Navigating DLL3-Targeting T-Cell Engagers and the Evolving Small Cell Lung Cancer Treatment Landscape

In today's episode, we spoke with Alissa Cooper, MD, and Noura Choudhury, MD. Dr Cooper is a physician at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School in Boston, Massachusetts, and Dr Choudhury is an assistant professor of medicine at the University of Chicago in Illinois.

In our exclusive interview, Drs Cooper and Choudhury discussed the evolving role of DLL3-targeting T-cell engagers in small cell lung cancer (SCLC), with a focus on tarlatamab-dlle (Imdelltra) and how emerging trial data may reshape the current treatment paradigm across lines of therapy.

The discussion opened with the ongoing phase 3 DeLLphi-305 trial (NCT06211036), which is evaluating tarlatamab plus a PD-L1 inhibitor as first-line maintenance therapy following chemoimmunotherapy. Dr Choudhury noted that a positive readout from DeLLphi-305 could significantly diminish the future role of lurbinectedin (Zepzelca) in the maintenance setting, but emphasized that any adoption of tarlatamab as a standard maintenance strategy would require a clear and meaningful overall survival benefit, as well as a favorable toxicity profile compared with existing options. Dr Cooper added that a key outstanding question is whether tarlatamab will carry a different toxicity profile in the maintenance setting compared with the induction and maintenance setting, where higher disease burden may increase the risk of cytokine release syndrome (CRS).

The conversation also addressed the investigational agent obrixtamig, another DLL3 x CD3 bispecific T-cell engager in early-phase development, and how clinicians should think about differentiating these agents as the field matures. Both physicians noted that cross-trial comparisons remain premature given differences in study populations and development stage, and expressed that DLL3 testing requirements for investigational agents are unlikely to carry over into a future approved label, consistent with tarlatamab's current FDA indication.

On the question of DLL3 immunohistochemistry testing in routine practice, both physicians acknowledged a shifting perspective. While DLL3 is highly expressed in approximately 85% to 90% of SCLC tumors, real-world access to testing varies significantly, and logistical delays may outweigh the benefit of waiting for results before initiating treatment in a disease that can progress rapidly. Dr Choudhury noted that her viewpoint has evolved as emerging data suggest that certain molecular subtypes may derive little benefit from tarlatamab, making more informed patient selection increasingly important. Both agreed that an ideal solution would involve a rapid, commercially integrated assay, but cautioned that liquid biopsy approaches remain hypothesis-generating at this stage.

Finally, Drs Cooper and Choudhury reflected on the growing body of real-world experience with tarlatamab since its FDA approval, highlighting ongoing efforts to better characterize who is at highest risk for serious toxicities such as high-grade CRS and immune effector cell–associated neurotoxicity syndrome. Dr Choudhury described a future vision of a risk stratification calculator that could guide decisions about which patients still warrant monitored inpatient administration even if the label is updated to allow outpatient use.