Tarlatamab is a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 (DLL3) and the cluster of differentiation 3 (CD3) molecule. In the phase 2 DeLLphi-301 trial of tarlatamab for patients with previously treated small cell lung cancer, tarlatamab 10 mg every 2 weeks achieved durable responses and encouraging survival outcomes. Analyses of updated safety data from the DeLLphi-301 trial demonstrated that the most common treatment-emergent adverse events were cytokine release syndrome (53%), pyrexia (38%), decreased appetite (36%), dysgeusia (32%), and an emia (30%). Cytokine release syndrome was mostly grade 1 or 2 in severity, occurred primarily after the first or second tarlatamab dose, and was managed with supportive care, which included the administration of antipyretics (e.g., acetaminophen), intravenous hydration, and/or glucocorticoids. Other treatment-emergent adverse effects of interest included neutropenia (16%) and immune effector cell-associated neurotoxicity syndrome and associated neurologic events (10%). Given that tarlatamab is the first T-cell engager approved for the treatment of small cell lung cancer, raising awareness with regard to the monitoring and management of tarlatamab-associated adverse events is essential. Here, the authors describe the timing, occurrence, and duration of these adverse events and review the management and risk-mitigation strategies used by clinical investigators during the DeLLphi-301 trial.