IMDELLTRA Solution for injection Ref.[110074] Active ingredients: Tarlatamab

5.1 Cytokine Release Syndrome

IMDELLTRA can cause cytokine release syndrome (CRS) including serious or lifethreatening reactions.

In the pooled safety population [see Adverse Reactions (6.1)], CRS occurred in 55% of patients who received IMDELLTRA, including 34% Grade 1, 19% Grade 2, 1.1% Grade 3 and 0.5% Grade 4. Recurrent CRS occurred in 24% of IMDELLTRA-treated patients including 18% Grade 1 and 6% Grade 2.

Most events (43%) of CRS occurred after the first dose with 29% of patients experiencing any grade CRS after the second dose and 9% of patients experiencing CRS following the third dose or later. Following the Day 1, Day 8, Day 15 infusions, 16%, 4.3%, and 2.1% of patients experienced ≥ Grade 2 CRS, respectively. The median time to onset of all grade CRS from most recent dose of IMDELLTRA was 13.5 hours (range: 1 to 268 hours). The median time to onset of ≥ Grade 2 CRS from most recent dose of IMDELLTRA was 14.6 hours (range: 2 to 566 hours).

Clinical signs and symptoms of CRS included pyrexia, hypotension, fatigue, tachycardia, headache, hypoxia, nausea and vomiting. 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 IMDELLTRA following the recommended step-up dosing and administer concomitant medications before and after Cycle 1 IMDELLTRA infusions as described in Table 3 to reduce the risk of CRS [see Dosage and Administration (2.3)]. Administer IMDELLTRA in an appropriate health care facility equipped to monitor and manage CRS. Ensure patients are well hydrated prior to administration of IMDELLTRA.

Closely monitor patients for signs and symptoms of CRS during treatment with IMDELLTRA. At the first sign of CRS, immediately discontinue IMDELLTRA infusion, evaluate the patient for hospitalization and institute supportive care based on severity. Withhold or permanently discontinue IMDELLTRA based on severity [see Dosage and Administration (2.5)]. Counsel patients to seek medical attention should signs if symptoms of CRS occur.

5.2 Neurologic Toxicity Including ICANS

IMDELLTRA can cause serious or life-threatening neurologic toxicity, including ICANS. In the pooled safety population [see Adverse Reactions (6.1)], neurologic toxicity including ICANS, occurred in 47% of patients who received IMDELLTRA, including 10% Grade 3. 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 occurred in 9% of IMDELLTRA-treated patients [see Adverse Reactions (6.1)]. Recurrent ICANS occurred in 1.6% of patients. 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 ICANS, respectively. The median time to onset of ICANS from the first dose of IMDELLTRA was 29.5 days (range: 1 to 154 days). ICANS can occur several weeks following administration of IMDELLTRA. The median time to resolution of ICANS was 33 days (range: 1 to 93 days).

The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.

Patients receiving IMDELLTRA are at risk of neurologic adverse reactions and ICANS resulting in depressed level of consciousness. 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.

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 severity. Withhold IMDELLTRA or permanently discontinue based on severity [see Dosage and Administration (2.5)].

5.3 Cytopenias

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

In the pooled safety population, [see Adverse Reactions (6.1)], decreased neutrophils occurred in 12% including 6% Grade 3 or 4 of IMDELLTRA-treated patients. The median time to onset for Grade 3 or 4 neutropenia was 29.5 days (range: 2 to 213). Decreased platelets occurred in 33% including 3.2% Grade 3 or 4. The median time to onset for Grade 3 or 4 decreased platelets was 50 days (range: 3 to 420). Decreased hemoglobin occurred in 58% including 5% Grade 3 or 4. Febrile neutropenia occurred in 0.5% of patients treated with IMDELLTRA.

Monitor patients for signs and symptoms of cytopenias. Perform complete blood counts prior to treatment with IMDELLTRA, before each dose, and as clinically indicated. Based on the severity of cytopenias, temporarily withhold, or permanently discontinue IMDELLTRA [see Dosage and Administration (2.5)].

5.4 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 occurred in 13% of patients. The most frequent infections were COVID-19 (9%, majority 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 prior to and during treatment with IMDELLTRA and treat as clinically indicated. Withhold or permanently discontinue IMDELLTRA based on severity [see Dosage and Administration (2.5)].

5.5 Hepatotoxicity

IMDELLTRA can cause hepatotoxicity.

In the pooled safety population [see Adverse Reactions (6.1)], elevated ALT occurred in 42% with Grade 3 or 4 ALT elevation occurring in 2.1% of IMDELLTRA-treated patients. Elevated AST occurred in 44% of patients, with Grade 3 or 4 AST elevation occurring in 3.2%. Elevated bilirubin occurred in 15% of patients, with Grade 3 or 4 total bilirubin elevations occurred in 1.6% of patients [see Adverse Reactions (6.1)]. Liver enzyme elevation can occur with or without concurrent CRS. Monitor liver enzymes and bilirubin prior to treatment with IMDELLTRA, before each dose, and as clinically indicated. Withhold IMDELLTRA or permanently discontinue based on severity [see Dosage and Administration (2.5)].

5.6 Hypersensitivity

IMDELLTRA can cause severe hypersensitivity reactions.

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 IMDELLTRA and manage as clinically indicated. Withhold or consider permanent discontinuation of IMDELLTRA based on severity [see Dosage and Administration (2.5)].

5.7 Embryo-Fetal Toxicity

Based on its mechanism of action, IMDELLTRA may cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMDELLTRA and for 2 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Cytokine Release Syndrome (CRS) [see Warnings and Precautions (5.1)]
• Neurologic Toxicity Including ICANS [see Warnings and Precautions (5.2)]
• Cytopenias [see Warnings and Precautions (5.3)]
• Infections [see Warnings and Precautions (5.4)]
• Hepatotoxicity [see Warnings and Precautions (5.5)]
• Hypersensitivity [see Warnings and Precautions (5.6)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Extensive Stage Small Cell Lung Cancer

The pooled safety population described in the WARNINGS AND PRECAUTIONS and below reflects exposure to intravenous IMDELLTRA, as a single agent, at the recommended dosage of IMDELLTRA 1 mg on Cycle 1 Day 1 followed by 10 mg on Days 8 and 15, and then every 2 weeks until disease progression or intolerable toxicity in 187 patients with extensive stage small cell lung cancer enrolled in Study DeLLphi300 and Study DeLLphi-301. Among 187 patients who received IMDELLTRA, 31% were exposed for 6 months or longer and 14% were exposed for greater than one year.

The most common (>20%) adverse reactions were cytokine release syndrome (55%), fatigue (51%), pyrexia (36%), dysgeusia (36%), decreased appetite (34%), musculoskeletal pain (30%), constipation (30%), anemia (27%) and nausea (22%). The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (57%), decreased sodium (16%), increased uric acid (10%), decreased total neutrophils (6%), decreased hemoglobin (5%), increased activated partial thromboplastin time (5%), decreased potassium (5%), increased aspartate aminotransferase (3.2%), decreased white blood cells (3.8%), decreased platelets (3.2%) and increased alanine aminotransferase (2.1%).

The demographic characteristics of patients who received IMDELLTRA were: median age 66 years (range: 35 to 82); 65% male; 70% White, 26% Asian, 2.1% Black or African American; and 2.1% Hispanic or Latino.

Serious adverse reactions occurred in 58% of patients who received IMDELLTRA. Serious adverse reactions in >3% of patients included cytokine release syndrome (24%), pneumonia (6%), pyrexia (3.7%) and hyponatremia (3.6%). Fatal adverse reactions occurred in 2.7% of patients who received IMDELLTRA including pneumonia 0.5%, aspiration (0.5%), pulmonary embolism (0.5%), respiratory acidosis (0.5%), and respiratory failure (0.5%).

Permanent discontinuation of IMDELLTRA due to an adverse reaction occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of IMDELLTRA in >1% of patients included cytokine release syndrome (1.6%) and tumor lysis syndrome (1.1%).

Dosage interruptions of IMDELLTRA due to an adverse reaction occurred in 27% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included fatigue (3.2%), cytokine release syndrome (2.7%) and respiratory tract infection (2.1%).

Table 13 summarizes adverse reactions observed in Study DeLLphi-300 and Study DeLLphi-301.

Table 13. Adverse Reactions (≥15%) in Patients with ES-SCLC Who Received IMDELLTRA in Study DeLLphi-300 and Study DeLLphi-301:

^a Graded using CTCAE Version 4.0 and Version 5.0.
^b Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019.
^c Includes fatigue and asthenia.
^d Includes myalgia, arthralgia, back pain, pain in extremity, neck pain, musculoskeletal chest pain, non-cardiac chest pain and bone pain.
^e Includes dyspnea and exertional dyspnea.

Table 14 summarizes laboratory abnormalities in Study DeLLphi-300 and Study DeLLphi-301.

Table 14. Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ES – SCLC in Study DeLLphi-300 and Study DeLLphi-301:

^a The denominator used to calculate the rate varied from 41 to 187 based on the number of patients with a baseline value and at least one post-treatment value.
^b All Grade lab abnormalities occurring at a frequency less than 20% included decreased neutrophils.

Risk Summary

Based on its mechanism of action, IMDELLTRA may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of IMDELLTRA in pregnant women to inform a drug-associated risk.

In an animal reproduction study, a murine surrogate molecule administered intravenously to pregnant mice crossed the placental barrier.

Tarlatamab-dlle causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance.

Human immunoglobulin G (IgG) and proteins comprising IgG-derived fragment crystallizable (Fc) domains are known to cross the placental barrier; therefore, IMDELLTRA has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively.

Data

Animal Data

Animal reproduction studies have not been conducted with tarlatamab-dlle. In an embryo-fetal developmental toxicity study, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause maternal toxicity, embryo-fetal toxicity or teratogenicity.

Risk Summary

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

IMDELLTRA may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating IMDELLTRA.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with IMDELLTRA and for 2 months after the last dose.

The safety and effectiveness of IMDELLTRA have not been established in pediatric patients.

Of the 187 patients with SCLC who received IMDELLTRA 10 mg as a single agent, 54% were 65 years of age or older and 12% were 75 years of age or older. No overall differences in IMDELLTRA pharmacokinetics, or safety were observed between older patients (≥65 years of age) and younger patients. Clinical studies of IMDELLTRA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.