Imdelltra Plus Imfinzi Delivers First Phase 3 Survival Win for a BiTE Therapy in First-Line Small Cell Lung Cancer

Amgen announced that the Phase 3 DeLLphi-305 trial met its primary endpoint at a pre-specified interim analysis, demonstrating a statistically significant and clinically meaningful improvement in overall survival (OS) with tarlatamab-dlle (Imdelltra) in combination with AstraZeneca's durvalumab (Imfinzi), compared with Imfinzi alone, as first-line maintenance treatment for extensive-stage small cell lung cancer (ES-SCLC).¹ The trial tested the combination in patients whose disease had not progressed following initial treatment with Imfinzi, platinum-based chemotherapy, and etoposide.¹ The combination also achieved statistically significant, clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR), the trial's secondary endpoints.¹ The safety profile of Imdelltra combined with Imfinzi was consistent with the known safety profiles of each individual medicine, with no new or unexpected safety signals identified.¹

This marks the first phase 3 study of a bispecific T-cell engager (BiTE) therapy to demonstrate an overall survival benefit in the first-line maintenance setting for ES-SCLC.¹ Jay Bradner, M.D., executive vice president, Research and Development, Artificial Intelligence and Data at Amgen, said, "Imdelltra has already revolutionized the standard of survival for patients with extensive stage small cell lung cancer whose disease progressed on or after prior treatment. These landmark results from DeLLphi-305 suggest Imdelltra will further revolutionize the standard for survival earlier in the treatment journey and meaningfully shift the treatment paradigm for people facing this devastating disease. Despite clinical advances, extensive stage small cell lung cancer remains one of the most aggressive and difficult-to-treat cancers, and substantial improvements in survival are rare, underscoring the importance of these findings."¹

How was the trial designed?

DeLLphi-305 is a global, randomized, open-label phase 3 trial sponsored by Amgen, with partial funding and durvalumab provided by AstraZeneca.¹ The trial randomized 563 patients 1:1 to receive either Imdelltra plus Imfinzi or Imfinzi alone, following completion of initial treatment with durvalumab, platinum-based chemotherapy, and etoposide, continuing until disease progression or unacceptable toxicity.¹ The trial included patients with both treated and untreated asymptomatic brain metastases at baseline.¹ Following Imdelltra infusion on Cycle 1 Day 1 and Cycle 1 Day 8, patients were monitored in a healthcare setting for one to two hours (six to eight hours in certain regions including Europe) to manage potential treatment-related adverse events.¹ The primary endpoint is OS, with PFS and ORR as secondary endpoints.¹

Why does the first-line setting matter for this disease?

ES-SCLC is one of the most aggressive forms of lung cancer, accounting for roughly 13–15% of the more than 2.6 million lung cancer cases diagnosed worldwide each year.¹ Despite treatment advances, outcomes remain poor: median survival is approximately one year from the start of first-line maintenance treatment, and only about 40% of patients go on to receive second-line therapy.¹ Jacob Sands, M.D., associate chief of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, said, "Given the aggressive nature of small cell lung cancer, many patients quickly relapse on current therapy and never reach second-line treatment. These patients do not have time to wait, making substantial progress in the first-line setting critically important. In my career treating people with extensive stage small cell lung cancer, these are among the most compelling survival results I have seen, indicating the potential to reshape the natural history of small cell lung cancer. DeLLphi-305 represents an unprecedented milestone and suggests we may be entering a new era where meaningfully longer survival is possible for more patients."¹

How does Imdelltra work, and how established is DLL3 as a target?

Imdelltra is a first-in-class BiTE molecule engineered to bind both delta-like ligand 3 (DLL3) on tumor cells and CD3 on T cells, activating T cells to kill DLL3-expressing SCLC cells and forming a cytolytic synapse that results in cancer cell lysis.² DLL3 is expressed on the surface of SCLC cells in roughly 85–96% of patients, while remaining minimally expressed on healthy cells, a differential that underlies its appeal as a therapeutic target.³ Imdelltra's mechanism builds on the broader BiTE platform, first developed by Amgen scientists to redirect cytotoxic T cells toward tumor-associated antigens using a bispecific antibody construct.⁴ Imdelltra previously received FDA accelerated approval in May 2024 based on DeLLphi-301 data, before converting to full approval in November 2025 based on the confirmatory Phase 3 DeLLphi-304 trial, which showed a 40% reduction in risk of death and more than five months of extended median overall survival compared with standard-of-care chemotherapy in second-line ES-SCLC.⁵

Who else is competing for the DLL3 target?

DeLLphi-305 arrives amid intensifying competition around DLL3 as a validated SCLC target across multiple treatment modalities. Amgen's own tarlatamab clinical program includes DeLLphi-313, a phase 1b study combining tarlatamab with zocilurtatug pelitecan, Zai Lab's DLL3-targeted antibody-drug conjugate, with and without durvalumab.¹ Roche has also entered the DLL3 space through an ADC obtained from Innovent Biologics, AbbVie holds a DLL3-directed trispecific T-cell binder licensed from China's Zejing Biopharmaceutical, Novartis is developing a DLL3 autologous CAR-T therapy in partnership with Legend Biotech, and Boehringer Ingelheim recently advanced its own DLL3 T-cell engager, obrixtamig, into Phase 3 testing for SCLC.⁶

The shift toward multi-specific antibody formats reflects a broader engineering trend across oncology. Sabeen Mekan, M.D., senior vice president and chief medical officer at Zymeworks, told BioPharm International in a video interview at BIO International Convention 2026, "Bispecific, trispecific, and multispecific formats are designed to improve targeting precision and enhance therapeutic activity by engaging multiple epitopes or biological mechanisms simultaneously."⁷

What happens next?

Amgen plans to present detailed data from DeLLphi-305 at an upcoming international medical congress and share the results with regulatory authorities.¹ The DeLLphi program continues to evaluate tarlatamab across earlier stages of disease and lines of treatment, both as monotherapy and in combination regimens, including the ongoing Phase 3 DeLLphi-306 (limited-stage SCLC following chemoradiotherapy) and DeLLphi-312 (first-line ES-SCLC induction and maintenance) trials.¹

References

1. Amgen Inc. IMDELLTRA® in Combination with Imfinzi® Demonstrated Landmark Improvement in Overall Survival in First-Line Extensive Stage Small Cell Lung Cancer. Press release. Published September 8, 2026. Accessed September 9, 2026.
2. Giffin MJ, Cooke K, Lobenhofer EK, et al. AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer. Clin Cancer Res. 2021;27(5):1526-1537. doi:10.1158/1078-0432.CCR-20-2845.
3. Rojo F, Corassa M, Mavroudis D, et al. International Real-World Study of DLL3 Expression in Patients With Small Cell Lung Cancer. Lung Cancer. 2020;147:237-243. doi:10.1016/j.lungcan.2020.07.026.
4. Baeuerle PA, Kufer P, Bargou R. BiTE: Teaching Antibodies to Engage T-Cells for Cancer Therapy. Curr Opin Mol Ther. 2009;11(1):22-30.
5. Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for Patients With Previously Treated Small-Cell Lung Cancer. N Engl J Med. 2023;389(22):2063-2075. doi:10.1056/NEJMoa2307980.
6. Liu A. Amgen's DLL3-Targeted Imdelltra Scores Overall Survival Win in First-Line Small Cell Lung Cancer. Fierce Pharma. Published September 8, 2026. Accessed September 9, 2026.
7. Schoenthaler E. 92Bio Doses First Patient in Phase 1 Trial of NTB-928, a FOLR1×CD3 Bispecific T-Cell Engager Engineered for Tumor Selectivity in Platinum-Resistant Ovarian Cancer. BioPharm International. Published July 1, 2026. Accessed September 9, 2026.