Tarlatamab-dlle (Imdelltra) has demonstrated a significant improvement in overall survival (OS) compared to standard chemotherapy in patients with small cell lung cancer (SCLC), regardless of prior anti–PD-(L)1 therapy or chemotherapy-free interval (CFI) duration. These findings emerged from the phase 3 DeLLphi-304 trial (NCT05740566), presented at the 2025 ESMO Congress.
The trial revealed that the median OS for patients receiving tarlatamab was 10.9 months, compared to 6.4 months for those on chemotherapy among patients with a CFI of less than 90 days. The hazard ratio (HR) for this comparison was 0.60 (95% CI, 0.43-0.84). In this group, the 12-month OS rates stood at 40% for tarlatamab versus 24% for chemotherapy.
In patients with a CFI of 90 days or longer, the median OS increased to 17.1 months for tarlatamab compared to 10.6 months for chemotherapy, with respective 12-month OS rates of 64% and 48% (HR, 0.65; 95% CI, 0.45-0.93).
Another significant finding was for patients who experienced disease progression within two weeks of their most recent platinum-based treatment. The Kaplan-Meier estimated 6-month OS rates were 55% for tarlatamab compared to 35% for chemotherapy. For patients who had previously received anti–PD-(L)1 agents, the median OS was 14.1 months for tarlatamab versus 8.3 months for chemotherapy, with 12-month OS rates of 53% versus 36% (HR, 0.61; 95% CI, 0.45-0.82).
Among patients who had not received prior anti–PD-(L)1 therapy, the median OS was 13.6 months for tarlatamab compared to 8.3 months for chemotherapy, with respective 12-month OS rates of 53% versus 40% (HR, 0.65; 95% CI, 0.42-1.03). The data indicates that prior exposure to anti–PD-(L)1 agents did not influence the OS benefits of tarlatamab compared to chemotherapy.
Dr. Pedro F. Simoes da Rocha, MD, PhD, from Vall d’Hebron University Hospital and the Vall d’Hebron Institute of Oncology in Barcelona, Spain, emphasized the significance of these results. “In the second line, standard chemotherapies have demonstrated modest survival benefits, especially in patients with platinum-resistant disease, who often have a poor prognosis. DeLLphi-304 is the first randomized phase 3 trial to demonstrate superior OS with tarlatamab compared with standard chemotherapy. Importantly, this survival benefit extended to patients with platinum-resistant disease,” he noted.
The DeLLphi-304 trial involved 509 patients who were randomly assigned in a 1:1 ratio to receive either tarlatamab (n = 254) or an investigator’s choice of chemotherapy (n = 255). The chemotherapy options included topotecan (n = 185), lurbinectedin (Zepzelca; n = 47), and amrubicin (n = 23). Investigators stratified patients based on prior anti–PD-(L)1 therapy, CFI interval, presence of brain metastases, and the intended chemotherapy.
Patients eligible for the trial had histologically or cytologically confirmed SCLC, disease progression after frontline platinum-based chemotherapy with or without anti–PD-(L)1 therapy, and an ECOG performance status of 0 or 1. Those with asymptomatic, treated, or untreated brain metastases could also participate.
In the tarlatamab and chemotherapy arms, 43% and 45% of patients had a CFI of less than 90 days, while 57% and 55% had a CFI of 90 days or longer. Additionally, 71% of patients in both groups had prior anti–PD-(L)1 therapy, whereas 29% did not. Investigators reported that subgroup baseline characteristics were well balanced between the treatment arms.
Treatment-related adverse effects (AEs) of grade 3 or higher were noted in 24% to 30% of patients receiving tarlatamab, compared to 58% to 69% in the chemotherapy group. Rates of any-grade cytokine release syndrome (CRS) occurred in 51% to 59% of patients on tarlatamab across various subgroups, with no subgroup status impacting the risk of CRS.
Previously, the FDA granted accelerated approval to tarlatamab as a treatment for patients with extensive-stage SCLC following progression on prior platinum-based chemotherapy in May 2024. Supporting data for this indication was derived from the phase 2 DELLphi-301 trial (NCT05060016).
The results from the DeLLphi-304 trial mark a significant advancement in the treatment landscape for SCLC, particularly for patients with limited options and challenging prognoses.
