Tarlatamab

Tarlatamab is a bispecific T-cell engager: a recombinant antibody made in Chinese hamster ovary cells that has two binding arms. One arm binds delta-like ligand 3 (DLL3), a protein on the surface of small cell lung cancer cells that is minimally expressed in normal tissues; the other binds CD3 on T-cells. By bringing a T-cell and a tumour cell together, tarlatamab directs the patient’s own immune cells against the cancer.

Mechanism of Action

• Dual binding: tarlatamab binds DLL3 on tumour cells and CD3 on T-cells at the same time. This triggers T-cell activation, release of inflammatory cytokines and release of cytotoxic proteins, which leads to redirected lysis (destruction) of the tumour cells.
• Target: DLL3 is an inhibitory ligand of Notch signalling and is present on the surface of up to 85% of small cell lung cancer cells.
• Pharmacodynamic response: after a single infusion there is T-cell redistribution and activation and a transient rise in cytokines. T-cell counts fell within 6 hours of the first 1 mg dose and returned to baseline in most patients before the day 8 infusion. Serum IL-2, IL-6, IL-8, IL-10, interferon-gamma and TNF-alpha rose briefly, peaked within the first 2 days and generally returned to baseline before day 8. With later doses fewer patients had cytokine rises, and they were less intense. Starting with a low 1 mg dose is part of reducing the risk of CRS.
• Exposure and safety: over the studied dose range, higher exposure was not linked to better efficacy but was linked to more neurological toxicity (including ICANS) and neutropenia.
• Immunogenicity: anti-drug antibodies were commonly detected; no effect on pharmacokinetics, efficacy or safety was seen, but data are still limited.

Pharmacokinetics

• Absorption: tarlatamab is given into a vein, so it is fully available. Peak concentration, trough concentration and AUC at steady state rise in proportion to dose between 1 mg and 100 mg every 2 weeks (10 times the recommended dose). Approximate steady-state exposure is reached by cycle 2, day 15.
• Distribution: population analysis estimates a central volume of distribution of 3.23 L and a steady-state volume of distribution of 8.19 L.
• Metabolism: the metabolic pathway has not been characterised. Like other protein medicines, tarlatamab is expected to be broken down into small peptides and amino acids by normal catabolic pathways.
• Elimination: systemic clearance is 0.728 L/day and the terminal half-life about 10.6 days.
• Special populations: clearance did not differ in a clinically meaningful way with age (20–86 years), body weight (35–149 kg), sex, race, mild or moderate renal impairment (eGFR 30 mL/min or more) or mild hepatic impairment. Data are limited in moderate hepatic impairment and absent in severe hepatic or severe renal impairment.

• Extensive-stage small cell lung cancer (ES-SCLC): as monotherapy in adults who require systemic therapy after disease progression on or after first-line treatment with platinum-based chemotherapy.

• Hypersensitivity to tarlatamab or to any of the excipients.

Safety was evaluated in 473 patients with small cell lung cancer who received the 10 mg target dose as monotherapy (median exposure 18.0 weeks). The most common reactions were cytokine release syndrome (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%) and lymphopenia (15.6%). The most common serious reactions were CRS (19.7%) and pyrexia (4.7%).

Very common (≥1/10): cytokine release syndrome, anaemia, neutropenia, lymphopenia, constipation, nausea, vomiting, diarrhoea, pyrexia, fatigue, asthenia, weight decreased, increased alanine aminotransferase, decreased appetite, hyponatraemia, hypokalaemia, dysgeusia, headache, dyspnoea, pruritus.

Common (≥1/100 to <1/10): thrombocytopenia, leukopenia, chills, increased aspartate aminotransferase, decreased white blood cell count, hypomagnesaemia, myalgia, dizziness, immune effector cell-associated neurotoxicity syndrome (ICANS), tremor, confusional state, delirium, rash, hypotension, hypertension.

Uncommon (≥1/1,000 to <1/100): neurotoxicity, seizure, ataxia, encephalopathy.

Grade 3 or higher lymphopenia was very common; grade 3 or higher CRS, neutropenia and anaemia were common.

Important Serious Reactions

• Cytokine release syndrome: occurred in 56.7% of patients (grade 1 in 39.3%, grade 2 in 15.4%, grade 3 in 1.7%, grade 4 in 0.2%), and was serious in 19.7%. After the first dose 41.4% had CRS of any grade and after the second dose 34.0%; 8.5% had CRS after the third dose or later. Grade 2 or higher CRS followed the day 1 infusion in 13.7% of patients and the day 8 infusion in 4.4%. The median time from the latest dose to the first onset of CRS was 15.9 hours (range 9.0 to 26.5 hours). CRS led to a treatment interruption or dose modification in 2.1% and to discontinuation in 0.6%. Fatal cases have been reported after marketing.
• ICANS: reported in 4.7% of patients on the 10 mg dose. The median time from the first dose to the first onset was 9.0 days (interquartile range 2 to 13 days), and the median time to resolution was 4 days (interquartile range 2 to 8 days). ICANS can be life-threatening or fatal.
• Neutropenia: occurred in 16.9% of patients, grade 3 or 4 in 8.2%. The median time to onset was 43 days (range 29 to 109 days). It led to dose interruption in 3.2% and to no discontinuations; granulocyte-colony stimulating factor (G-CSF) was needed in 6%.

No interaction studies have been performed.

• CYP450 substrates: the transient release of cytokines when tarlatamab is started may suppress CYP450 enzymes and raise the levels of other medicines that depend on them. Patients taking CYP450 substrates, particularly those with a narrow therapeutic index, should be monitored for their known side effects, and the dose of the other medicine adjusted as needed.
• Planned premedication: dexamethasone and intravenous fluids are part of the dosing regimen on day 1 and day 8 (see Administration and Dosage).

Treatment should be started under the direction of, and supervised by, physicians experienced in cancer therapy, and given in an appropriate healthcare facility that can monitor and manage CRS. The powder is reconstituted and then diluted before it is given as an intravenous infusion (preparation instructions are in section 6.6 of the SmPC).

Recommended Dosing Schedule

• Day 1: 1 mg.
• Day 8: 10 mg.
• Day 15 and every 2 weeks thereafter: 10 mg.
• Treatment continues until disease progression or unacceptable toxicity.
• Starting at the 1 mg dose is important to reduce the risk of CRS, and patients should be euvolaemic (have a normal circulating fluid volume) before the infusions begin.

Concomitant Medicines on Day 1 and Day 8

• Dexamethasone 8 mg intravenously (or equivalent), within 1 hour before the infusion.
• 1 litre of sodium chloride 9 mg/mL (0.9%) solution intravenously, immediately after the infusion is finished (recommended per standard-of-care guidelines).

Monitoring and Discharge

• Patients are monitored from the start of the infusion for 6 to 8 hours on day 1 and day 8. Further monitoring, and monitoring after later infusions, is at the physician’s discretion.
• On day 1 and day 8, patients must stay within reach of an appropriate healthcare facility for 24 hours from the start of each infusion, accompanied by a caregiver. Before discharge, patients and caregivers are told the signs and symptoms of CRS and ICANS.

Method of Administration

• Intravenous infusion of the whole contents over 1 hour at a constant flow rate with an infusion pump that is programmable, lockable, non-elastomeric and fitted with an alarm; for the 250 mL preparation the rate is 250 mL/hour.
• The line used for the premedication can be used for tarlatamab, with a flush between the other medicines and tarlatamab. The line is primed with sodium chloride 0.9% or with the final prepared tarlatamab, and flushed over 3–5 minutes with sodium chloride 0.9% at the end.

Restarting After a Dose Delay

The usual concomitant medicines are given again as for day 1 and day 8, and the schedule is then resumed.

• After the 1 mg dose on day 1: if 14 days or less have passed, give 10 mg; if more than 14 days, give 1 mg and, if tolerated, 10 mg one week later.
• After the 10 mg dose on day 8: if 21 days or less have passed, give 10 mg; if more than 21 days, give 1 mg and, if tolerated, 10 mg one week later.
• After the 10 mg dose on day 15 or later: if 28 days or less have passed, give 10 mg; if more than 28 days, give 1 mg and, if tolerated, 10 mg one week later.

Dose Modifications for Side Effects

No dose reduction is recommended; side effects are managed by withholding or permanently stopping treatment. Severity is graded with NCI CTCAE version 5.0, and CRS and ICANS with the ASTCT consensus criteria (2019). Steroids are tapered according to standard of care.

Cytokine release syndrome (CRS): diagnosed from the clinical picture, after other causes of fever, low oxygen and low blood pressure have been looked for and treated. For severe or life-threatening CRS, anti-IL-6 treatment (for example tocilizumab) and intensive-care admission are recommended.

• Grade 1 (fever of 38 °C or above without low blood pressure or hypoxia): withhold until it resolves, then resume at the next scheduled dose. Give an antipyretic such as paracetamol; consider dexamethasone 4–10 mg orally or intravenously.
• Grade 2 (fever, low blood pressure that responds to fluids without vasopressors, and/or hypoxia needing low-flow oxygen by nasal cannula or blow-by): withhold until it resolves, then resume at the next scheduled dose. Admission to hospital with monitoring of fever, blood pressure and oxygen levels (pulse oximetry or cardiac telemetry) is recommended, with an antipyretic, oxygen and intravenous fluids as indicated; consider dexamethasone 8 mg and tocilizumab (or equivalent).
• Grade 3 (fever with unstable circulation needing a vasopressor, and/or worsening hypoxia or respiratory distress needing high-flow nasal cannula above 6 L/min or a face mask): withhold until it resolves, then resume at the next scheduled dose; stop permanently if grade 3 CRS recurs. In addition to the grade 2 measures: intensive monitoring (intensive care is recommended), dexamethasone 8 mg intravenously every 8 hours for up to 3 doses, vasopressor and high-flow oxygen support as needed, and tocilizumab (or equivalent). Before the next dose, the day 1 and day 8 concomitant medicines are given again.
• Grade 4 (life-threatening: several vasopressors and/or respiratory support under positive pressure): stop permanently; intensive care and the grade 3 treatment.
• After grade 2 or 3 CRS, patients are monitored at the physician’s discretion in a healthcare facility when treatment resumes.

ICANS: other causes of neurological symptoms are ruled out, and intensive care is given for severe or life-threatening neurological toxicity. Severity is scored partly with the ICE score (Immune Effector Cell-Associated Encephalopathy assessment).

• Grade 1 (ICE score 7–9 with no depressed level of consciousness): withhold until it resolves, then resume at the next scheduled dose; supportive care.
• Grade 2 (ICE score 3–6 and/or mild drowsiness waking to voice): withhold until it resolves, then resume at the next scheduled dose. Supportive care and dexamethasone 8–10 mg orally or intravenously; if symptoms worsen, repeat dexamethasone every 12 hours or give methylprednisolone 1 mg/kg intravenously every 12 hours. Monitor neurological symptoms and consider asking a neurologist.
• Grade 3 (ICE score 0–2 and/or depressed consciousness waking only to touch, and/or a clinical seizure that resolves rapidly, non-convulsive seizures on EEG that resolve with treatment, and/or focal or local oedema on neuroimaging): withhold until it resolves, then resume at the next scheduled dose; stop permanently if there is no improvement to grade 1 or below within 7 days, or if grade 3 recurs. Intensive care is recommended, with consideration of mechanical ventilation to protect the airway, dexamethasone 10 mg intravenously every 6 hours or methylprednisolone 1 mg/kg intravenously every 12 hours, and repeat CT or MRI every 2–3 days if grade 3 or higher neurotoxicity persists.
• Grade 4 (for example ICE score 0, stupor or coma, life-threatening or repeated seizures, diffuse cerebral oedema): stop permanently; intensive care, consideration of mechanical ventilation, high-dose corticosteroids such as methylprednisolone 1,000 mg/day in divided intravenous doses for 3 days, repeat neuroimaging as above, and treatment of convulsive status epilepticus according to institutional guidelines.

Neutropenia: grades 1 and 2 need no interruption. For grade 3, interrupt for at least 3 days and until it improves to grade 2 or below, then resume; consider G-CSF. For grade 4, interrupt in the same way and consider G-CSF; stop permanently if it lasts more than 7 days or grade 4 recurs.

Hepatotoxicity: for grade 3 increases in ALT, AST or bilirubin, withhold until they improve to grade 1 or below. For grade 4, or for AST or ALT above 3 times the upper limit of normal with bilirubin above 2 times the upper limit without another cause, stop permanently. In patients with raised liver enzymes at baseline, multiples of the baseline value are used.

Other side effects: for grade 3 or 4 reactions, withhold until recovery to grade 1 or baseline; consider stopping permanently if a reaction does not resolve within 28 days, and consider permanent discontinuation for grade 4 events.

Special Populations

• Elderly (65 years and older): no dose adjustment.
• Hepatic impairment: no adjustment in mild impairment; data are limited in moderate impairment and it has not been studied in severe impairment, so no dose recommendation can be made for moderate or severe impairment.
• Renal impairment: no adjustment in mild or moderate impairment; not studied in severe impairment, so no dose recommendation can be made from severe impairment to end-stage renal disease.
• Children and adolescents: no relevant use in small cell lung cancer.

Cytokine Release Syndrome (CRS)

CRS can be life-threatening or fatal. Symptoms may include fever, low blood pressure, low oxygen levels, tiredness, fast heartbeat, headache, chills, nausea and vomiting. Tarlatamab must be given in a healthcare facility equipped to monitor and manage CRS, and patients should be euvolaemic before the infusions. Patients and caregivers must be told that CRS can start after discharge and that they must seek immediate medical attention if any sign appears. Close monitoring is needed when treatment starts, and treatment must begin at the recommended starting dose.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

ICANS can be life-threatening or fatal and can occur up to several weeks after an administration. It may show as headache, encephalopathy, confusion, delirium, seizure, ataxia, neurotoxicity or tremor. Patients are monitored closely for signs of ICANS during treatment, and patients and caregivers must be told that it can start after discharge and that they must seek immediate medical attention if any sign appears.

Neutropenia

Neutropenia is common. Patients are monitored for its signs and symptoms during treatment and it is managed as described under dose modifications.

Infections

Serious infections, including life-threatening and fatal ones, have been reported. The most frequent were pneumonia, urinary tract infection, COVID-19, upper respiratory tract infection, respiratory tract infection, candida infection, oral candidiasis and nasopharyngitis. Patients are monitored for signs and symptoms of infection before and during treatment.

Hypersensitivity

Hypersensitivity reactions have been reported, including rare severe events. Signs may include rash and bronchospasm. Patients are monitored during treatment and managed as clinically indicated; treatment may be withheld or permanently stopped depending on severity.

Hepatotoxicity

Tarlatamab has been associated with raised liver enzymes, with or without CRS. Liver enzymes and bilirubin are checked before treatment and as clinically indicated.

Traceability

Because this is a biological medicine, the name and batch number of the administered product must be clearly recorded.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy status: for women of childbearing potential, pregnancy status must be verified before treatment starts.
• Contraception: women of childbearing potential must use effective contraception during treatment and for 2 months after the last dose.
• Pregnancy: there are no data in pregnant women. A mouse study with a murine surrogate molecule showed that it crosses the placenta, and, based on its mechanism of action and the potential for reactions such as CRS, tarlatamab may cause foetal harm. It is not recommended in pregnancy or in women of childbearing potential who are not using contraception.
• Breastfeeding: it is unknown whether tarlatamab passes into human milk and a risk to the infant cannot be excluded. Breastfeeding must be stopped during treatment and for at least 2 months after the last dose.
• Fertility: no clinical trials have looked at the effect on fertility.

Polysorbate 80

Polysorbate 80 is an excipient with known effect: 0.04 mg in each 1 mg vial and 0.2 mg in each 10 mg vial.

Effect on Driving

Because of the possibility of ICANS-related neurological events, tarlatamab may have a major influence on the ability to drive and use machines. If any neurological symptom occurs, patients should not drive or do hazardous work, such as operating heavy or potentially dangerous machinery, until it has gone.

Store and transport refrigerated at 2–8 °C. Do not freeze. Keep the vials in the original packaging to protect them from light. The cold chain must be kept unbroken from dispatch until the infusion is prepared. Each pack holds 1 vial of powder and 2 vials of stabiliser solution. For storage after reconstitution and dilution, see Shelf Life.

• Unopened vial: 4 years.
• Diluted solution in the infusion bag: chemical and physical in-use stability has been shown for 28 days at 2–8 °C and for 8 hours at 20–25 °C. From a microbiological point of view the product should be used immediately. If it is not, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2–8 °C, unless reconstitution and dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx), subject to restricted medical prescription (Annex II B), on the prescription of a physician experienced in cancer therapy. Imdylltra is infused in a healthcare facility equipped to monitor and manage CRS, so it is supplied to the hospital or clinic that administers it. It is supplied and transported refrigerated at 2–8 °C.