In patients with extensive-stage small cell lung cancer (SCLC), tarlatamab-dlle, a bispecific T-cell engager, plus durvalumab as first-line maintenance therapy extended median overall survival by more than 8 months, more than tripled progression-free survival, and reduced the risk of death by 58% compared to durvalumab alone, according to results of the phase III open-label, multicenter, randomized DeLLphi-305 study. Overall survival benefits were consistent across subgroups, including patients with brain and liver metastases.
These results were presented by Jacob Sands, MD, Associate Chief of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2026 (Abstract LBA3). The landmark interim phase III results were simultaneously published in The New England Journal of Medicine.
"This trial is positive in every way. We have seen substantial improvement in median progression-free survival, substantial improvement in median overall survival, and we're improving the time of disease control substantially for a broader group of patients than what we've seen from any prior study and any prior treatment," said Dr. Sands. "This immunotherapy combination sets a new standard of care with tarlatamab plus durvalumab in the maintenance setting after induction chemotherapy plus durvalumab."
The DeLLphi-305 is the first phase III study including a bispecific T-cell engager therapy to demonstrate an overall survival benefit in the first-line maintenance setting for extensive-stage SCLC. Tarlatamab is already approved by the U.S. Food and Drug Administration as a later line of therapy, and this study shows it may be even more effective in the first-line maintenance setting.
Tarlatamab is designed to bind to CD3 proteins on immune cells called T cells and to DLL3 proteins on small cell lung cancer cells. The drug is designed to pull the cell types closer together and enhance the anticancer effects of the immune system.
Extensive-stage SCLC is one of the most aggressive forms of lung cancer and advances to metastatic disease earlier than other types of lung cancer. Approximately 80% of patients with SCLC are diagnosed with extensive-stage disease. Standard initial treatment combines chemotherapy and an immune checkpoint inhibitor. Median survival with first-line therapy has been 12 to 13 months, and frontline gains have been limited. This is what makes the median overall survival in DeLLphi-305 of 21.1 months so meaningful.
More on DeLLphi-305
The trial included 563 patients with extensive-stage SCLC who had received standard first-line treatment with durvalumab plus platinum and etoposide chemotherapy and had not experienced disease progression. Patients were randomly assigned 1:1 to receive first-line maintenance therapy with either tarlatamab plus durvalumab or durvalumab alone.
At 1 year, nearly 80% of patients treated with the combination therapy remained alive compared to 53% with durvalumab alone. At a median follow-up of 13.9 months, the combination therapy reduced the risk of disease progression or death by 66% compared to durvalumab alone, with a median progression-free survival of 7.4 months vs 1.9 months. Six times as many patients showed anticancer activity with the combination compared with durvalumab alone.
Side effects of the combination therapy were consistent with individual agents and included low and abnormally low neutrophil count, decreased appetite, fatigue and weight loss. Cytokine-release syndrome occurred in 49.6% of patients and was most commonly grade 1 or 2, and most cases were resolved with supportive care.
"Given the aggressive nature of SCLC, many patients quickly relapse on current therapy and never reach second-line treatment," explained Dr. Sands. "These patients do not have time to wait, making substantial progress in the first-line setting critically important. [These] remarkable results signify the opportunity to help significantly more patients with extensive-stage SCLC achieve meaningfully longer survival."
DISCLOSURE: The DeLLphi-305 trial is sponsored by Amgen, with partial funding and durvalumab provided by AstraZeneca. For full disclosures of the study authors, visit nejm.org.
