Defining the Objectives of an Analysis of Tarlatamab in Brain Metastases

Small cell lung cancer carries a particularly high risk of central nervous system (CNS) involvement, with up to 80% of patients developing brain metastases at some point during their disease course. Despite this, the pivotal phase 3 trial supporting tarlatamab (Imdelltra), DeLLphi-304 (NCT05740566), excluded patients with active or untreated brain metastases from enrollment. This left clinicians with limited prospective data on how the bispecific T-cell engager performs in the CNS. That gap became increasingly relevant in daily practice following tarlatamab’s approval in 2025, as oncologists began encountering patients with brain metastases who might otherwise be candidates for the drug but fell outside the population directly studied in the trial that led to its approval.¹

In an interview with CancerNetwork® at the 2026 SNO ASCO CNS Metastases Conference in Boston, MA, Laura Alder, MD, assistant professor of medicine at Duke Cancer Center, discussed the design of a retrospective analysis intended to address that uncertainty.² Alder explained that the analysis was built around 3 specific objectives: evaluating how well tarlatamab worked in patients with active, untreated brain metastases that had no history of radiation and were actively progressing; assessing the safety of administering radiation concurrently with tarlatamab, given the known risk of immune effector cell-associated neurotoxicity syndrome (ICANS) and the absence of prior reported data in that setting; and determining the degree of benefit patients derived from continuing tarlatamab after local therapy in cases of isolated CNS progression where the rest of the body remained stable on treatment. Together, these 3 aims were designed to generate data directly relevant to a patient population that had been excluded from the original registrational trial, but that oncologists were already treating in routine practice.

Transcript:

CancerNetwork: What was the rationale for this analysis?

Alder: Three things, really. Three objectives. One, we wanted to see how well tarlatamab worked in active, untreated—no history of radiation—brain metastases that were actively progressing because we thought that was really important. Secondly, we wanted to know the safety of receiving radiation while on tarlatamab because we know there’s a risk of ICANS, which is a type of neurotoxicity, and there really hasn’t been any reported data, again, excluded in the trials, of active radiation while receiving tarlatamab for progressing brain metastases. Similar to that, we wanted to see: what if someone progressed only in the brain, isolated CNS progression, and everything was stable in the body? What was the benefit of continuing tarlatamab after local therapy like SRS [stereotactic radiosurgery]? What was the degree of benefit that the patients received? So those are the 3 aims we sought to answer with this study.

I think the primary takeaway is a couple. One, tarlatamab does seem to have intracranial efficacy, really happily so. Then two, these numbers are small, and we need a prospective validation, but it seems very promising to continue tarlatamab with isolated CNS progression after local therapy, again preferably SRS and not whole brain [radiation] because those patients derive multiple months of additional benefit from continuing that tarlatamab.

References

1. FDA grants traditional approval to tarlatamab-dlle for extensive stage small cell lung cancer. News release. FDA. November 19, 2025. Accessed November 19, 2025. https://tinyurl.com/yc7b96fw
2. Alder L, Hess DL, Green AL, et al. Intracranial efficacy and treatment beyond CNS progression with tarlatamab in small cell lung cancer: a multi-institutional real-world analysis. Presented at the 2026 SNO ASCO CNS Metastases Conference; August 13-15, 2026; Boston, MA.