Phase 3 DeLLphi-304 Trial Shows Tarlatamab Significantly Improves OS, PFS in Previously Treated SCLC

Tarlatamab significantly improved overall survival (OS), progression-free survival (PFS), and patient-reported outcomes compared to chemotherapy as a second-line treatment for patients with small cell lung cancer (SCLC), according to results from the phase 3 DeLLphi-304 trial presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Charles Rudin, MD, PhD, of the Fiona and Stanley Druckenmiller Center for Lung Cancer Research and the Memorial Sloan Kettering Cancer Center, presented the study results at the 2025 ASCO Annual Meeting. The results were also simultaneously published in the New England Journal of Medicine.

“The data from DeLLphi-304 mark a major milestone for people with relapsed small cell lung cancer. Tarlatamab is associated with significant improvements in both overall and progression-free survival over standard chemotherapy in patients with recurrent or progressive disease,” Dr. Rudin said in an Amgen press release ahead of the data presentation at the 2025 ASCO Annual Meeting. “This study also provides confirmatory data on management of potential toxicities associated with bispecific T-cell engager therapies in a large patient cohort, which is crucial to continuing to improve the experience of patients treated with these medicines.”

Tarlatamab, which is a bispecific T-cell engager immunotherapy, previously demonstrated “promising activity” in phase 1 and phase 2 trials that included patients with previously treated SCLC. At ASCO 2025, Dr. Rudin reported results of the randomized controlled, phase 3 DeLLphi-304 study, which evaluated tarlatamab versus chemotherapy in patients with SCLC following progression on or after platinum-based chemotherapy.

Study investigators randomized 509 patients 1:1 to receive tarlatamab (n=254) or chemotherapy (n=255), which was topotecan, lurbinectedin, or amrubicin. Patients were stratified by prior treatment with a PD-(L)1 inhibitor, chemotherapy-free interval, brain metastases, and intended chemotherapy. The primary endpoint of the DeLLphi trial was overall survival (OS), with key secondary endpoints including progression-free survival (PFS) and patient-reported outcomes (PRO). Other secondary endpoints were objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and safety.

The study results showed that patients receiving tarlatamab had a median OS of 13.6 months, which was significantly longer than the median OS of 8.3 months in those receiving chemotherapy (hazard ratio [HR], 0.60 [95% CI: 0.47, 0.77]; P < 0.001). The median PFS was 4.2 months in those receiving tarlatamab, significantly longer than the median PFS of 3.2 months in those receiving chemotherapy (HR, 0.72 [95% CI: 0.59, 0.88]; P < 0.001). The median follow-up was 11.2 months for tarlatamab and 11.7 months for chemotherapy.

Tarlatamab also improved cancer-related symptoms of dyspnea and cough compared to chemotherapy and showed lower rates of grade 3 or higher treatment-related adverse events (TRAEs) than chemotherapy (27% vs 62%).

In addition, discontinuations due to TRAEs were lower with tarlatamab than chemotherapy (3% vs 6%). The most common grade 3 or higher TRAEs were neutropenia (4%) and lymphopenia (4%) with tarlatamab and anemia (28%) and neutropenia (22%) with chemotherapy. Cytokine release syndrome with tarlatamab was “primarily low grade,” with 42% of cytokine release events being grade 1, 13% being grade 2, and 1% being grade 3.

The study investigators weighed in on the implications of the trial, emphasizing that with the significant improvements in OS, PFS, and PROs, combined with the “favorable safety and tolerability profile” compared to chemotherapy, this data is “defining a new standard of care for these patients.”