The DLL3-targeted bispecific T-cell engager agent tarlatamab demonstrated significant overall survival in combination with anti‒PD-L1 therapy of either atezolizumab or durvalumab as first-line maintenance therapy for patients with extensive-stage small cell lung cancer (ES-SCLC), according to findings from the phase Ib DeLLphi-303 trial presented at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC; Abstract OA13.01).
“The combination of tarlatamab with anti‒PD-L1 therapy as first-line maintenance demonstrates a manageable safety profile and unprecedented overall survival in this patient population,” said lead investigator Kelly G. Paulson, MD, PhD, Medical Director of Melanoma Program, Providence-Swedish Cancer Institute, and Lead, Center for Immuno-Oncology, Paul G. Allen Research Center, Seattle, Washington. “These results support further evaluation of this combination in the active phase III DeLLphi-305 trial (NCT06211036) as a promising therapeutic strategy in first-line ES-SCLC.”
Rationale and Study Methods
Tarlatamab is a bispecific T-cell engager immunotherapy agent designed to target cancer cells expressing DLL3. Previous studies of tarlatamab have shown that the agent led to improved survival over chemotherapy in the second-line setting for patients with SCLC.
Eighty-eight patients with ES-SCLC who had completed 4 to 6 cycles of first-line platinum-etoposide chemotherapy and anti‒PD-L1 therapy without disease progression were enrolled in the DeLLphi-303 study. They were started on maintenance treatment within 8 weeks of the start of their last chemoimmunotherapy cycle with either intravenous atezolizumab at 1,680 mg every 4 weeks or intravenous durvalumab at 1,500 mg every 4 weeks plus intravenous tarlatamab at 10 mg every 2 weeks until disease progression.
Key Study Findings
At a median follow-up of 18.4 months, the median overall survival was 25.3 months (95% confidence interval [CI] = 20.3 to not reached) and the median progression-free survival was 5.6 months (95% CI = 3.5‒9.0). At 12 months, the overall survival rate was 34% and the overall survival rate was 82%. Both progression-free and overall survival were similar whether patients received atezolizumab or durvalumab.
The safety profile for the combination was considered acceptable. Cytokine-release syndrome was the most common tarlatamab-related adverse event reported, which occurred in 56% of patients, predominantly at grade 1, followed by dysgeusia in 45% and fatigue in 31%. Immune effector cell–associated neurotoxicity syndrome occurred in only 6% of patients. Treatment-emergent and treatment-related adverse events decreased over time.
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