resume IMDYLLTRA.
Consider using granulocyte-colony stimulating factor (G-CSF).
Grade 4
- Interrupt IMDYLLTRA for at least 3 days and until the event improves to grade ≤ 2, then resume IMDYLLTRA.
- If event lasts for > 7 days or grade 4 event reoccurs, permanently discontinue IMDYLLTRA.
Consider using granulocyte-colony stimulating factor (G-CSF).
Hepatotoxicity
(see section 4.4)c
Grade 3
Increased ALT or AST or bilirubin
- Withhold IMDYLLTRA until improved to grade ≤ 1.
Grade 4
Increased ALT or AST or bilirubin
- Permanently discontinue
IMDYLLTRA.
AST or ALT > 3 × ULN with total bilirubin> 2 × ULN in the absence of alternative causes
- Permanently discontinue
IMDYLLTRA.
Other adverse reactions (see section 4.8)
Grade 3 or 4
Withhold IMDYLLTRA until recovery to grade ≤ 1 or baseline.

Consider permanently discontinuing if adverse reaction does not resolve within 28 days.

- Consider permanent discontinuation for grade 4 events.
a Severity based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.
b See table 3 for recommendations on restarting IMDYLLTRA after dose delays.
c For patients with liver enzyme elevations at baseline, multiples of baseline values should be used for hepatotoxicity assessment.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal

Special populations

Elderly

No dose adjustment is necessary in elderly patients (≥ 65 years of age).

Hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment (see section 5.2). Limited data is available in patients with moderate hepatic impairment. IMDYLLTRA has not been studied in patients with severe hepatic impairment. No dose recommendations can be made for patients with moderate or severe hepatic impairment.

Renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2).
IMDYLLTRA has not been studied in patients with severe renal impairment. No dose recommendations can be made for patients with severe renal impairment to end-stage renal disease.

Paediatric population

There is no relevant use of IMDYLLTRA in the paediatric population for the treatment of small cell lung cancer.

Method of administration

IMDYLLTRA is for intravenous use.

IMDYLLTRA is to be reconstituted and then further diluted prior to administration by intravenous infusion.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

The infusion line for premedication can be used for IMDYLLTRA. An infusion line flush should be conducted between administering concomitant medicinal products and IMDYLLTRA.

Administer the entire contents of IMDYLLTRA as an intravenous infusion over 1 hour at a constant flow rate using an infusion pump, see table 7. The pump should be programmable, lockable, non-elastomeric, and have an alarm.

The infusion line is primed with sodium chloride 9 mg/mL (0.9%) solution for injection OR final prepared IMDYLLTRA.

Upon completion of the IMDYLLTRA infusion, the intravenous infusion line should be flushed over 3-5 minutes using sodium chloride 9 mg/mL (0.9%) solution for injection.

Table 7. Tarlatamab administration information

Infusion duration for 250 mL intravenous preparation
Infusion rate (mL/hour)
1 hour
250 mL/hour

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile

The safety of IMDYLLTRA was evaluated in 473 patients with small cell lung cancer (SCLC) who received the tarlatamab target dose of 10 mg as monotherapy in clinical trials.

The most common adverse reactions are: CRS (56.7%), decreased appetite (36.4%), pyrexia (31.9%), dysgeusia (31.3%), constipation (30.4%), anaemia (30.0%), fatigue (29.8%), nausea (24.9%), asthenia (19.0%), neutropenia (16.9%), hyponatraemia (16.7%), headache (16.3%), lymphopenia (15.6%).

The most common serious adverse reactions are CRS (19.7%) and pyrexia (4.7%).

Tabulated list of adverse reactions

Adverse reactions reported in clinical trials are listed by system organ class and by frequency. The frequencies of adverse reactions is based on pooled data from one phase 1, one phase 2, and one phase 3 clinical trials with 473 patients. The median duration of exposure was 18.0 weeks (range:
0.1 to 175.1 weeks).

Adverse reactions are listed according to the MedDRA system organ classification and by frequency.
Frequency categories are defined as 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 (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 8. Adverse reactions

MedDRA system organ class
Adverse reaction
All grades
Grade ≥ 3
Blood and lymphatic system disorders
Anaemia
Very common
Common
Neutropeniaa, c
Very common
Common
Lymphopeniab
Very common
Very common
Thrombocytopenia
Common
Uncommon
Leukopenia
Common
Uncommon
Gastrointestinal disorders
Constipation
Very common
Uncommon
Nausea
Very common
Uncommon
Vomiting
Very common
Uncommon
Diarrhoea
Very common
Uncommon

MedDRA system organ class
Adverse reaction
All grades
Grade ≥ 3
General disorders and administration site conditions
Pyrexia
Very common
Uncommon
Fatigue
Very common
Common
Asthenia
Very common
Common
Chills
Common
Not reported
Immune system disorders
Cytokine release syndromec
Very common
Common
Investigations
Weight decreased
Very common
Common
Alanine aminotransferase increased
Very common
Common
Aspartate aminotransferase increased
Common
Common
White blood cell count decreased
Common
Common
Metabolism and nutrition disorders
Decreased appetite
Very common
Common
Hyponatraemia
Very common
Common
Hypokalaemia
Very common
Common
Hypomagnesaemia
Common
Uncommon
Musculoskeletal and connective tissue disorders
Myalgia
Common
Not reported
Nervous system disorders
Dysgeusia
Very common
Not reported
Headache
Very common
Not reported
Dizziness
Common
Not reported
Immune effector cell-associated neurotoxicity syndromec
Common
Uncommon
Tremor
Common
Not reported
Neurotoxicity
Uncommon
Not reported
Seizure
Uncommon
Uncommon
Ataxia
Uncommon
Uncommon
Encephalopathy
Uncommon
Uncommon
Psychiatric disorders
Confusional state
Common
Uncommon
Delirium
Common
Uncommon
Respiratory, thoracic and mediastinal disorders
Dyspnoea
Very common
Common
Skin and subcutaneous tissue disorders
Pruritus
Very common
Uncommon
Rash
Common
Uncommon
Vascular disorders
Hypotension
Common
Common
Hypertension
Common
Common a Includes neutrophil count decreased.
b Includes lymphocyte count decreased.
c Additional information is provided in “Descriptions of selected adverse reactions”.

Description of selected adverse reactions

Cytokine release syndrome (CRS)

In clinical trials with pooled safety data from 473 patients with SCLC receiving the IMDYLLTRA 1 mg as first dose and 10 mg second and later dose, CRS occurred in 56.7% of patients, with grade 1 in 39.3%, grade 2 in 15.4% of patients, grade 3 in 1.7% of patients and grade 4 events in 0.2% of patients. Serious events of CRS were reported in 19.7% of patients. After the first dose of IMDYLLTRA, 41.4% of patients experienced any grade CRS, with 34.0% of patients experiencing any grade CRS after the second dose. The majority of CRS events occurred after the first two doses, with 8.5% of patients experiencing CRS following third dose or later. Following the day 1 infusion, 13.7% of patients experienced ≥ grade 2 CRS. Following the day 8 infusion, 4.4% of patients experienced ≥ grade 2 CRS. The median time from the most recent dose of IMDYLLTRA to the first onset of CRS was 15.9 hours (range: 9.0 to 26.5 hours). For those grade 1 events that progressed to grade 2 or greater, the median time from grade 1 event to grade 2 or greater events was 22.1 hours (interquartile range: 8.5 - 31.6 hours). Cytokine release syndrome led to treatment interruption and/or dose modification in 2.1% of patients and to discontinuation of tarlatamab in 0.6% of patients.

Fatal CRS cases have been reported in the post-marketing setting.

For clinical management of CRS, see section 4.4.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Tarlatamab can cause ICANS, including life-threatening or fatal events.

In clinical trials with pooled safety data from 473 patients with SCLC receiving IMDYLLTRA at 10 mg, ICANS was reported in 4.7% of patients. The median time from the first dose of IMDYLLTRA to the first onset of ICANS was 9.0 days (interquartile range: 2 to 13 days). The median time to resolution of ICANS was 4 days (interquartile range: 2 to 8 days).

For clinical management of ICANS, see section 4.4.

Neutropenia

In clinical trials with pooled safety data from 473 patients with SCLC receiving IMDYLLTRA at 10 mg, neutropenia occurred in 16.9% of patients including 8.2% of patients experiencing grade 3 or grade 4 events. The median time from the first dose of IMDYLLTRA to the first onset of neutropenia was 43 days (range: 29 to 109 days). Neutropenia leading to dose interruption occurred in 3.2% patients with none leading to treatment discontinuation. Treatment with G-CSF was required in 6% of patients.

For clinical management of neutropenia, see section 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Cytokine release syndrome (CRS)

Administration of tarlatamab has been associated with CRS, including life-threatening or fatal events, see section 4.8. CRS may be associated with symptoms including pyrexia, hypotension, hypoxia, fatigue, tachycardia, headache, chills, nausea, and vomiting.

Patients and caregivers should be advised of the potential for CRS onset after discharge and instructed to seek immediate medical attention if any signs or symptoms occur.

Tarlatamab should be administered in a healthcare facility equipped to monitor and manage CRS. It should be ensured that patients are euvolemic prior to initiating the infusions. Patients should be closely monitored for signs and symptoms of CRS during the initiation of tarlatamab treatment. To mitigate the risk of CRS, it is important to initiate tarlatamab at the recommended starting dose in table 1.

CRS should be managed according to the recommendations in table 4.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Administration of tarlatamab has been associated with ICANS, including life-threatening or fatal events, see section 4.8. ICANS can occur up to several weeks following administration of tarlatamab.
Adverse reactions that may be associated with ICANS include headache, encephalopathy, confusion, delirium, seizure, ataxia, neurotoxicity, and tremor. Patients should be closely monitored for signs and symptoms of ICANS during tarlatamab treatment.

Patients and caregivers should be advised of the potential for ICANS onset after discharge and instructed to seek immediate medical attention if any signs or symptoms occur.

ICANS should be managed according to the recommendations in table 5.

Neutropenia

Administration of tarlatamab has been associated with neutropenia, see section 4.8. Patients should be closely monitored for signs and symptoms of neutropenia during tarlatamab treatment.

Neutropenia should be managed according to the recommendations in table 6.

Infections

Serious infections, including life-threatening and fatal infections, have been reported in patients treated with tarlatamab. The most frequent infections include pneumonia, urinary tract infection, COVID-19, upper respiratory tract infection, respiratory tract infection, candida infection, oral candidiasis and nasopharyngitis.

Patients should be monitored for signs and symptoms of infections prior to and during treatment with tarlatamab.

Hypersensitivity

Hypersensitivity reactions have been reported in patients treated with tarlatamab including rare severe events. Clinical signs and symptoms of hypersensitivity may include but are not limited to rash and bronchospasm. Patients should be monitored for signs and symptoms of hypersensitivity during treatment with tarlatamab and managed as clinically indicated. It should be considered to withhold or to permanently discontinue tarlatamab based on severity, see table 6 for management of other adverse reactions.

Hepatotoxicity

Administration of tarlatamab has been associated with elevated liver enzymes. Liver enzyme elevation can occur with or without concurrent CRS.

Liver enzymes and bilirubin should be monitored prior to treatment with tarlatamab, and as clinically indicated. Potential toxicities should be managed according to the recommendations in table 6.

Women of child bearing potential/contraception

Pregnancy status of females of child bearing potential should be verified prior to initiating treatment with tarlatamab. Females of reproductive potential have to use effective contraception during treatment and for 2 months after the last dose of tarlatamab (see section 4.6).

Excipients with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

This medicinal product contains 0.04 mg of polysorbate 80 in each 1 mg vial and 0.2 mg in each 10 mg vial. Polysorbates may cause allergic reactions.

No interaction studies have been performed. Initiation of tarlatamab treatment causes transient release of cytokines that may suppress CYP450 enzymes and may result in increased exposures of concomitant CYP substrates. Patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, should be monitored for known adverse events. The dose of the concomitant medicinal product should be adjusted as needed.

Women of child bearing potential/contraception

Women of child bearing potential have to use effective contraception during and for 2 months after treatment with tarlatamab.

Pregnancy

There are no available data from the use of tarlatamab in pregnant women.

A reproductive toxicity study conducted in mice using the murine surrogate molecule muS757 showed transplacental transport of muS757 (see section 5.3). Based on its mechanism of action and potential development of adverse reactions (like CRS) following tarlatamab exposure, tarlatamab may cause foetal harm when administered to a pregnant woman (see section 5.1).

Tarlatamab is not recommended during pregnancy and in women of child bearing potential not using contraception.

Pregnancy status for females of child-bearing potential should be verified prior to starting treatment with tarlatamab.

Breast-feeding

It is unknown whether tarlatamab is secreted in human milk. Because many medicinal products, including antibodies, can be secreted in human milk, a risk to the newborns/infants cannot be

excluded. Breast-feeding should be discontinued during treatment with tarlatamab and for at least 2 months after the last dose.

Fertility

There are no clinical trials to evaluate the effect of tarlatamab on fertility.

Due to the potential for ICANS associated neurological events following tarlatamab infusion, tarlatamab may have major influence on the ability to drive and use machines. In the event of any neurologic symptoms, patients should be advised to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until they resolve.

Doses up to 100 mg every 2 weeks and 200 mg every 3 weeks have been evaluated in clinical trials. In the event of an overdose, the patient must be closely monitored for signs or symptoms of adverse reactions and should be treated symptomatically, and supportive measures instituted as required.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, other monoclonal antibodies and antibody drug conjugates, ATC code: L01FX33

Mechanism of action

Tarlatamab is a bispecific delta-like ligand 3 (DLL3)-directed CD3 T-cell engager that binds to DLL3 expressed on the surface of tumour cells and CD3 expressed on the surface of T-cells. The bispecific binding of tarlatamab to T-cells and DLL3-positive tumour cells triggers T-cell activation, production of inflammatory cytokines, and release of cytotoxic proteins, which results in redirected lysis of tumour cells.

Pharmacodynamic effects

The pharmacodynamic response after a single infusion of tarlatamab was characterised by T-cell redistribution and activation, and transient cytokine elevation. Peripheral T-cell redistribution (i.e., T-cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred within 24 hours after the initial dose of tarlatamab at 1 mg on day 1. T-cell counts declined within 6 hours post infusion and returned to baseline levels in the majority of the patients prior to the next infusion on day 8.

Serum cytokines IL-2, IL-6, IL-8, IL-10, IFN-γ and TNF-α were transiently elevated following the initial dose of tarlatamab at 1 mg on day 1. Cytokine levels peaked within the first 2 days following the start of tarlatamab infusion and generally returned to baseline levels prior to the next infusion on day 8. In subsequent treatments, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial infusion on day 1.

Immunogenicity

Anti-drug antibodies (ADA) were commonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited.

Clinical efficacy and safety

Study DeLLphi-304

The efficacy of IMDYLLTRA was studied in a phase 3 multicentre, randomised, open-label trial (Study DeLLphi-304). Eligible patients were required to have SCLC with disease progression following 1 platinum-based regimen. In regions where standard of care (SOC) first-line systemic treatment for patients diagnosed with extensive-stage disease included platinum-based chemotherapy in combination with PD-(L)1 inhibitor, patients were required to have failed PD-(L)1 inhibitor as part of their first-line systemic treatment or to be ineligible to receive PD-(L)1 inhibitor therapy.
Additionally, patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and at least one measurable lesion as defined by response evaluation criteria in solid tumours (RECIST v1.1). The trial excluded patients with symptomatic brain metastases or active immunodeficiency.

Tarlatamab population pharmacokinetic (PK) analyses in adult subjects (n = 702) with previously treated advanced SCLC were performed to characterise the time course of tarlatamab serum concentrations after intravenous administration, to quantify inter-individual variability and to evaluate effects of subject specific covariates on the PK parameters of tarlatamab.

The peak serum concentration (Cmax), trough serum concentration (Ctrough) and area under the serum concentration versus time curve at steady state (AUCtau) of tarlatamab increased dose proportionally in the evaluated dose range of 1 mg to 100 mg Q2W (10 times the recommended dose). Approximate steady state in serum tarlatamab exposures were achieved by cycle 2 day 15.

Distribution

The typical value (inter-subject CV%) for central volume of distribution is 3.23 L (38%) and steady state volume of distribution is 8.19 L as estimated by population PK analysis.

Biotransformation

The metabolic pathway of tarlatamab has not been characterised. Like other protein therapeutics, tarlatamab is expected to be degraded into small peptides and amino acids via catabolic pathways.

Elimination

The systemic clearance (inter-subject CV%) was 0.728 L/day (34%) and terminal elimination half-life was approximately 10.6 days in subjects with SCLC as estimated by population PK analysis.

Special populations

No clinically meaningful differences in the clearance of tarlatamab were observed based on age (range: 20-86 years), bodyweight (range: 35-149 kg), sex, race, mild or moderate renal impairment (eGFR ≥ 30 mL/min), or mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and