SCLC has the highest propensity for brain metastases among all malignancies. Systemic treatment for SCLC, particularly in the setting of brain metastases, is very limited. Tarlatamab, the CD3/delta-like ligand 3 bispecific T-cell engager, has changed the treatment landscape of relapsed SCLC since its Food and Drug Administration approval in May 2024. Patients with treated and stable brain metastases were included in the phase 1 DeLLphi-300 trial and phase 2 DeLLphi-301 trials of tarlatamab. Nevertheless, it remains unknown if tarlatamab is safe and efficacious in the setting of untreated, active or symptomatic brain metastases. Our case series provides, to our knowledge, the first reported evidence of the safety and efficacy of tarlatamab in patients with untreated brain metastases. In our cohort of 10 patients with relapsed SCLC and untreated brain metastases, including those with symptomatic intracranial disease and one with suspected leptomeningeal disease, clinical response or stability was seen in 90% of patients. We present several cases in which rapid, dramatic radiographic responses and clinical improvement were observed in patients with innumerable growing brain metastases (>20 lesions) who would otherwise require whole brain radiation, suggesting that tarlatamab can control intracranial metastases as monotherapy, potentially sparing or deferring the need for brain radiation.