Tarlatamab Plus Durvalumab Improves Survival in First-Line ES-SCLC

The phase 3 DeLLphi-305 study (NCT06211036) met its primary end point at a prespecified interim analysis, showing a statistically significant and clinically meaningful improvement in overall survival (OS) with tarlatamab-dlle (Imdelltra) plus durvalumab (Imfinzi) vs durvalumab alone as first-line maintenance therapy in extensive stage small cell lung cancer (ES-SCLC).¹ The trial also met its secondary end points of progression-free survival (PFS) and objective response rate (ORR).

DeLLphi-305 enrolled patients with ES-SCLC whose disease had not progressed following induction with durvalumab, platinum-based chemotherapy, and etoposide. Exact OS, PFS, and ORR figures were not disclosed in the announcement; Amgen, the sponsor, said it plans to present detailed findings from the trial at an upcoming international medical congress and to share the data with regulatory authorities.

Tarlatamab is a first-in-class bispecific T-cell engager (BiTE) that binds both DLL3 on tumor cells and CD3 on T cells, activating T cells to lyse DLL3-expressing SCLC cells.^2,3 DLL3 is expressed on the surface of SCLC cells in approximately 85% to 96% of patients but is minimally expressed on healthy tissue.⁴ Tarlatamab is already FDA approved for adults with ES-SCLC with disease progression on or after platinum-based chemotherapy; its use as first-line maintenance therapy remains investigational.

Overall, the safety profile of tarlatamab plus durvalumab was consistent with the known safety profiles of the individual agents, and no new or unexpected safety signals were identified.¹ Patients were monitored in a health care setting for 1 to 2 hours (6 to 8 hours in certain regions, including Europe) following tarlatamab infusion on cycle 1, day 1 and cycle 1, day 8.

Study Design

DeLLphi-305 is a global, randomized, open-label trial sponsored by Amgen, with partial funding and durvalumab supplied by AstraZeneca. Investigators randomized 563 patients who had completed induction with durvalumab, platinum-based chemotherapy, and etoposide 1:1 to receive tarlatamab plus durvalumab or durvalumab alone until progression or unacceptable toxicity. The trial included patients with treated and untreated asymptomatic brain metastases at baseline. OS is the primary outcome measure; PFS and ORR are secondary end points.

The study builds on DeLLphi-303 (NCT05361395), a phase 1b trial that evaluated tarlatamab in combination with anti–PD-L1 checkpoint inhibitors as first-line maintenance therapy in ES-SCLC and reported encouraging efficacy and tolerability. DeLLphi-305 was designed to test tarlatamab earlier in the disease course, in a population that includes more patients with SCLC who may stand to benefit.

Clinical Context and Limitations

SCLC accounts for approximately 13% to 15% of the more than 2.6 million lung cancer cases diagnosed worldwide each year and remains one of the most aggressive lung cancer subtypes.^5,6 Despite advances in ES-SCLC treatment, outcomes remain poor: median survival is approximately 1 year from the start of first-line maintenance therapy, and only about 40% of patients go on to receive second-line therapy.^7-10 This is the first phase 3 study of a BiTE therapy to demonstrate an OS benefit in the first-line maintenance setting for ES-SCLC.¹

Jacob Sands, MD, associate chief, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, said in a news release that because many patients with SCLC relapse quickly and never reach second-line treatment, progress in the first-line setting is 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,” Sands said in a news release. “DeLLphi-305 represents an unprecedented milestone and suggests we may be entering a new era where meaningfully longer survival is possible for more patients.”

REFERENCES

1. IMDELLTRA in combination with Imfinzi demonstrated landmark improvement in overall survival in first-line extensive stage small cell lung cancer. News release. Amgen. September 8, 2026. Accessed September 8, 2026. https://tinyurl.com/2f58wet2

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. 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

4. 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

5. Oronsky B, Abrouk N, Caroen S, et al. A 2022 update on extensive stage small-cell lung cancer (SCLC). J Cancer. 2022;13(9):2945-2953. doi:10.7150/jca.75622

6. Sabari JK, Lok BH, Laird JH, Poirier JT, Rudin CM. Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol. 2017;14(9):549-561. doi:10.1038/nrclinonc.2017.71

7. Cramer-van der Welle CM, Schramel FMNH, van Leeuwen AS, Groen HJM, van de Garde EMW; Santeon SCLC Study Group. Real-world treatment patterns and outcomes of patients with extensive disease small cell lung cancer. Eur J Cancer Care (Engl). 2020;29(5):e13250. doi:10.1111/ecc.13250

8. Shaw J, Pundole X, Balasubramanian A, et al. Recent treatment patterns and real-world survival following first-line anti-PD-L1 treatment for extensive-stage small cell lung cancer. Oncologist. 2024;29(12):1079-1089. doi:10.1093/oncolo/oyae234

9. Paz-Ares L, Borghaei H, Liu SV, et al. Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2025;405(10495):2129-2143. doi:10.1016/S0140-6736(25)01011-6

10. Reck M, Mok TSK, Mansfield A, et al. Brief report: exploratory analysis of maintenance therapy in patients with extensive-stage SCLC treated first line with atezolizumab plus carboplatin and etoposide. J Thorac Oncol. 2022;17(9):1122-1129. doi:10.1016/j.jtho.2022.05.016