Dr Leal on the Development of DLL3-Targeted Agents in SCLC

Ticiana Leal, MD, associate professor, director, Thoracic Medical Oncology Program, Department of Hematology and Medical Oncology, Emory University School of Medicine, sheds light on the DLL3-targeted agents in development for patients with small cell lung cancer (SCLC) and neuroendocrine tumors.

DLL3 is highly expressed in SCLC, as well as in large-cell and extrapulmonary neuroendocrine carcinomas (NEC), Leal says. The antibody-drug conjugate rovalpituzumab tesirine (Rova-T) was previously in development for patients with DLL3-high SCLC. The agent demonstrated efficacy in this population in the phase 3 TAHOE trial (NCT03061812), Leal notes. However, findings from the phase 3 MERU trial (NCT03033511) of Rova-T in SCLC led to the discontinuation of this drug’s research and development program in 2019, Leal explains.

In a presentation at the 2024 Winter Lung Cancer Conference, Leal discussed 3 DLL3-directed agents under investigation in patients with SCLC. Of the 3 agents, the T-cell engager tarlatamab is the furthest in development, and findings from the phase 1 DeLLphi-300 (NCT03319940) and phase 2 DeLLphi-301 (NCT05060016) trials indicate promising overall response rate (ORR) and overall survival data with the agent in patients with heavily pretreated disease, Leal emphasizes.

Leal also spotlighted the trispecific T-cell–activating construct HPN328 and early data with BI 765432, a bispecific monoclonal antibody. A phase 1 trial (NCT0442908) of BI 765432 enrolled patients with SCLC (n = 57) and DLL3-positive large-cell (n = 9) and extrapulmonary (n = 41) NEC, according to Leal. BI 765432 elicited an ORR of 25% in the overall study population. Among the patients with large-cell NEC, 3 achieved a partial response with BI 765432. The agent was also found to have an acceptable safety profile in this population, Leal notes.

Cytokine release syndrome (CRS) is a common toxicity with tarlatamab, HPN328, and BI 765432; however, most instances of CRS with these agents have been grade 1 or 2 and can be managed with supportive care and tocilizumab (Actemra), when necessary, Leal concludes.