IMDELLTRA is a bispecific antibody that targets both delta-like ligand 3 (DLL3) and CD3 T cells.

It is used to treat adults with extensive-stage small cell lung cancer (ES-SCLC) whose disease has worsened after receiving platinum-based chemotherapy.

This approval is granted under an accelerated program based on how well patients respond to the treatment and how long the response lasts.

Continued approval may depend on further evidence of clinical benefits from ongoing or future trials.

Important Dosing Information

Administer IMDELLTRA according to the step-up dosing schedule to reduce the incidence and severity of cytokine release syndrome (CRS).

For Cycle 1, administer the recommended medications listed in Table 3 before and after the IMDELLTRA infusions to lower the risk of CRS reactions.

IMDELLTRA should only be given by a qualified healthcare professional who can manage severe reactions like CRS and neurological toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS).

Due to the risk of CRS and neurological toxicity, including ICANS, monitor patients for 22 to 24 hours from the start of the IMDELLTRA infusion on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting.

Patients should stay within one hour of a healthcare facility for 48 hours after the start of the infusion on these days and be accompanied by a caregiver.

Before administering IMDELLTRA, evaluate the patient's complete blood count, liver enzymes, and bilirubin levels before each dose, and as clinically indicated. Ensure patients are well hydrated before receiving IMDELLTRA.

Recommended Dosing:

Read Dosing Details Given By Manufacturer in Their Imdelltra Prescribing Information

Contraindications and Warnings:

• Cytokine Release Syndrome

IMDELLTRA can cause cytokine release syndrome (CRS), including serious or life-threatening reactions.

In the pooled safety population [see Adverse Reactions (6.1)], CRS occurred in 55% of patients who received IMDELLTRA.

This includes 34% with Grade 1, 19% with Grade 2, 1.1% with Grade 3, and 0.5% with Grade 4 CRS. Recurrent CRS occurred in 24% of IMDELLTRA-treated patients, including 18% with Grade 1 and 6% with Grade 2.

Most CRS events (43%) happened after the first dose, with 29% of patients experiencing CRS after the second dose and 9% after the third dose or later.

Following the Day 1, Day 8, and Day 15 infusions, 16%, 4.3%, and 2.1% of patients experienced Grade 2 or higher CRS, respectively.

The median time to onset of all-grade CRS from the most recent dose of IMDELLTRA was 13.5 hours (range: 1 to 268 hours).

The median time to onset of Grade 2 or higher CRS from the most recent dose was 14.6 hours (range: 2 to 566 hours).

Clinical signs and symptoms of CRS include fever, low blood pressure, fatigue, rapid heartbeat, headache, low oxygen levels, nausea, and vomiting.

Potentially life-threatening complications of CRS can involve cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, kidney and/or liver failure, and disseminated intravascular coagulation (DIC).

Administer IMDELLTRA according to the recommended step-up dosing schedule and give concomitant medications before and after Cycle 1 infusions as detailed in Table 3 to reduce the risk of CRS.

IMDELLTRA should be given in a healthcare facility equipped to monitor and manage CRS. Ensure patients are well hydrated before administration.

Closely monitor patients for signs and symptoms of CRS during treatment. At the first sign of CRS, immediately stop the IMDELLTRA infusion, evaluate the patient for hospitalization, and provide supportive care based on severity.

Withhold or permanently discontinue IMDELLTRA based on the severity of CRS. Advise patients to seek medical attention if symptoms of CRS occur.

• Neurologic Toxicity Including ICANS

IMDELLTRA can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS).

In the pooled safety population [see Adverse Reactions (6.1)], neurologic toxicity, including ICANS, occurred in 47% of patients receiving IMDELLTRA, with 10% experiencing Grade 3 severity.

The most frequent neurologic toxicities were headache (14%), peripheral neuropathy (7%), dizziness (7%), insomnia (6%), muscular weakness (3.7%), delirium (2.1%), syncope (1.6%), and neurotoxicity (1.1%).

ICANS specifically occurred in 9% of IMDELLTRA-treated patients, with recurrent ICANS in 1.6%. Most patients experienced ICANS following Cycle 2, Day 1 (24%).

Following Day 1, Day 8, and Day 15 infusions, 0.5%, 0.5%, and 3.7% of patients experienced Grade 2 or higher ICANS, respectively.

The median time to ICANS onset from the first dose of IMDELLTRA was 29.5 days (range: 1 to 154 days), and ICANS can occur several weeks post-administration. The median time to ICANS resolution was 33 days (range: 1 to 93 days).

ICANS can present concurrently with CRS, following CRS resolution, or independently of CRS. Clinical signs and symptoms of ICANS may include confusion, decreased level of consciousness, disorientation, drowsiness, lethargy, and slowed thinking.

Patients receiving IMDELLTRA are at risk of neurologic adverse reactions and ICANS, which can result in a depressed level of consciousness.

Advise patients to avoid driving and engaging in hazardous activities, such as operating heavy machinery, if they experience any neurologic symptoms until these symptoms resolve.

Closely monitor patients for signs and symptoms of neurologic toxicity and ICANS during treatment. At the first sign of ICANS, immediately evaluate the patient and provide supportive therapy based on the severity of symptoms. Withhold or permanently discontinue IMDELLTRA based on the severity of ICANS.

• Cytopenias

IMDELLTRA can cause cytopenias, including neutropenia, thrombocytopenia, and anemia.

In the pooled safety population, decreased neutrophil levels occurred in 12% of IMDELLTRA-treated patients, with 6% experiencing Grade 3 or 4 severity.

The median time to onset for Grade 3 or 4 neutropenia was 29.5 days (range: 2 to 213 days). Decreased platelet levels occurred in 33% of patients, including 3.2% with Grade 3 or 4 severity.

The median time to onset for Grade 3 or 4 thrombocytopenia was 50 days (range: 3 to 420 days). Decreased hemoglobin levels were observed in 58% of patients, with 5% experiencing Grade 3 or 4 severity. Febrile neutropenia occurred in 0.5% of patients treated with IMDELLTRA.

Monitor patients for signs and symptoms of cytopenias. Perform complete blood counts before starting treatment with IMDELLTRA, prior to each dose, and as clinically indicated.

Depending on the severity of the cytopenias, temporarily withhold or permanently discontinue IMDELLTRA.

• Infections

IMDELLTRA can cause serious infections, including life-threatening and fatal infections.

In the pooled safety population [see Adverse Reactions (6.1)], infections, including opportunistic infections, occurred in 41% of patients who received IMDELLTRA. Grade 3 or 4 infections were observed in 13% of patients.

The most frequent infections were COVID-19 (9%, primarily during the COVID-19 pandemic), urinary tract infection (10%), pneumonia (9%), respiratory tract infection (3.2%), and candida infection (3.2%).

Monitor patients for signs and symptoms of infection before and during treatment with IMDELLTRA and treat as clinically indicated. Withhold or permanently discontinue IMDELLTRA based on the severity of the infection.

• Hepatotoxicity

IMDELLTRA can cause hepatotoxicity.

In the pooled safety population [see Adverse Reactions (6.1)], elevated ALT levels occurred in 42% of IMDELLTRA-treated patients, with Grade 3 or 4 elevations in 2.1%.

Elevated AST levels were observed in 44% of patients, with Grade 3 or 4 elevations in 3.2%. Elevated bilirubin levels occurred in 15% of patients, with Grade 3 or 4 elevations in 1.6%. Liver enzyme elevation can occur with or without concurrent CRS.

Monitor liver enzymes and bilirubin levels before starting treatment with IMDELLTRA, before each dose, and as clinically indicated. Withhold or permanently discontinue IMDELLTRA based on the severity of the liver enzyme elevations.

• Hypersensitivity

IMDELLTRA can cause severe hypersensitivity reactions.

Clinical signs and symptoms of hypersensitivity may include rash and bronchospasm. Monitor patients for signs and symptoms of hypersensitivity during treatment with IMDELLTRA and manage as clinically indicated. Withhold or consider permanent discontinuation of IMDELLTRA based on the severity of the reaction.

• Embryo-Fetal Toxicity

Due to its mechanism of action, IMDELLTRA may cause fetal harm if administered to a pregnant woman. Patients should be informed of the potential risk to a fetus.

Females of reproductive potential should use effective contraception during IMDELLTRA treatment and for 2 months after the last dose to minimize the risk of pregnancy.

• Side Effects of Imdelltra:

a: IMDELLTRA: bispecific delta-like ligand 3 (DLL3)-directed CD3 T cell engager

b: Cytokine release syndrome includes preferred terms Cytokine release syndrome, and Cytokine storm

c Fatigue includes preferred terms Fatigue and Asthenia

d Musculoskeletal pain includes preferred terms Musculoskeletal pain, Back pain, and Arthralgia

e Dyspnea includes preferred terms Dyspnea, and Shortness of breath

Laboratory abnormalities associated with Imdelltra:

IMDELLTRA: bispecific delta-like ligand 3 (DLL3)-directed CD3 T cell engager b Neutrophils: includes preferred terms Neutropenia and Absolute neutrophil count decreased

Mechanism of Action of Imdelltra:

Tarlatamab-dlle is a bispecific T-cell engager that attaches to DLL3, a protein expressed on the surface of various cells, including tumor cells, and to CD3, a protein found on the surface of T-cells.

This binding activates T-cells, leading to the release of inflammatory cytokines and the destruction of cells expressing DLL3. In mouse models of small cell lung cancer (SCLC), tarlatamab-dlle demonstrated anti-tumor activity.

Metabolism

Tarlatamab-dlle is anticipated to undergo metabolism into small peptides through catabolic pathways.

Elimination

Tarlatamab-dlle's median terminal elimination half-life ranges from 4.3 to 26.5 days, with a median of 11.2 days. The estimated systemic clearance in patients with small cell lung cancer (SCLC) is 0.65 L/day, accounting for 44% of the administered dose.

Specific Populations

No clinically significant variances in the pharmacokinetics of tarlatamab-dlle were noted across various factors such as age (ranging from 32 to 82 years), body weight (ranging from 35 to 149 kg), sex, race (White and Asian), or mild to moderate renal impairment (eGFR ≥ 30 to < 90 mL/min), or mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN).

However, the effects of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR < 15 mL/min), or moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN, any AST) on the pharmacokinetics of tarlatamab-dlle remain uncertain.

Effects of Tarlatamab-dlle on CYP450 Substrates

Tarlatamab-dlle induces a transient release of cytokines, which may suppress CYP450 enzymes. This suppression might lead to increased exposure of concomitant CYP substrates during and up to 14 days after the occurrence of cytokine release syndrome.

Read: An Overview of Lung Cancer Treatment