IMDELLTRA (AMG757)

1 INDICATIONS AND USAGE IMDELLTRA is indicated for the treatment of adult patients with extensive stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy. IMDELLTRA is a bispecific delta-like ligand 3 (DLL3)-directed CD3 T- cell engager indicated for the treatment of adult patients with extensive stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum - based chemotherapy. ( 1 )

2 DOSAGE AND ADMINISTRATION Administer as an intravenous infusion over 1 hour. ( 2.2 ) Administer IMDELLTRA according to the step - up dosing schedule in Table 1 to reduce the risk of cytokine release syndrome. ( 2.2 ) Administer concomitant medications as recommended. ( 2.3 ) Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting. Recommend patients to remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from the start of the infusion with IMDELLTRA following Cycle 1 Day 1 and Cycle 1 Day 8 doses, accompanied by a caregiver. ( 2.2 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.2 , 2.6 ) 2.1 Important Dosage and Administration Information Administer IMDELLTRA according to the step-up dose and schedule in Table 1 to reduce the incidence and severity of cytokine release syndrome (CRS) [see Dosage and Administration (2.2) ] . Evaluate complete blood count, liver enzymes and bilirubin prior to administration of all doses of IMDELLTRA up through Cycle 5 Day 15 and then prior to administration of IMDELLTRA on Day 1 of each cycle starting with Cycle 6. More frequent evaluation may be necessary if clinically indicated [see Warnings and Precautions (5.3 , 5.5) ] . Ensure patients are well hydrated prior to administration of IMDELLTRA [see Warnings and Precautions (5.1) ] . For Cycle 1, administer recommended concomitant medications in Table 3 before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions to reduce the risk of CRS reactions [see Dosage and Administration (2.3) ] . IMDELLTRA should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions, such as CRS and neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS) [see Warnings and Precautions (5.1 , 5.2) ] . Due to the risk of CRS and neurologic toxicity, including ICANS, monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting [see Dosage and Administration (2.5) and Warnings and Precautions (5.1 , 5.2) ] . Recommend patients to remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the infusion with IMDELLTRA following Cycle 1 Day 1 and Cycle 1 Day 8 doses, 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. 2.2 Recommended Dosage and Administration Administer IMDELLTRA as an intravenous infusion for one hour. The recommended step-up dose and schedule for IMDELLTRA is provided in Table 1. Administer step-up dose and schedule on Cycle 1 Day 1 to reduce the incidence and severity of CRS. After step-up dose and schedule on Cycle 1 Day 1, administer IMDELLTRA every 2 weeks until disease progression or unacceptable toxicity. Table 1. Recommended Dose and Schedule of IMDELLTRA Dosing Schedule Day Dose of IMDELLTRA Administration Instructions Recommended Monitoring Note: See Table 4 for recommendation on restarting IMDELLTRA after dose delays. Step-up Dose and Schedule Cycle 1 Day 1 Administer recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3. Step-up dose 1 mg Administer IMDELLTRA as a 1-hour intravenous infusion in an appropriate healthcare setting. Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting. Recommend that patients remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the IMDELLTRA infusion accompanied by a caregiver. Day 8 10 mg Day 15 10 mg Observe patients for 6-8 hours post IMDELLTRA infu…

5 WARNINGS AND PRECAUTIONS Cytopenias : Monitor complete blood counts prior to administration of all doses of IMDELLTRA up through Cycle 5 Day 15 and then prior to administration of IMDELLTRA on Day 1 of each cycle starting with Cycle 6. More frequent evaluation may be necessary as clinically indicated. Withhold or permanently discontinue based on severity. ( 5.3 ) Infections : Monitor for signs and symptoms of infection; treat appropriately. Withhold or permanently discontinue based on severity. ( 5.4 ) Hepatotoxicity : Monitor liver enzymes and bilirubin prior to administration of all doses of IMDELLTRA up through Cycle 5 Day 15 and then prior to administration of IMDELLTRA on Day 1 of each cycle starting with Cycle 6. More frequent evaluation may be necessary as clinically indicated. Withhold or permanently discontinue based on severity. ( 5.5 ) Hypersensitivity : Monitor for signs and symptoms of hypersensitivity and treat accordingly. Withhold or permanently discontinue based on severity. ( 5.6 ) Embryo - Fetal Toxicity : May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception ( 5.7 , 8.1 , 8.3 ) 5.1 Cytokine Release Syndrome IMDELLTRA can cause cytokine release syndrome (CRS) including life-threatening or fatal reactions. In the pooled safety population [see Adverse Reactions (6.1) ] , CRS occurred in 57% (268/473) of patients who received IMDELLTRA, including 39% Grade 1, 15% Grade 2, 1.7% Grade 3 and 0.2% Grade 4. Recurrent CRS occurred in 24% of IMDELLTRA-treated patients including 20% Grade 1 and 3.4% Grade 2; one patient experienced recurrent Grade 3. Among the 268 patients who experienced CRS, 73% had CRS after the first dose, 60% had CRS after the second dose, and 15% had CRS following the third or later dose. Following the Cycle 1 Day 1, Day 8, Day 15 infusions, 24%, 8%, and 1% of patients experienced Grade ≥ 2 CRS, respectively. From Cycle 2 onwards, 1.5% of patients experienced Grade ≥ 2 CRS. Of the patients who experienced CRS, 31% received steroids and 10% required tocilizumab. The median time to onset of all grade CRS from most recent dose of IMDELLTRA was 16 hours (range: start of infusion to 15 days). The median time to onset of Grade ≥ 2 CRS from most recent dose of IMDELLTRA was 15 hours (range: start of infusion to 15 days). 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 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions as described in Table 3 to reduce the risk of CRS [see Dosage and Administration (2.3) ] . Administer IMDELLTRA in an appropriate healthcare 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 and caregivers to seek medical attention should signs or symptoms of CRS occur. 5.2 Neurologic Toxicity Including ICANS IMDELLTRA can cause life-threatening or fatal neurologic toxicity including ICANS. In the pooled safety population [see Adverse Reactions (6.1) ] , neurologic toxicity occurred in 65% of patients who received IMDELLTRA, with Grade 3 or higher events in 7% of patients including fatal events in 0.2%. The most frequent neurologic toxicities were dysgeusia (34%), heada…

4 CONTRAINDICATIONS None . None. ( 4 )

8.1 Pregnancy 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.

6 ADVERSE REACTIONS 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) ] The most common adverse reactions (> 20%) were cytokine release syndrome, fatigue, decreased appetite, anemia, dysgeusia, pyrexia, constipation, musculoskeletal pain, and nausea. The most common (≥ 5%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased sodium, decreased total neutrophils, and increased uric acid. To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. The pooled safety population described in the WARNINGS AND PRECAUTIONS 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 473 patients with small cell lung cancer enrolled in three clinical trials: DeLLphi-300, DeLLphi-301 and DeLLphi-304. Among 473 patients who received IMDELLTRA, 40% were exposed for 6 months or longer and 19% were exposed for greater than one year. The most common (≥ 20%) adverse reactions were CRS (57%), fatigue (48%), decreased appetite (38%), dysgeusia (34%), pyrexia (33%), constipation (31%), musculoskeletal pain (31%), and nausea (25%). The most common (≥ 5%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (43%), decreased sodium (12%), decreased total neutrophils (9%), and increased uric acid (6%). Extensive Stage Small Cell Lung Cancer The safety of IMDELLTRA was evaluated in 252 patients in DeLLphi-304, a multicenter, randomized, open label trial in patients with extensive stage small cell lung cancer (ES- SCLC) with disease progression following treatment with platinum-based chemotherapy with or without an anti-PD-(L)1 antibody [see Clinical Studies (14.1) ]. Patients received IMDELLTRA (n=252) or investigator's choice or investigator's choice of topotecan [n=176], lurbinectedin [n=45] or amrubicin [n=23]. Among patients who received IMDELLTRA, 41% were exposed for 6 months or longer and 18% were exposed for greater than one year. The demographic characteristics of patients who received IMDELLTRA were: median age 64 years (range: 20 to 86); 71% male; 60% White, 38 % Asian, 0.8% Black or African American; and 4.8% were of Hispanic or Latino ethnicity. Serious adverse reactions occurred in 52% of patients who received IMDELLTRA. Serious adverse reactions in >3% of patients included CRS (17%), pyrexia (6%), pneumonia (5%) and ICANS (3.6%). Fatal adverse reactions occurred in 8% of patients who received IMDELLTRA, including one fatal adverse reaction of ICANS (0.4%). Fatal adverse reactions occurring in more than one patient included pneumonia (1.6%), cardio-respiratory arrest (1.6%), and sepsis (0.8%). Permanent discontinuation of IMDELLTRA due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of IMDELLTRA in > 1% of patients included pneumonia (1.2%). Dosage interruptions of IMDELLTRA due to an adverse reaction occurred in 38% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included neutropenia (5%), fatigue (4.4%), pneumonia (4%), decreased appetite (2.8%), COVID-19 (2%). Table 13 …