Detailed instructions for Tarlatamab

Tarlatamab is the world's first bispecific T cell adapter targeting DLL3/CD3 developed by Amgen. Its innovative mechanism can simultaneously recognize the DLL3 protein on the surface of tumor cells and the CD3 receptor on the surface of T cells, thereby activating the specific killing effect of T cells on tumors. The drug received accelerated approval from the US FDA on May 16, 2024, becoming the first targeted immunotherapy for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) that has progressed after platinum-based chemotherapy.

1. Indications

Small cell lung cancer

Talatuzumab is suitable for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has progressed during or after platinum-based chemotherapy.

2. Usage and dosage

1. Recommended dosage

(1) Cycle 1‌: 1 mg of talatumumab on day 1, 10 mg of talatumumab on day 8, and 10 mg of talatumumab on day 15.

(2) Cycle 2‌: Day 1 and day 15 are both 10 mg of talatumumab.

(3) Cycles 3 and 4‌: 10 mg talatumumab on days 1 and 15.

(5) Cycle 5 and subsequent‌: 10 mg of talatumumab on days 1 and 15.

2. Restart dose after dose delay

(1) 1 mg on day 1 of cycle 1‌

If the drug is discontinued for 2 weeks or less (≤14 days), re-administer talatumumab 10 mg and resume the original planned dosage regimen. If the drug is discontinued for more than 2 weeks (>14 days), give an incremental dose of 1 mg first. If tolerated well, increase to 10 mg after 1 week, and then resume the original plan.

(2) 10 mg on day 8 of cycle 1‌

Withdrawal for 3 weeks or less (≤21 days), give talatumumab 10 mg directly, and resume the original plan. If the drug is discontinued for more than 3 weeks (>21 days), give an incremental dose of 1 mg first, increase to 10 mg 1 week after tolerance, and then resume the original plan.

(3) 10 mg on day 15 of cycle 1, and every 2 weeks thereafter‌

After discontinuation for 4 weeks or less (≤28 days), directly administer talatumumab 10 mg, and resume the original plan. If the drug is discontinued for more than 4 weeks (>28 days), give an incremental dose of 1 mg first, increase to 10 mg 1 week after tolerance, and then continue treatment according to the original plan.

3. Medication management

(1) Cycle 1: Starting from the 1st and 8th day, monitor the patient for 22 to 24 hours. After the infusion on Day 8, observe the patient for 6-8 hours.

(2) Cycle 2‌: Observe the patient for 6-8 hours after infusion.

(3) Cycles 3 and 4‌: Observe the patient for 3-4 hours after infusion.

(4) Cycle 5 and subsequent‌: Observe the patient for 2 hours after infusion.

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2. Dose adjustment

1. Cytokine release syndrome dose adjustment

(1) Level 1‌: Symptoms are mild and only symptomatic treatment is required, such as acetaminophen in case of fever. Talatumumab needs to be withheld until symptoms resolve and then resumed at the next scheduled dose.

(2) Level 2‌: Symptoms require moderate intervention, including suspension of talatumumab, symptomatic treatment, and consideration of hospitalization for 24-hour cardiac telemetry and pulse oximetry monitoring. In the meantime, dexamethasone and tocilizumab may be considered. After resolution of symptoms, resume talatumumab at the next scheduled dose.

(3) Level 3‌: Symptoms are severe and talatumumab needs to be suspended immediately. In addition to level 2 treatment, ICU care is required with dexamethasone, vasopressors, and tocilizumab. For recurrent Grade 3 events, talatumumab should be permanently discontinued. After resolution of symptoms, resume treatment starting with the next scheduled dose in an appropriate medical setting and monitor for 22 to 24 hours.

(4) Grade 4‌: Symptoms are life-threatening, requiring permanent discontinuation of talatumumab and ICU care. Treatment is the same as Level 3, but special attention should be paid to the patient's vital signs and changes in condition.

2. Dose adjustment for nervous system toxicity‌

Level 1: ICE score 7-9, the patient does not have a depressed level of consciousness. Withhold talatumumab until ICANS resolves and resume, while providing supportive care.

Level 2‌: ICE score 3-6, mild drowsiness may occur. Withhold talatumumab until resumption after ICANS subsides, administer dexamethasone or methylprednisolone injection, and monitor for neurological symptoms.

Level 3‌: ICE score 0-2, decreased level of consciousness, possible awakening to tactile stimulation, or epileptic seizure. Withhold talatumumab until resumption after ICANS resolution, ICU care is recommended, mechanical ventilation should be considered to protect the airway, and high-dose corticosteroids should be administered. If there is no improvement within 7 days or recurrence of grade 3 toxicity, permanently discontinue talatumumab.

Level 4‌: ICE score 0, the patient cannot be awakened and may suffer from coma or life-threatening prolonged epileptic seizures. Talatumumab was permanently discontinued, ICU care was performed, mechanical ventilation was considered to protect the airway, and high-dose corticosteroids were administered. And repeat neuroimaging examination (CT or MRI) every 2-3 days according to the situation to treat convulsive status epilepticus.

3. Adverse reaction dose adjustment

(1) Cytopenia‌

a. Grade 3 or 4 neutropenia: Withhold talatumumab until recovery to ≤ grade 2. Consider G-CSF therapy. If it does not recover within 3 weeks, it will be permanently disabled.

b. Recurrent grade 4 neutropenia: Permanently discontinue talatumumab.

c. Febrile Neutropenia: Discontinue talatumumab until recovery to ≤Grade 2 and fever resolves.

d. Hemoglobin <8g/dL: Discontinue taratumumab until recovery to ≥8g/dL.

e. Grade 3 or 4 platelet count decrease: Withhold taratumumab until recovery to ≤Grade 2 without evidence of bleeding. If it does not recover within 3 weeks, it will be permanently disabled.

(2) Infection‌

a. All grade infections: Discontinue talatumumab during the pressor phase until the infection resolves.

b. Grade 3 infection: Discontinue talatumumab during the treatment phase until the infection improves to ≤ grade 1.

c.Grade 4 infection: Permanently discontinue talatumumab.

(3) Hepatotoxicity‌

a.Grade 3 elevation of ALT, AST or bilirubin: suspend talatumumab until the adverse event improves to grade 1.

b. Grade 4 elevations in ALT, AST, or bilirubin: Permanently discontinue talatumumab.

c.AST or ALT>3×ULN, total bilirubin>2×ULN (no other reasons): Permanently discontinue talatumumab.

(4) Other adverse reactions‌

Grade 3 or 4 adverse reactions: Withhold talatumumab until recovery to ≤Grade 1 or baseline. If symptoms do not subside within 28 days, consider permanently discontinuing the medication.

3. Adverse reactions

1. Common adverse reactions (≥20%)

Common adverse reactions of taratumumab are cytokine release syndrome, fatigue, fever, dysgeusia, decreased appetite, musculoskeletal pain, constipation, anemia and nausea.

2. Common grade 3 or 4 laboratory abnormalities (≥2%)

Talatuzumab is lymphopenia, sodium decrease, uric acid increase, total neutrophil count decrease, hemoglobin decrease, activated partial thromboplastin time increase, potassium decrease, aspartate aminotransferase increase, leukopenia, platelet decrease and alanine aminotransferase increase.

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IV. Specifications and properties

1. Tarlatamab-dlle for injection is a sterile, preservative-free, white to slightly yellow freeze-dried powder.

2. The 1 mg package contains 1 vial of 1 mg talatumumab single-dose vial and 2 vials of 7 mL intravenous solution stabilizer.

3. The 10 mg package contains 1 bottle of 10 mg talatumumab single-dose bottle and 2 bottles of 7 mL intravenous solution stabilizer.

5. Precautions

1. Cytokine release syndrome

Talatuzumab may cause severe or life-threatening CRS, with symptoms including fever, hypotension, fatigue, tachycardia, headache, hypoxia, nausea and vomiting. Potential complications include cardiac dysfunction, respiratory distress, and multiorgan failure. Management measures include the use of an escalating dose regimen, concomitant medications given before and after the infusion to reduce risk, and administration in a facility with appropriate medical support. During treatment, the patient's hydration status and signs of CRS need to be closely monitored; once symptoms occur, the infusion is immediately suspended, hospitalization needs are assessed, and supportive care is provided or the dosage regimen is adjusted according to the severity.

2. Nervous system toxicity

Talatuzumab may cause severe or life-threatening neurotoxicity, such as immune effector cell-associated neurotoxic syndrome (ICANS). Symptoms involve decreased level of consciousness, confusion, disorientation, drowsiness, headache, peripheral neuropathy, dizziness, insomnia, muscle weakness, delirium, or syncope. ICANS may occur independently of or alongside CRS. Management includes close monitoring of neurological signs during treatment; if signs occur, immediate evaluation and provision of supportive care, withholding or permanent discontinuation of the drug depending on severity. Patients should avoid driving or engaging in hazardous activities until symptoms subside.

3. Cytopenia‌

Talatuzumab can cause cytopenias, including neutropenia, thrombocytopenia or anemia. Management priorities include monitoring complete blood counts prior to treatment, prior to administration, and as clinically indicated, and withholding or permanently discontinuing medications based on severity.

4. Infection‌

Talatuzumab may induce serious infections (including opportunistic infections). Management measures emphasize monitoring for signs and symptoms of infection, prompt treatment as clinically indicated, and suspending or permanently discontinuing medications based on severity.

5. Hepatotoxicity‌

Talatuzumab may cause an increase in liver enzymes (such as ALT, AST) and bilirubin. Management includes monitoring of liver function and bilirubin levels prior to treatment, prior to administration, and as clinically indicated, and withholding or permanently discontinuing the drug based on severity.

6. Hypersensitivity reaction‌

Talatuzumab can cause severe hypersensitivity reactions, with symptoms including rash, bronchospasm, etc. Relevant signs need to be monitored during treatment, and the drug should be suspended or considered permanently discontinued depending on the severity.

7. Embryo-fetal toxicity‌

Based on its mechanism of action, talatumumab may cause harm to the fetus when taken by pregnant women. It is recommended that females of childbearing potential use effective contraception during treatment and for 2 months after the last dose.

6. Contraindications

The contraindications of talatumumab have not been specified in the instructions

7. Medication for special groups

1. Pregnancy

Talatuzumab may cause harm to the fetus when administered to pregnant women. There are no data available on the use of talatumumab in pregnant women to inform the risks associated with the drug. Human immunoglobulin G (IgG) and proteins containing an IgG-derived fragment crystallizable (Fc) domain are known to cross the placental barrier; therefore, talatumumab has the potential to be transmitted from the mother to the developing fetus. Inform women of potential risks to the fetus.

2. Lactation

There are no data on the presence of talatumumab in breast milk or its effects on breastfed children or milk production. Maternal IgG is known to be present in breast milk. The effects of local gastrointestinal exposure and limited systemic exposure to talatumumab in breastfed children are unknown. Because of the potential for serious adverse reactions in breastfed children, advise patients not to breastfeed during treatment with talatumumab and for 2 months after the last dose.

3. People with reproductive potential

Talatuzumab may cause harm to the fetus when administered to pregnant women. Verify pregnancy status in females of childbearing potential before initiating talatumumab. Advise females of childbearing potential to use effective contraception during treatment with talatumumab and for 2 months after the last dose.

4. Pediatric patients

The safety and effectiveness of talatumumab in pediatric patients have not been determined.

5. Elderly patients

No overall differences in the pharmacokinetics or safety of talatumumab were observed between elderly patients (≥65 years old) and younger patients. Clinical studies of talatumumab did not include sufficient numbers of patients aged 65 and older to determine whether they responded differently to younger patients.

8. Validity period

24 months.

9. Storage conditions

Talatuzumab and its accompanying intravenous solution stabilizer (IVSS) must be refrigerated and stored at 2°C to 8°C, and protected from light. Freezing is strictly prohibited. Before clinical use, if temporary storage is required, the vials with complete original packaging can be placed at room temperature between 20°C and 25°C for a maximum storage time of no more than 24 hours, and they must be kept protected from light during this period.

10. Pharmacokinetics

1. Distribution

The steady-state volume of distribution of talatumumab is 8.6L (18.3%).

2. Metabolism

Talatuzumab is expected to be metabolized into small peptides through the catabolic pathway.

3. Elimination

In patients with small cell lung cancer, the median terminal elimination half-life (minimum, maximum) of Talatumumab is 11.2 (4.3 to 26.5) days, and the estimated systemic clearance rate is 0.65L/day (44%).