How should grade 2 cytokine‑release syndrome be managed in an adult with extensive‑stage small‑cell lung cancer receiving Imdelltra (tarlatamab‑dlle)?

Management of Grade 2 Cytokine Release Syndrome with Imdelltra (Tarlatamab)

For grade 2 CRS during tarlatamab treatment, interrupt the infusion immediately, provide aggressive supportive care with antipyretics and IV hydration, and administer tocilizumab 8 mg/kg (maximum 800 mg) intravenously; if symptoms persist or worsen, add dexamethasone 10 mg IV every 6 hours. 1, 2

Immediate Management Steps

Stop the Infusion

• Interrupt tarlatamab infusion immediately when grade 2 CRS is identified (fever ≥38°C with hypotension requiring vasopressors and/or hypoxia requiring high-flow oxygen >6 L/min, facemask, or non-rebreather). 1, 2

Supportive Care Measures

• Administer acetaminophen 650-1000 mg orally as an antipyretic. 2
• Provide aggressive IV hydration to maintain hemodynamic stability. 2
• Obtain blood cultures and initiate broad-spectrum antibiotics to rule out infection, as fever is present in 97% of CRS cases. 1
• Monitor vital signs continuously and alert the intensive care unit for potential transfer. 1

Pharmacologic Intervention

Tocilizumab Administration

• Administer tocilizumab 8 mg/kg IV (maximum 800 mg) as first-line immunomodulatory therapy for grade 2 CRS. 1, 3, 2
• For patients <30 kg, use tocilizumab 12 mg/kg. 1, 3
• Tocilizumab can be repeated once (maximum 1 additional dose) if symptoms persist after 3 days without improvement, provided there is no concurrent immune effector cell-associated neurotoxicity syndrome (ICANS). 1

Corticosteroid Therapy

• If symptoms deteriorate or persist despite tocilizumab, add dexamethasone 10 mg IV every 6 hours for 1-3 days. 1, 2
• Corticosteroids can be administered concurrently with the second dose of tocilizumab if needed in grade 2 CRS. 1
• Evidence suggests corticosteroids do not significantly impact tarlatamab efficacy, though prolonged courses may be associated with shorter progression-free survival. 1

Resuming Treatment

Criteria for Restarting Tarlatamab

• Once the patient stabilizes and CRS resolves to grade 1 or less, resume tarlatamab infusion at half the original rate and titrate to tolerance. 1
• Monitor closely during infusion restart for recurrence of symptoms. 1

Subsequent Dose Considerations

• Continue with the standard 10 mg every 2 weeks dosing schedule after resolution, as subsequent doses exhibit a more favorable safety profile with lower CRS rates. 4, 5
• The median onset of CRS is 13 hours after infusion, with a median duration of 4 days, and nearly all CRS events occur during cycle 1. 1, 4

Critical Monitoring Parameters

High-Risk Features Requiring Enhanced Vigilance

• Patients with baseline oxygen dependence, ECOG performance status ≥2, untreated CNS metastases, or bulky disease have higher rates of grade 2-3 CRS (up to 66.6% with CNS involvement). 5
• High fever (≥38.9°C) and hemodynamic instability within 36 hours of tarlatamab infusion predict severe CRS with high sensitivity. 1

Concurrent ICANS Assessment

• Evaluate for concurrent ICANS (occurs in 8-10% of patients), which presents with tremor, confusion, dysphasia, or deteriorating handwriting. 1, 5
• If grade 2 or higher ICANS develops concurrently, do not repeat tocilizumab and prioritize corticosteroid therapy, as tocilizumab does not cross the blood-brain barrier effectively. 1

Common Pitfalls to Avoid

• Do not delay tocilizumab administration while waiting for infection workup results, as early intervention improves outcomes. 2
• Avoid resuming infusion at full rate after CRS resolution; always restart at half-rate and titrate up. 1
• Do not confuse CRS with infection-related fever; CRS typically occurs within 13 hours of infusion and includes hypotension/hypoxia, whereas infection has a different temporal pattern. 1
• Do not use prophylactic tocilizumab or corticosteroids before tarlatamab infusion, as this has not been validated and may interfere with efficacy. 2

Inpatient Monitoring Requirements

• 24-hour inpatient observation is mandatory after the first two doses of cycle 1 (days 1 and 8) due to the 51% incidence of CRS, with 20% being grade 2. 1, 4
• After cycle 1, outpatient administration with reduced observation time is appropriate given the substantially lower CRS rates in subsequent cycles. 5, 2