Tarlatamab plus durvalumab extends survival in first-line maintenance for extensive-stage small cell lung cancer

Patients with extensive-stage small cell lung cancer who received the bispecific T-cell engager tarlatamab together with durvalumab as first-line maintenance therapy lived substantially longer than patients treated with durvalumab alone, according to phase 3 results presented by investigators at Dana-Farber Cancer Institute at the European Society for Medical Oncology Congress 2026 in Madrid. In the randomized DeLLphi-305 study, the combination extended median overall survival by more than eight months, more than tripled progression-free survival, and reduced the risk of death by 58 percent compared with durvalumab maintenance alone. The findings, presented by Jacob Sands, Associate Chief of the Lowe Center for Thoracic Oncology at Dana-Farber, during the Presidential Symposium on Oct.

24, were published simultaneously in the New England Journal of Medicine. The trial enrolled 563 patients with extensive-stage small cell lung cancer who had completed standard first-line treatment with durvalumab plus platinum and etoposide chemotherapy and whose disease had not progressed. Participants were then randomized one-to-one to receive first-line maintenance therapy with either tarlatamab plus durvalumab or durvalumab alone.

This design directly tested whether introducing tarlatamab earlier, rather than holding it in reserve for later lines of treatment, could improve outcomes in the window immediately after initial chemotherapy and immunotherapy. The numerical results reported a sharp separation between the two maintenance strategies. At a median follow-up of 13.9 months, the combination reduced the risk of disease progression or death by 66 percent compared with durvalumab alone.

Median progression-free survival was 7.4 months with the combination versus 1.9 months with durvalumab alone. At one year, nearly 80 percent of patients treated with the combination remained alive, compared with 53 percent of those receiving durvalumab alone. Six times as many patients showed anti-cancer activity with the combination as with durvalumab alone.

Median overall survival in the trial reached 21.1 months with the combination, a figure the investigators emphasized against the historical backdrop of first-line therapy for this disease. Median survival with existing first-line treatment has been 12 to 13 months, and gains at the front line have been limited. Extensive-stage small cell lung cancer is among the most aggressive forms of lung cancer and progresses to metastatic disease earlier than other lung cancer types, and approximately 80 percent of patients with small cell lung cancer are diagnosed with extensive-stage disease.

Sands described the trial as positive in every measured dimension. In his assessment, the study showed substantial improvement in median progression-free survival, substantial improvement in median overall survival, and substantially longer disease control for a broader group of patients than any prior study or prior treatment in this setting. He stated that the immunotherapy combination sets a new standard of care with tarlatamab plus durvalumab in the maintenance setting after induction chemotherapy plus durvalumab.

The survival benefit was reported as consistent across subgroups, including patients with brain metastases and patients with liver metastases. The DeLLphi-305 study is the first phase 3 trial of a bispecific T-cell engager therapy to demonstrate an overall survival benefit in the first-line maintenance setting for extensive-stage small cell lung cancer. Tarlatamab is engineered as a bispecific molecule, meaning its two binding arms recognize different targets simultaneously.

One arm binds CD3 proteins on T cells, the immune cells responsible for cytotoxic anti-cancer activity, while the other binds DLL3 proteins displayed on small cell lung cancer cells. By engaging both targets at once, the drug is designed to pull the two cell types into close proximity and thereby enhance the anti-cancer effects of the patient's own immune system, directing T-cell activity toward the tumor cells carrying DLL3. Tarlatamab is already approved by the U.S. Food and Drug Administration as a later line of therapy for this disease.

The DeLLphi-305 results indicate it may be even more effective when moved into the first-line maintenance setting, before patients have experienced progression on initial therapy. Sands noted that given the aggressive nature of small cell lung cancer, many patients quickly relapse on current therapy and never reach second-line treatment at all. Those patients, he said, do not have time to wait, which makes substantial progress in the first-line setting critically important; he characterized the results as signifying an opportunity to help significantly more patients with extensive-stage disease achieve meaningfully longer survival.

The safety profile of the combination was reported as consistent with the individual agents. Observed side effects included low and abnormally low neutrophil counts, decreased appetite, fatigue, and weight loss. The trial was open-label, meaning participants and investigators knew which treatment was assigned, and it was conducted across multiple centers.

The DeLLphi-305 trial was sponsored by Amgen, with partial funding and durvalumab supplied by AstraZeneca. The results were presented at the ESMO Congress 2026 Presidential Symposium in Madrid on Oct. 24 and published in the New England Journal of Medicine under the title Tarlatamab-Durvalumab Maintenance for Extensive-Stage Small-Cell Lung Cancer.

For a disease in which frontline gains have been limited and median survival has remained in the 12-to-13-month range, the demonstration of a 21.1-month median overall survival, a 58 percent reduction in the risk of death, and consistent benefit across metastatic subgroups marks a substantial shift in the reported outcomes achievable in the first-line maintenance setting for extensive-stage small cell lung cancer.

Subject of Research: Phase 3 trial of tarlatamab plus durvalumab first-line maintenance therapy for extensive-stage small cell lung cancer

Article Title: Immunotherapy combo extends survival for patients with aggressive small cell lung cancer, based on trial results presented by Dana-Farber at ESMO Congress 2026

Article References: Immunotherapy combo extends survival for patients with aggressive small cell lung cancer, based on trial results presented by Dana-Farber at ESMO Congress 2026. Original publication (Bibliographic details unavailable.)

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Keywords: small cell lung cancer, tarlatamab, durvalumab, bispecific T-cell engager, DeLLphi-305, ESMO Congress 2026, Dana-Farber Cancer Institute, immunotherapy, maintenance therapy, overall survival, New England Journal of Medicine, DLL3