Landmark findings from a prespecified interim analysis of the Phase III DeLLphi-304 trial (NCT05740566) show that the T-cell engager Imdelltra (tarlatamab) significantly outperformed standard chemotherapy in patients with small-cell lung cancer (SCLC) whose disease progressed following first-line platinum-based therapy.^1,2

Imdelltra (Tarlatamab) Demonstrates Superior Survival Benefit Over Chemotherapy in Relapsed Small-Cell Lung Cancer in Phase III DeLLphi-304 Trial

Results from the trial, published by The New England Journal of Medicine, demonstrated that Imdelltra produced a notable improvement in overall survival (OS) compared to chemotherapy agents such as topotecan, lurbinectedin, or amrubicin, while producing improvements in progression-free survival (PFS) and patient-reported outcomes, particularly in managing disease symptoms such as dyspnea and cough.

These benefits were observed in heavily pretreated patients, such as those with platinum-resistant disease, brain metastases, and prior exposure to anti–PD-L1 or PD-1 immunotherapy, which are patient populations that typically have poor prognoses.

“During the past 30 years, progress in the second-line treatment of small-cell lung cancer has been limited, with topotecan being the sole standard treatment in most countries,” the study authors wrote. “Lurbinectedin and amrubicin are approved in selected countries, but treatment with these agents has not resulted in markedly longer overall survival than topotecan in randomized phase 3 trials. Both of these chemotherapy options showed limited benefit, with a median overall survival of 7.5 to 9.3 months, and were associated with notable hematologic toxic effects. Poor outcomes coupled with challenging side-effect profiles underscore the need for better therapies in the context of second-line treatment.”¹

Imdelltra is a first-in-class immunotherapy designed to attach to DLL3 on tumor cells and CD3 on T cells, which subsequently activates T cells to kill DLL3-expressing SCLC cells. The DLL3 protein is expressed on the surface of SCLC cells in approximately 85%-96% of SCLC patients while being minimally expressed on healthy cells, which presents an intriguing target for investigators.

In May 2024, the FDA granted accelerated approval to Imdelltra for adults with extensive-stage SCLC (ES-SCLC) whose disease progressed following treatment with platinum-based chemotherapy. The regulatory action marked the first and only T-cell engager therapy approved by the FDA for ES-SCLC.³

Phase III DeLLphi-304 Trial Design and Patient Population

• The multinational, open-label DeLLphi-304 trial compared Imdelltra to chemotherapy in the second-line treatment of patients with SCLC who experienced disease progression during or following platinum-based chemotherapy.
• A total of 509 patients were randomly assigned in a 1:1 ratio to receive Imdelltra (n = 254) or chemotherapy comprised of topotecan, lurbinectedin, or amrubicin (n = 255).
• The trial’s primary endpoint was OS, with key secondary endpoints of investigator-assessed PFS and patient-reported outcomes.

Overall Survival and Progression-Free Survival Outcomes

• Results show that patients administered Imdelltra had a median OS of 13.6 months (95% confidence interval [CI], 11.1 to not reached) compared to 8.3 months in the chemotherapy cohort (95% CI, 7.0 to 10.2; stratified hazard ratio for death, 0.60; 95% CI, 0.47 to 0.77; P<0.001).
• Median PFS among patients administered Imdelltra was 4.2 months (95% CI, 3.4 to 4.5) compared to 3.7 months (95% CI, 2.9 to 4.2) in the chemotherapy cohort. Kaplan–Meier PFS estimates were 31% at six months and 20% at 12 months in the Imdelltra cohort compared to 23% at six months and 4% at 12 months in the chemotherapy cohort.
• Confirmed objective response was 35% (95% CI, 29 to 41) in the Imdelltra cohort compared to 20% (95% CI, 16 to 26) in the chemotherapy cohort.

Symptom Improvement and Patient-Reported Outcomes

• Patients administered Imdelltra reported significantly greater decreases in symptom scores compared to chemotherapy for dyspnea (mean between-group difference, −9.14 points; 95% CI, −12.64 to −5.64; P<0.001) and cough (odds ratio for decrease in cough score, 2.04; 95% CI, 1.17 to 3.55; P=0.01; risk ratio for decrease in cough score, 1.74; 95% CI, 0.99 to 2.49).
• In terms of safety, adverse events (AEs) of grade 3 or higher were 54% in the Imdelltra cohort compared to 80% in the chemotherapy cohort while incidence of AEs causing treatment discontinuation were 5% in the Imdelltra cohort compared to 12% in the chemotherapy cohort.

Implications for Future Treatment of Small-Cell Lung Cancer

“The DeLLphi-304 trial is a landmark trial that represents an important advance in the treatment of patients with small-cell lung cancer,” the study authors concluded. “The results of this trial involving patients who had had a relapse underscore the importance of examining the use of tarlatamab in earlier lines of therapy, and such trials are ongoing (i.e., DeLLphi-305, DeLLphi-306, and DeLLphi-312). Collectively, the survival benefit, toxic effects of mainly low grade, and favorable patient-reported outcomes support the use of tarlatamab as treatment for small-cell lung cancer that has progressed during or after initial platinum-based chemotherapy.”¹

References

1. Mountzios G., et al. Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy. N Engl J Med 2025. DOI: 10.1056/NEJMoa2502099.

2. Study Comparing Tarlatamab With Standard of Care Chemotherapy in Relapsed Small Cell Lung Cancer (DeLLphi-304). ClinicalTrials.gov. Updated May 18, 2025. Accessed June 10, 2025. https://clinicaltrials.gov/study/NCT05740566

3. FDA APPROVES IMDELLTRA™ (TARLATAMAB-DLLE), THE FIRST AND ONLY T-CELL ENGAGER THERAPY FOR THE TREATMENT OF EXTENSIVE-STAGE SMALL CELL LUNG CANCER. Amgen. May 16, 2024. Accessed June 10, 2025. https://wwwext.amgen.com/newsroom/press-releases/2024/05/fda-approves-imdelltra-tarlatamabdlle-the-first-and-only-tcell-engager-therapy-for-the-treatment-of-extensivestage-small-cell-lung-cancer