4.1. Therapeutic indications

IMDYLLTRA is indicated for the treatment of adult patients with small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

4.2. Posology and method of administration

Treatment with IMDYLLTRA should be initiated and supervised by physicians experienced in the treatment of small cell lung cancer.

IMDYLLTRA should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) (see Section 4.4).

Posology

Pre-treatment medicinal products should be administered prior to each dose of IMDYLLTRA on Day 1 and Day 8 of the dosing schedule (see below).

Recommended dosing Schedule

The recommended dosage and 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.

Table 1. IMDYLLTRA recommended dosage and schedule.

Dose of IMDYLLTRA

Day 1

1 mg

Day 8

10 mg

Day 15 and every 2 weeks thereafter

10 mg

Administer IMDYLLTRA as a 1‑hour intravenous infusion in an appropriate healthcare setting. Ensure patients are well hydrated prior to administration of IMDYLLTRA. Premedicate with dexamethasone 8 mg IV 1 hour prior to first two doses (Day 1 and Day 8). Consider IV fluids for patients after infusion of IMDYLLTRA (Day 1 and Day 8).

Monitor patients during the infusion and for at least 16 hours after the first infusion (Day 1).

On Day 8, monitor patients for 6-8 hours post infusion and at subsequent infusions monitor patients for 2-4 hours post infusion at the discretion of the healthcare professional.

On Day 1 and Day 8, recommend patients to remain within 1 hour of an appropriate healthcare setting, such as the treatment hospital, for 24 hours starting from each IMDYLLTRA infusion, accompanied by a caregiver.

Inform both the patient and the caregiver on the signs and symptoms of Cytokine Release Syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) prior to discharge.

Duration of treatment

Administer IMDYLLTRA until disease progression or unacceptable toxicity.

Dose modifications and Adverse Reaction Management

If a dose of IMDYLLTRA is delayed because of an adverse event, therapy will be restarted based on the recommendations listed in Table 6. See Table 2 and Table 3 for recommended actions for the management of CRS and ICANS respectively and Table 4 for neutropenia and other adverse reactions.

Cytokine Release Syndrome (CRS)

Diagnose CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 2. Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygen) should be monitored for signs and symptoms of CRS including fever, hypotension and hypoxia using pulse oximetry or cardiac telemetry as indicated. For severe or life-threatening CRS, recommend anti-IL-6 therapy, for example, tocilizumab and admission in an intensive-care unit (ICU) for supportive therapy. Table 2 provides the guidelines for grading and dosage modification and management of cytokine release syndrome.

Table 2. Guidelines for Grading, Dosage Modification and Management of Cytokine Release Syndromea

CRS Grade

Defining Symptoms

IMDYLLTRA

Dosage 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 treatment (e.g., paracetamol) for fever.

• Consider dexamethasonec 4 mg (or equivalent) to 10 mg PO or IV.

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.

• Recommend hospitalisation with monitoring for fever, hypotension and hypoxia using pulse oximetry or cardiac telemetry as indicated.

• Administer symptomatic treatment (e.g., paracetamol) for fever.

• Administer supplemental oxygen and intravenous fluids when indicated.

• Consider dexamethasonec (or equivalent) 8 mg PO or IV.1

• Consider tocilizumab (or equivalent).

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

Grade 3

Severe symptoms defined as temperature ≥ 38°C with:

Haemodynamic instability requiring a vasopressor (with or without vasopressin) 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:

• Recommend intensive monitoring, e.g., ICU care.

• Administer dexamethasonec (or equivalent) 8 mg IV every 8 hours up to 3 doses.

• Vasopressor support as needed.

• High flow oxygen support as needed.

• Recommend tocilizumab (or equivalent)

• Prior to the next dose, administer concomitant medications as recommended for Day 1 and Day 8 (see Table 1).

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

Grade 4

Life-threatening symptoms defined as temperature ≥38°C with:

Haemodynamic instability requiring multiple vasopressors (excluding vasopressin).

Worsening hypoxia or respiratory distress despite oxygen administration requiring positive pressure.

Permanently discontinue IMDYLLTRA.

• ICU care.

• Grade 3 treatment.

a CRS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (2019).

b See section 4.2, Table 5 for recommendations on restarting IMDYLLTRA after dose delays.

c Taper steroids per standard of care guidelines.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Monitor patient for signs and symptoms of ICANS. Rule out other causes of neurologic symptoms. Provide intensive care for severe or life-threatening neurologic toxicities. If ICANS is suspected, manage according to the recommendations in Table 3.

Table 3. Guidelines for Grading, Dose Modification and Management of Immune Effector Cell-Associated Neurotoxicity Syndromea

ICANS Gradea

Defining Symptoms

IMDYLLTRA Dosage Modifications

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.

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 to 10 mg PO or IV.

• If symptoms worsen, repeat dexamethasone every 12 hours or methylprednisoloned (or equivalent) 1 mg/kg IV 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 or Grade 3 toxicity reoccurs within 7 days of restart, permanently discontinue IMDYLLTRA.

• For recurrent Grade 3 events, permanently discontinue.

• Recommend intensive monitoring, e.g., ICU care.

• Consider mechanical ventilation for airway protection. Dexamethasoned (or equivalent) 10 mg IV every 6 hours or methylprednisoloned (or equivalent) 1 mg/kg IV 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.

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 papilledema, 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 1000 mg/day in divided doses IV 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 6 for recommendations on restarting IMDYLLTRA after dose delays (see section 4.2).

d Taper steroids per standard of care guidelines.

Table 4. Recommended Treatment Interruptions of IMDYLLTRA for the Management of Cytopenias, and Other Adverse Reactions

Adverse Reactions

Severityb

Dosage Modificationa

Cytopenias (see section 4.4)

Grade 3 neutropenia

Withhold IMDYLLTRA until recovery to Grade ≤ 2.

Consider administration of granulocyte colony stimulating factor (G-CSF).

Grade 4 neutropenia

Withhold IMDYLLTRA until recovery to Grade ≤ 2.

Consider administration of granulocyte colony stimulating factor (G-CSF).

Permanently discontinue if recover to Grade ≤ 2 does not occur within 3 weeks.

Recurrent Grade 4 neutropenia

Permanently discontinue IMDYLLTRA.

Febrile neutropenia

Withhold IMDYLLTRA until neutropenia recovers to Grade ≤ 2 and fever resolves.

Haemoglobin <8 g/dL

Withhold IMDYLLTRA until haemoglobin is ≥8 g/dL.

Grade 3 or Grade 4 decreased platelet count

Withhold IMDYLLTRA until platelet count is Grade ≤ 2 and no evidence of bleeding.

Permanently discontinue if recovery to Grade ≤ 2 does not occur within 3 weeks.

Recurrent Grade 4 decreased platelet count

Permanently discontinue IMDYLLTRA.

Elevated Liver Tests (see section 4.4)

Grade 3

Increased ALT or AST or bilirubin

Withhold IMDYLLTRA until adverse events improve 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 Refer to Table 6 for recommendations on restarting IMDYLLTRA after dose delay.

b Severity based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.

Recommended Concomitant Medications for IMDYLLTRA Administration for Day 1 and Day 8

Administer concomitant medications for IMDYLLTRA administration as presented in Table 5 to reduce the risk of cytokine release syndrome (see section 4.4).

Table 5. Concomitant Medications for IMDYLLTRA Administration for Day 1 and Day 8

Treatment Day

Medication

Administration

Day 1 and Day 8

Administer 8 mg of dexamethasone intravenously (or equivalent)

Within 1 hour prior to IMDYLLTRA administration

Administration of 1 liter of normal saline intravenously is recommended per standard of care guidelines

Immediately after completion of IMDYLLTRA infusion

Restarting IMDYLLTRA After Dosage Delay

If a dose of IMDYLLTRA is delayed, restart therapy based on the recommendations listed in Table 6 and resume the dosing schedule accordingly (see Table 1). Administer required concomitant medications as indicated in section 4.2.

Table 6. Recommendations for Restarting Therapy with IMDYLLTRA After Dosage Delay

Last Dose Administered

Time Since the Last Dose Administered

Action a

Day 1

1 mg

14 days or less

Administer IMDYLLTRA 10 mg, then continue with the planned dosage schedule

Greater than 14 days

Restart IMDYLLTRA 1 mg, then continue with the planned dosage schedule.

Day 8

10 mg

21 days or less

Administer IMDYLLTRA 10 mg, then continue with the planned dosage schedule

Greater than 21 days

Restart IMDYLLTRA 1 mg, then continue with the planned dosage schedule.

Day 15 and every 2 weeks thereafter

10 mg

28 days or less

Administer IMDYLLTRA 10 mg, then continue with the planned dosage schedule

Greater than 28 days

Restart IMDYLLTRA 1 mg, then continue with the planned dosage schedule.

a Administer recommended concomitant medications before and after Day 1 and Day 8 of IMDYLLTRA infusions and monitor patients accordingly (see section 4.2, Table 1 and Table 5).

Special populations

Elderly

In clinical studies, no overall differences in IMDYLLTRA pharmacokinetics, safety or efficacy were observed between elderly patients (≥ 65 years of age) and younger patients. No dose adjustment is necessary in elderly patients (≥ 65 years of age).

Hepatic Impairment

Based on population pharmacokinetic analyses, no dose adjustment is required in patients with mild hepatic impairment. IMDYLLTRA has not been studied in patients with moderate or severe hepatic impairment.

Renal impairment

Based on population pharmacokinetic analyses, no dose adjustment is required in patients with mild or moderate renal impairment. IMDYLLTRA has not been studied in patients with severe renal impairment.

Paediatric population

The safety and efficacy of IMDYLLTRA in children aged ≤ 18 years of age have not yet been established.

Method of administration

IMDYLLTRA is for intravenous use.

IV line for premedication can be used for IMDYLLTRA. IV line flush should be conducted between administering concomitant medication and IMDYLLTRA.

Administer the entire contents of IMDYLLTRA as an intravenous infusion over 1 hour at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm (see section 6.6). IV tubing is primed with 0.9% Sodium Chloride for Injection, OR final prepared IMDYLLTRA. Upon completion of the IMDYLLTRA infusion, the IV administration line should be flushed over 3-5 minutes using 0.9% Sodium Chloride for Injection.

IMDYLLTRA should be infused over 1 hour at an infusion rate of 250mL/hour, see Table 7.

Table 7. IMDYLLTRA Administration Information

Infusion Duration for 250 mL IV Preparation

Infusion Rate (mL/hour)

1 hour

250

For instructions on the handling and preparation of the medicinal product before administration, see section 6.6.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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 IMDYLLTRA has been associated with cytokine release syndrome (CRS) which may be serious or life‑threatening (see section 4.8). CRS may be associated with symptoms including pyrexia, hypotension, fatigue, hypoxia, tachycardia, headache, chills, nausea, and vomiting. The majority of these events did not lead to IMDYLLTRA discontinuation in clinical trials.

Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).

Administer IMDYLLTRA in a healthcare setting equipped to monitor and manage CRS. Ensure patients are euvolemic prior to initiating the infusions. Section 4.2. Patients should be closely monitored for signs and symptoms of CRS during the initiation of IMDYLLTRA treatment. To mitigate the risk of CRS, it is important to initiate IMDYLLTRA at the recommended starting dose in Table 1. CRS should be managed according to the recommendations in Table 2.

At the first sign of CRS, immediately interrupt IMDYLLTRA infusion, evaluate the patient for hospitalisation and institute supportive care based on severity. Management of these events may require the dose to be either modified or permanently discontinued (see section 4.2). Counsel patients to seek medical attention should signs or symptoms of CRS occur.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Administration of IMDYLLTRA has been associated with ICANS which may be serious or life-threatening. ICANS can occur up to several weeks following administration of IMDYLLTRA. Adverse events 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 IMDYLLTRA treatment. ICANS should be managed according to the recommendations in Table 3.

CNS metastases

There is limited experience of IMDYLLTRA in patients with central nervous system (CNS) involvement. The risk/benefit of IMDYLLTRA has not been established in patients with active brain metastases.

The overall safety profile was similar for patients with or without a history of active CNS metastases.

Hypersensitivity

Hypersensitivity reactions have been reported in patients treated with IMDYLLTRA including rare severe events. Clinical signs and symptoms of hypersensitivity may include but are not limited to rash and bronchospasm. Monitor patients for signs and symptoms of hypersensitivity during treatment with IMDYLLTRA and manage as clinically indicated. Withhold or consider permanent discontinuation of IMDYLLTRA based on severity (see sections 4.2).

Cytopenias

IMDYLLTRA can cause cytopenias including neutropenia, thrombocytopenia, and anaemia. Monitor patients for signs and symptoms of cytopenias. Perform complete blood counts prior to treatment with IMDYLLTRA, as clinically indicated. Based on the severity of cytopenias, temporarily withhold, or permanently discontinue IMDYLLTRA as clinically indicated.

Elevated Liver Tests

IMDYLLTRA can cause transient elevation of liver enzymes.

Liver enzyme elevation can occur with or without concurrent CRS. Monitor liver enzymes and bilirubin prior to treatment with IMDYLLTRA, as clinically indicated.

Withhold IMDYLLTRA or permanently discontinue based on severity as clinically indicated.

4.5. Interaction with other medicinal products and other forms of interaction

No formal drug interaction studies have been conducted with IMDYLLTRA. Initiation of IMDYLLTRA treatment causes transient release of cytokines that may suppress CYP450 enzymes and may result in increased exposures of concomitant CYP substrates. In patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index e.g., sirolimus and tacrolimus, monitor for known adverse events. Adjust the dose of the concomitant drug as needed.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

Breast-feeding

It is unknown whether IMDYLLTRA is excreted in human milk. Because many medicinal products, including antibodies, can be secreted in human milk, a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue IMDYLLTRA treatment taking into account the benefit of breast-feeding for the child and the benefit of IMDYLLTRA treatment for the woman.

Fertility

No studies have been conducted to evaluate the effects of IMDYLLTRA on fertility.

4.7. Effects on ability to drive and use machines

Studies on the effects of IMDYLLTRA on the ability to drive and use machines have not been performed. However, due to the potential for ICANS and other associated neurological events, following tarlatamab infusion, advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, in the event of any neurologic symptoms until they resolve.

4.8. Undesirable effects

Summary of the safety profile

The safety of IMDYLLTRA, based on pooled data from Study DeLLphi-300, and Study DeLLphi-301 and Study DeLLphi-304, was evaluated in 473 patients with small cell lung cancer (SCLC) who received 10 mg as monotherapy. The median duration of exposure to IMDYLLTRA was 18 weeks (range: 6 to 38).

The most common adverse reactions were cytokine release syndrome (56.7%), pyrexia (31.9%), dysgeusia (31.3%), decreased appetite (36.4%), constipation (30.4%), fatigue (29.8%), anaemia (30.0%), and asthenia (19.0%).

Tabulated list of adverse reactions

Adverse reactions reported in IMDYLLTRA clinical studies are displayed in Table 8 below. Frequency is provided by MedDRA category: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 10,000). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

Table 8. Adverse reactions

MedDRA system organ class

Very Common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥ 1/1,000 to < 1/100)

Blood and lymphatic systems disorders

Anaemia

Neutropeniaa, c

Lymphopeniab

Gastrointestinal disorders

Constipation

Nausea

General disorders and administration site conditions

Pyrexia

Fatigue

Asthenia

Immune system disorders

Cytokine release syndrome b

Metabolism and nutrition disorders

Decreased appetite

Hyponatraemia

Nervous system disorders

Dysgeusia

Headache

Immune effector cell‑associated neurotoxicity syndrome c

Tremor

Neurotoxicity

Seizure

Ataxia

Encephalopathy

Psychiatric disorders

Confusional state

Delirium

Respiratory, thoracic, and mediastinal disorders

Dyspnoea

Investigations

Weight decreased

a Includes neutropenia and neutrophil count decreased.

b Includes lymphopenia and 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 for 473 patients with SCLC enrolled in Study DeLLphi‑300, Study DeLLphi‑301 and Study DeLLphi-304, receiving the IMDYLLTRA 10 mg 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. No patients had Grade 5 events. 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% 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 to 26.5 hours).

In patients treated with IMDYLLTRA at 10 mg enrolled in Study DeLLphi‑304 (n=252), CRS occurred in 56.3% of patients, including Grade 1 in 42.5%, Grade 2 in 12.7 % and Grade 3 in 1.2% of patients. No patients had Grade 4 or Grade 5 events. Most patients experienced CRS after the first two doses of IMDYLLTRA with 6.3% experiencing CRS after the third dose or later. Following the Day 1 infusion, 11.5% of patients experienced ≥ Grade 2 CRS. Following the Day 8 infusion, 4.8% of patients experienced ≥ Grade 2 CRS. For those Grade 1 events that progressed to Grade 2 or greater, the median time from Grade 1 event to Grade 2 events was 22.3 hours (range: 6.5 – 40.1 hours).

ICANS

In clinical trials with pooled safety data for 473 patients with SCLC enrolled in Study DeLLphi‑300, Study DeLLphi‑301 and Study DeLLphi-304 receiving IMDYLLTRA 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 (range: 2 to 13 days). The median time to resolution of ICANS was 4 days (range: 2 to 8 days).

Neutropenia

In clinical trials with pooled safety data for 473 patients with SCLC enrolled in Study DeLLphi‑300, Study DeLLphi‑301 and Study DeLLphi-304 receiving IMDYLLTRA 10 mg, neutropenia occurred in 16.9% including 8.2% of patients experiencing Grade 3 and 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 and/or reduction of tarlatamab occurred in 34.9% patients with none leading to treatment discontinuation.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-tarlatamab antibodies in other studies, including those of tarlatamab or of other DLL3 T-cell engager products.

Across Study DeLLphi‑300, Study DeLLphi‑301 and Study DeLLphi-304, the incidence of anti-tarlatamab antibody development was 7.7% (34/444) in patients receiving the dose of 10 mg. In Studies DeLLphi‑301 and DeLLphi-304 which employed the neutralising assay, 7.5% (27/359) of the patients developed anti-tarlatamab antibody, including 3.1% (11/359) of patients developed anti-tarlatamab neutralising antibodies. Positive anti-tarlatamab antibody status had no clinically relevant impact on efficacy, safety and pharmacokinetics.

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

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There is no clinical experience with overdose with IMDYLLTRA. Doses up to 100 mg every two weeks and 200 mg every three weeks have been administered in clinical trials. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.