IMDELLTRA (AMG757)

Tarlatamab-dlle is a bispecific DLL3-directed CD3 T-cell engager that binds to DLL3 expressed on the surface of cells, including tumor cells, and CD3 expressed on the surface of T cells. Tarlatamab-dlle is produced using recombinant DNA technology in Chinese hamster ovary cells. It consists of 982 amino acids and has a molecular weight of approximately 105 kilodaltons. IMDELLTRA (tarlatamab-dlle) for injection is supplied as a sterile, preservative-free, white to slightly yellow, lyophilized powder in a single-dose vial for reconstitution and further dilution. Each 1 mg vial contains tarlatamab-dlle (1 mg), glutamic acid (0.72 mg), polysorbate 80 (0.04 mg), sucrose (37.1 mg), and sodium hydroxide to adjust pH to 4.2. After reconstitution with 1.3 mL of Sterile Water for Injection the resulting concentration is 0.9 mg/mL IMDELLTRA. Each 10 mg vial contains tarlatamab-dlle (10 mg), glutamic acid (3.7 mg), polysorbate 80 (0.2 mg), sucrose (194.4 mg), and sodium hydroxide to adjust pH to 4.2. After reconstitution with 4.4 mL of Sterile Water for Injection the resulting concentration is 2.4 mg/mL IMDELLTRA. IV Solution Stabilizer is supplied as a sterile, preservative-free, colorless to slightly yellow, clear solution. Each vial of IV Solution Stabilizer contains citric acid monohydrate (36.75 mg), lysine hydrochloride (1598.8 mg), polysorbate 80 (7 mg), sodium hydroxide to adjust pH to 7.0, and water for injection.

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 )

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 infusion Extended monitoring in a healthcare setting is not required unless the patient experiences Grade ≥ 2 CRS, ICANS or neurological toxicity during prior treatments. See Tables 5 and 6 for monitoring recommendations. Cycle 2 Day 1 and 15 10 mg Observe patients for 6-8 hours post IMDELLTRA infusion . Cycles 3 and 4 Day 1 and 15 10 mg Observe patients for 3-4 hours post IMDELLTRA infusion . Cycle 5 and subsequent infusions Day 1 and 15 10 mg Observe patients for 2 hours post IMDELLTRA infusion . Administration The intravenous (IV) catheter for concomitant medications administration can be used to administer the IMDELLTRA infusion. To ensure patency, flush the IV catheter over 3 to 5 minutes using 0.9% Sodium Chloride for Injection. Administer the reconstituted and diluted IMDELLTRA as a 1-hour intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm. Flush the IV-line upon completion of the IMDELLTRA infusion. Table 2 provides the infusion duration and rate. Table 2. IMDELLTRA Infusion Duration and Rate Infusion Duration for 250 mL IV Preparation Infusion Rate 1 hour 250 mL/hour 2.3 Recommended Concomitant Medications for IMDELLTRA Administration for Cycle 1 Day 1 and Cycle 1 Day 8 Administer recommended concomitant medications for IMDELLTRA during Cycle 1 Day 1 and Cycle 1 Day 8 as presented in Table 3 to reduce the risk of CRS [see Warnings and Precautions (5.1) ] . Table 3. Recommended Concomitant Medications for IMDELLTRA Administration for Cycle 1 Day 1 and Cycle 1 Day 8 Treatment Day Medication Administration Cycle 1 Day 1 and Cycle 1 Day 8 Administer dexamethasone 8 mg intravenously (or equivalent) Within 1 hour prior to IMDELLTRA administration Administer 1 liter of normal saline intravenously over 2 to 4 hours Immediately after completion of IMDELLTRA infusion 2.4 Restarting IMDELLTRA After Dosage Delay If a dose of IMDELLTRA is delayed, restart based on the recommendation as listed in Table 4 and resume the dose and schedule accordingly [see Dosage and Administration (2.2) ] . Administer recommended concomitant medications as indicated in Table 3. Table 4. Recommendations for Restarting IMDELLTRA After Dosage Delay Last Dose Administered Time Since the Last Dose Administered Action Administer recommended concomitant medications before and after Cycle 1 Day 1 and Cycle 1 Day 8 IMDELLTRA infusions and monitor patients accordingly [see Dosage and Administration (2.1 , 2.2 and 2.3) ] . 1 mg on Cycle 1 Day 1 2 weeks or less (≤ 14 days) Administer IMDELLTRA 10 mg, then resume with the planned dose and schedule. Greater than 2 weeks (> 14 days) Administer IMDELLTRA step-up dose 1 mg. If tolerated, increase to 10 mg 1 week later. Then resume with the planned dose and schedule. 10 mg on Cycle 1 Day 8 3 weeks or less (≤ 21 days) Administer IMDELLTRA 10 mg, then resume with the planned dose and schedule. Greater than 3 weeks (> 21 days) Administer IMDELLTRA step-up dose 1 mg. If tolerated, increase to 10 mg 1 week later. Then resume with the planned dose and schedule. 10 mg on Cycle 1 Day 15 and subsequent Cycles every 2 weeks thereafter 4 weeks or less (≤ 28 days) Administer IMDELLTRA 10 mg, then resume with the planned dose and schedule. Greater than 4 weeks (> 28 days) Administer IMDELLTRA step-up dose 1 mg. If tolerated, increase to 10 mg 1 week later. Then resume with the planned dose and schedule. 2.5 IMDELLTRA Dosage Modifications and Adverse Reaction Management No dose reduction for IMDELLTRA is recommended. See Table 5 and Table 6 for recommended management of CRS, neurologic toxicity including ICANS respectively and Table 7 for cytopenias, infections and other adverse reactions. Cytokine Release Syndrome (CRS) Diagnose CRS based on clinical presentation [see Warnings and Precautions (5.1) ] . Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 5. Monitor patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygen) with continuous cardiac telemetry and pulse oximetry. For severe or life-threatening CRS, recommend administering tocilizumab or equivalent therapy and intensive monitoring (e.g., ICU) for supportive therapy. Perform laboratory testing to monitor for disseminated intravascular coagulation (DIC), hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function. Table 5 provides the guidelines for grading and dosage modification and management of cytokine release syndrome. Table 5. Guidelines for Grading and Dosage Modification and Management of Cytokine Release Syndrome CRS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (2019). CRS Grade Defining Symptoms IMDELLTRA Dosage Modification Management Grade 1 Symptoms require symptomatic treatment only (e.g., fever ≥ 100.4°F without hypotension or hypoxia). Withhold IMDELLTRA until event resolves, then resume IMDELLTRA at the next scheduled dose See Table 4 for recommendations on restarting IMDELLTRA after dose delays [see Dosage and Administration (2.4) ] . . Administer symptomatic treatment (e.g., acetaminophen) for fever. Consider dexamethasone 4 mg to 10 mg oral or IV (or equivalent) Taper steroids per standard of care guidelines. . Grade 2 Symptoms require and respond to moderate intervention. Fever ≥ 100.4°F, Hypotension responsive to fluids not requiring vasopressors and/or Hypoxia requiring low flow nasal cannula or blow-by. Withhold IMDELLTRA until event resolves, then resume IMDELLTRA at the next scheduled dose . Recommend hospitalization for a minimum of 24 hours with cardiac telemetry and pulse oximetry. Administer symptomatic treatment (e.g., acetaminophen) for fever. Administer supplemental oxygen and intravenous fluids when indicated. Consider dexamethasone (or equivalent) 8 mg oral or IV. Consider tocilizumab (or equivalent). When resuming the next planned dose, monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours in an appropriate healthcare setting . Grade 3 Severe symptoms defined as temperature ≥ 100.4°F with: Hemodynamic instability requiring a vasopressor (with or without vasopressin) and/or Worsening hypoxia or respiratory distress requiring high flow nasal cannula (> 6 L/min oxygen) or face mask. Withhold IMDELLTRA until the event resolves, then resume IMDELLTRA at the next scheduled dose . For recurrent Grade 3 events, permanently discontinue IMDELLTRA. In addition to Grade 2 treatment: Recommend intensive monitoring, e.g., ICU care. Administer dexamethasone c (or equivalent) 8 mg IV every 8 hours up to 3 doses. Vasopressor support as needed. High flow oxygen support as needed. Recommend tocilizumab (or equivalent). Prior to the next dose, administer concomitant medications as recommended for Cycle 1 Day 1 and Cycle 1 Day 8 (see Table 3 ). When resuming the next planned dose, monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours in an appropriate healthcare setting . Grade 4 Life-threatening symptoms defined as temperature ≥ 100.4°F with: Hemodynamic instability requiring multiple vasopressors (excluding vasopressin). and/or Worsening hypoxia or respiratory distress despite oxygen administration requiring positive pressure. Permanently discontinue IMDELLTRA. ICU care. Per Grade 3 treatment. Recommend tocilizumab (or equivalent) Neurologic Toxicity including ICANS At the first sign of neurologic toxicity, including ICANS, withhold IMDELLTRA and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for severe or life-threatening neurologic toxicities, including ICANS [see Warnings and Precautions (5.2) ] . Manage ICANS and neurologic toxicity according to the recommendations in Table 6 and consider further management per current practice guidelines. Table 6. Guidelines for Management of Neurologic Toxicity including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) ICANS based on American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (2019) ICANS Grade Defining Symptoms IMDELLTRA Dosage Modifications Management Grade 1 ICE score 7-9 If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (names 3 objects, e.g., point to clock, pen, button = 3 points); Following commands (e.g., "show me 2 fingers" or "close your eyes and stick out your tongue" = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points with no depressed level of consciousness. Withhold IMDELLTRA until ICANS resolves, then resume IMDELLTRA at the next scheduled dose See Table 4 for recommendations on restarting IMDELLTRA after dose delays [see Dosage and Administration (2.4) ] . Supportive care. Grade 2 ICE score 3-6 and/or mild somnolence awaking to voice. Withhold IMDELLTRA until ICANS resolves, then resume IMDELLTRA at the next scheduled dose . Supportive care. Dexamethasone Taper steroids per standard of care guidelines (or equivalent) 8 to 10 mg oral or IV. Can repeat every 12 hours or methylprednisolone (or equivalent) 1 mg/kg IV every 12 hours if symptoms worsen. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours following the next dose of IMDELLTRA. Grade 3 ICE score 0-2 and/or depressed level of consciousness awakening only to tactile stimulus and/or any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention and/or Focal or local edema on neuroimaging. Withhold IMDELLTRA until the ICANS resolves, then resume IMDELLTRA at the next scheduled dose . If there is no improvement to Grade ≤ 1 within 7 days permanently discontinue IMDELLTRA. For recurrent Grade 3 events, permanently discontinue IMDELLTRA. Recommend intensive monitoring, e.g., ICU care. Consider mechanical ventilation for airway protection. Dexamethasone (or equivalent) 10 mg IV every 6 hours or methylprednisolone (or equivalent) 1 mg/kg IV every 12 hours. Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent Grade ≥ 3 neurotoxicity. Monitor patients from the start of the IMDELLTRA infusion for 22 to 24 hours following the next dose of IMDELLTRA. Grade 4 ICE score 0 (patient is unarousable and unable to perform ICE) and/or Stupor or coma and/or Life-threatening prolonged seizure (> 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between and/or diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing or papilledema, cranial nerve VI palsy, or Cushing's triad. Permanently discontinue IMDELLTRA. ICU care. Consider mechanical ventilation for airway protection. High dose corticosteroids (e.g., methylprednisolone 1000 mg/day in divided doses IV for 3 days). Consider repeat neuroimaging (CT or MRI) every 2-3 days if patient has persistent Grade ≥ 3 neurotoxicity. Treat convulsive status epilepticus per institutional guidelines. Table 7. Recommended Treatment Interruptions of IMDELLTRA for the Management of Cytopenias, Infections, and Other Adverse Reactions Adverse Reactions Severity Severity based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Dosage Modification Refer to Table 4 for dose restarting guidance. Cytopenias [see Warnings and Precautions (5.3) ] Grade 3 Neutropenia Withhold IMDELLTRA until recovery to Grade ≤ 2. Consider administration of granulocyte colony stimulating factor (G-CSF). Permanently discontinue if recovery to Grade ≤ 2 does not occur within 3 weeks. Grade 4 Neutropenia Withhold IMDELLTRA until recovery to Grade ≤ 2. Consider administration of granulocyte colony stimulating factor (G-CSF). Permanently discontinue if recovery to Grade ≤ 2 does not occur within 1 week. Recurrent Grade 4 Neutropenia Permanently discontinue IMDELLTRA Febrile neutropenia Withhold IMDELLTRA until neutropenia recovers to Grade ≤ 2 and fever resolves. Hemoglobin <8 g/dL Withhold IMDELLTRA until hemoglobin is ≥8 g/dL. Grade 3 or Grade 4 Decreased platelet count Withhold IMDELLTRA until platelet count is Grade ≤ 2 and no evidence of bleeding. Permanently discontinue if recovery to Grade ≤ 2 does not occur within 3 weeks. Recurrent Grade 4 Decreased platelet count Permanently discontinue IMDELLTRA. Infections [see Warnings and Precautions (5.4) ] All Grades Withhold IMDELLTRA in the step-up phase in patients until infection resolves. Grade 3 Withhold IMDELLTRA during the treatment phase until infection improves to Grade ≤ 1 . Grade 4 Permanently discontinue IMDELLTRA. Hepatotoxicity [see Warnings and Precautions (5.5) ] Grade 3 Increased ALT or AST or bilirubin Withhold IMDELLTRA until improved to Grade ≤ 1. Grade 4 Increased ALT or AST or bilirubin Permanently discontinue IMDELLTRA. AST or ALT > 3 × ULN with total bilirubin > 2 × ULN in the absence of alternative causes Permanently discontinue IMDELLTRA. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 or 4 Withhold IMDELLTRA until recovery to Grade ≤ 1 or baseline. Consider permanently discontinuing if adverse reaction does not resolve within 28 days. Consider permanent discontinuation for Grade 4 events. 2.6 Preparation Material Compatibility Information IV bags composed of ethyl vinyl acetate (EVA), polyolefin, and polyvinyl chloride (PVC) have been shown to be compatible with IMDELLTRA at the specified administration conditions. IV line and catheter materials composed of polyolefin, PVC, and polyurethane have been shown to be compatible with IMDELLTRA at the specified administration conditions. The use of Closed System Transfer Device (CSTD) is not recommended due to potential wrong dose medication error risk. Amgen has not performed compatibility testing of vial adaptor CSTDs with IMDELLTRA. Step 1: Reconstitute IMDELLTRA with Sterile Water for Injection Table 8 provides the required amount of sterile water for injection required to reconstitute IMDELLTRA 1 mg and 10 mg vials. Do not use IV Solution Stabilizer (IVSS) to reconstitute IMDELLTRA . The IV Solution Stabilizer (IVSS) is used to coat the intravenous bag prior to addition of reconstituted IMDELLTRA to prevent adsorption of IMDELLTRA to IV bags and IV tubing. Table 8. Required Amount of Sterile Water for Injection to Reconstitute IMDELLTRA Each vial contains overfill to allow for withdrawal of 1.1 mL (1 mg vial) or 4.2 mL (10 mg vial) after reconstitution to ensure delivery at the stated concentration of labeled vial strength. IMDELLTRA Vial Strength Amount of Sterile Water for Injection Needed to Reconstitute IMDELLTRA Resulting Concentration 1 mg 1.3 mL 0.9 mg/mL 10 mg 4.4 mL 2.4 mg/mL Using a needle and syringe filled with the required amount of sterile water, inject the sterile water against the glass vial. Avoid injecting the water directly onto the powder to prevent foaming. Gently swirl the contents to mix. Do not shake. Inspect parenteral drug products for particulate matter and discoloration prior to administration. Inspect that the solution is clear to opalescent, colorless to slightly yellow. Do not use if the solution is cloudy or has particulates. Further dilute reconstituted IMDELLTRA. The reconstituted IMDELLTRA must be further diluted within 4 hours of reconstitution or discarded. Prepare the infusion bag: Steps 2 to 5 Step 2 : Withdraw 0.9% Sodium Chloride for Injection Using a 250 mL prefilled bag of 0.9% Sodium Chloride for Injection, withdraw the amount of sodium chloride specified in Table 9 and discard. Table 9. Required Amount of 0.9% Sodium Chloride to Withdraw from 250 mL IV Bag IMDELLTRA Vial Strength IMDELLTRA Dose Volume of 0.9% Sodium Chloride to Withdraw From 250 mL IV Bag 1 mg 1 mg 14 mL 10 mg 10 mg 17 mL Step 3: Add IV Solution Stabilizer to the infusion bag Inject 13 mL of IV Solution Stabilizer (IVSS) into the 250 mL 0.9% Sodium Chloride infusion bag , see Table 10 . Gently mix the contents of the infusion bag to avoid foaming. Do not shake. Table 10. Required Amount of IV Solution Stabilizer (IVSS) to Add to IV Bag IMDELLTRA Vial Strength IMDELLTRA Dose Volume of IV Solution Stabilizer (IVSS) to Add to IV Bag 1 mg 1 mg 13 mL 10 mg 10 mg 13 mL Step 4: Dilute the reconstituted IMDELLTRA into the infusion bag Transfer the required volume of reconstituted IMDELLTRA listed in Table 11 to the infusion bag (containing IV Solution Stabilizer) . NOTE: The final concentrations for the different strength vials are NOT the same following reconstitution and further dilution. Table 11. Required Amount of Reconstituted IMDELLTRA to Add to 250 mL IV Bag IMDELLTRA Vial Strength IMDELLTRA Dose Volume of Reconstituted IMDELLTRA to Add to 250 mL IV Bag 1 mg 1 mg 1.1 mL 10 mg 10 mg 4.2 mL Gently mix the contents of the bag. Do not shake. Step 5: Remove air from IV bag Remove air from the prepared IV bag using an empty syringe to avoid foaming. Step 6: Prime IV tubing Prime intravenous tubing with either 0.9% Sodium Chloride for Injection or with the final prepared product. See Table 12 for maximum storage time of prepared IMDELLTRA infusion. Prepared IMDELLTRA Infusion Bag Storage Requirements Administer reconstituted and diluted IMDELLTRA immediately. Table 12 displays the maximum storage time for the prepared IMDELLTRA infusion bag. Maximum storage time includes total duration from the time of reconstitution of the vial of IMDELLTRA to the end of the infusion. Table 12. Maximum Storage Time for Prepared IMDELLTRA Infusion Bag Room Temperature 20°C to 25°C (68°F to 77°F) Refrigerated 2°C to 8°C (36°F to 46°F) Prepared IMDELLTRA Infusion Bag 8 hours 7 days Discard the prepared IMDELLTRA infusion bag after maximum storage time (from time of reconstitution). If refrigerated, allow the prepared IMDELLTRA infusion bag to come room temperature prior to administration, and complete the infusion within 8 hours (including preparation and infusion time). Do not re-refrigerate prepared infusion bag.

None . None. ( 4 )

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 summarizes adverse reactions observed in DeLLphi-304. Table 13. Adverse Reactions (≥ 15%) in Patients with SCLC Who Received IMDELLTRA in DeLLphi-304 Adverse Reaction IMDELLTRA Graded using CTCAE Version 4.0 and Version 5.0. (N = 252) Standard of Care (N = 244) Any Grade (%) Grade 3 or 4 (%) Any Grade (%) Grade 3 or 4 (%) Immune system disorders Cytokine release syndrome Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019. 56 1.2 1.2 0 General disorders and administration site conditions Fatigue Includes fatigue and asthenia 39 6 43 10 Pyrexia Includes body temperature increased, hyperthermia, pyrexia 29 1.2 11 1.2 Metabolism and nutrition disorders Decreased appetite 37 2 23 1.6 Gastrointestinal disorders Constipation 30 0.4 22 0 Nausea 25 0.4 32 0 Nervous system disorders Dysgeusia Includes ageusia, dysgeusia, hypogeusia 28 0 2.5 0 Headache Includes headache and tension headache 16 0 9 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, back pain, bone pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain 27 1.6 21 2.5 Respiratory, thoracic and mediastinal disorders Cough Includes cough and productive cough 17 0 17 0 Clinically relevant adverse reactions occurring in < 15% of patients who received IMDELLTRA were immune effector cell-associated neurotoxicity syndrome, neurotoxicity, tremor, seizure, ataxia, confusional state, delirium, dyspnea, encephalopathy and weight decreased. Table 14 summarizes laboratory abnormalities in DeLLphi-304. Table 14. Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with SCLC in DeLLphi-304 Laboratory Abnormality IMDELLTRA The denominator used to calculate the rate varied for IMDELLTRA (Range: 229 to 250) and SOC (Range: 205 to 226) based on the number of patients with a baseline value and at least one post-treatment value. N=252 Standard of care N=244 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Lymphocytes decreased 65 27 62 27 Hemoglobin decreased 51 4.5 86 29 White blood cells decreased 50 7 70 29 Platelets decreased 25 0.4 55 20 Neutrophils decreased All Grade lab abnormalities occurring at a frequency less than 20% included decreased neutrophils. 15 10 44 36 Chemistry Sodium decreased 57 8 38 7 Potassium decreased 41 4.8 34 4 Aspartate amino transferase increased 40 2.8 29 0.4 Sodium increased 35 0.4 27 0 Alanine aminotransferase increased 32 2 25 0.9 Activated Partial Thromboplastin Time (sec) increased 26 1.3 16 0.9 Creatinine increased 23 0.8 19 0.4 Alkaline phosphate increased 22 0.4 26 1.4 Magnesium decreased 21 0.8 15 1.8 Potassium increased 21 0.8 12 1.8 Creatine Phosphokinase increased 21 1.7 11 0 DeLLphi-300 and DeLLphi-301 The safety of IMDELLTRA, as a single agent, at the recommended dosage was evaluated in patients with extensive stage small cell lung cancer enrolled in DeLLphi-300 and DeLLphi-301 [see Clinical Studies (14.1) ]. Among 187 patients who received IMDELLTRA, 31% were exposed for 6 months or longer and 14% were exposed for greater than one year. 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 15 summarizes adverse reactions observed in DeLLphi-300 and DeLLphi-301. Table 15. Adverse Reactions (≥ 15%) in Patients with ES-SCLC Who Received IMDELLTRA in DeLLphi-300 and DeLLphi-301 Adverse Reaction IMDELLTRA Graded using CTCAE Version 4.0 and Version 5.0. (N = 187) Any Grade (%) Grade 3 or 4 (%) Immune system disorders Cytokine release syndrome Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019. 55 1.6 General disorders and administration site conditions Fatigue Includes fatigue and asthenia. 51 10 Pyrexia 36 0 Nervous system disorders Dysgeusia 36 0 Metabolism and nutrition disorders Decreased appetite 34 2.7 Nausea 22 1.6 Gastrointestinal disorders Constipation 30 0.5 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes myalgia, arthralgia, back pain, pain in extremity, neck pain, musculoskeletal chest pain, non- cardiac chest pain and bone pain. 30 1.1 Respiratory, thoracic and mediastinal disorders Dyspnea Includes dyspnea and exertional dyspnea. 17 2.1 Cough 17 0 Table 16 summarizes laboratory abnormalities in DeLLphi-300 and DeLLphi-301 IMDELLTRA 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. All Grades (%) Grade 3 or 4 (%) Laboratory Abnormality Hematology Lymphocytes decreased 84 57 Hemoglobin decreased 58 5 White blood cells decreased 44 3.8 Platelets decreased 33 3.2 Neutrophils decreased All Grade lab abnormalities occurring at a frequency less than 20% included decreased neutrophils . 12 6 Chemistry Sodium decreased 68 16 Potassium decreased 50 5 Aspartate amino transferase increased 44 3.2 Alanine aminotransferase increased 42 2.1 Magnesium decreased 33 1.6 Creatinine increased 29 0.5 Sodium increased 26 0 Alkaline phosphate increased 22 0

16.2 Storage and Handling Store IMDELLTRA and IV Solution Stabilizer (IVSS) vials refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. Do not freeze. IMDELLTRA and IV Solution Stabilizer (IVSS) vials may be kept at room temperature between 20°C to 25°C (68°F to 77°F) for up to 24 hours in the original carton to protect from light.