# DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer

Source: https://onco.cc/key-papers/paper-dellphi-301-nejm-2023/  
OnCo record `paper-dellphi-301-nejm-2023` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A bispecific antibody that pulls T cells onto small-cell lung cancer cells produced responses in 40% of patients whose cancer had come back after chemotherapy, lasting far longer than any previous drug in this setting.

## Summary

Open-label phase 2 trial of 220 patients with small-cell lung cancer that had progressed after platinum-based chemotherapy (and usually immunotherapy), testing tarlatamab, a DLL3 x CD3 bispecific T-cell engager, at 10 mg or 100 mg every two weeks. Primary endpoint was objective response rate.

At 10 mg the response rate was 40%, median PFS 4.9 months and median OS 14.3 months, with cytokine release syndrome in about half of patients, mostly grade 1-2 and mainly during the first cycle. It led to accelerated FDA approval in 2024 and was confirmed by the phase 3 DeLLphi-304 trial, which showed a survival benefit over chemotherapy (median OS 13.6 vs 8.3 months, HR 0.60).

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2023
- DOI: 10.1056/NEJMoa2307980
- Authors: Ahn MJ, Cho BC, Felip E, et al.
- Findings: Objective response 40% at 10 mg and 32% at 100 mg; median duration of response over 9 months.; At 10 mg: median PFS 4.9 months; median overall survival 14.3 months in a population with a historical OS of 6-8 months.; Cytokine release syndrome 51% (10 mg) and 61% (100 mg), mostly grade 1-2 in cycle 1; ICANS or associated neurological events in about 8% (10 mg).; Discontinuation for treatment-related adverse events 3% at the 10 mg dose, which was selected for further development.; DeLLphi-304 phase 3 (2025): OS 13.6 vs 8.3 months versus chemotherapy, HR 0.60.
- What it means: Patients with small-cell lung cancer that has relapsed after chemotherapy now have a drug that works far better than topotecan or lurbinectedin, and it is the first T-cell engager approved for a solid tumour. Treatment requires inpatient monitoring for the first doses because of cytokine release syndrome, which most centres now manage on a short-stay basis. It does not yet apply to first-line treatment, where trials are ongoing.
- Caveats: Single-arm phase 2 with a randomised dose comparison, not a randomised comparison against chemotherapy (that came with DeLLphi-304).; Cytokine release syndrome and neurotoxicity require hospital-based step-up dosing and limit use in frail patients or centres without experience.; Every-two-week intravenous dosing is burdensome for patients with a short life expectancy.; DLL3 expression was not required for entry and was not predictive, so there is no selection biomarker.

## Sources

- NEJM 2023: https://doi.org/10.1056/NEJMoa2307980
- ClinicalTrials.gov NCT05060016: https://clinicaltrials.gov/study/NCT05060016
- PubMed: https://pubmed.ncbi.nlm.nih.gov/37861218/

## Connected records

- key papers: [Comprehensive genomic profiles of small cell lung cancer](https://onco.cc/key-papers/paper-george-sclc-genomic-profiles-nature-2015/), [Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN)](https://onco.cc/key-papers/paper-paz-ares-caspian-durvalumab-es-sclc-lancet-2019/), [Efficacy and Safety of Rovalpituzumab Tesirine in Third-Line and Beyond Patients with DLL3-Expressing, Relapsed/Refractory Small-Cell Lung Cancer: Results From the Phase II TRINITY Study](https://onco.cc/key-papers/paper-dll3-sclc-clin-cancer-res-2019/), [Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data](https://onco.cc/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/), [Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy](https://onco.cc/key-papers/paper-tarlatamab-sclc-n-engl-j-med-2025/)
- cancers: [Extensive-stage small-cell lung cancer](https://onco.cc/cancers/extensive-stage-sclc/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/)
- fronts: [Drug Discovery Platforms](https://onco.cc/fronts/drug-discovery/), [Immunotherapy](https://onco.cc/fronts/immunotherapy/)
- technologies: [Bispecific antibodies](https://onco.cc/technologies/bispecific-antibody/), [T-cell engagers (bispecific)](https://onco.cc/technologies/t-cell-engager/)
- targets: [CD3](https://onco.cc/targets/cd3/), [DLL3](https://onco.cc/targets/dll3/)
- drugs: [Tarlatamab](https://onco.cc/drugs/tarlatamab/)
- companies: [Amgen](https://onco.cc/companies/amgen/)
- institutions: [Samsung Medical Center](https://onco.cc/institutions/samsung-medical-center/)
- terms: [Accelerated approval](https://onco.cc/terms/accelerated-approval/), [Cytokine release syndrome (CRS)](https://onco.cc/terms/crs/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [ICANS (neurotoxicity)](https://onco.cc/terms/icans/), [Objective response rate (ORR)](https://onco.cc/terms/orr/)
- trials: [A Phase 2 Study of Tarlatamab in Patients With Small Cell Lung Cancer (SCLC)](https://onco.cc/trials/nct05060016/), [DeLLphi-304](https://onco.cc/trials/dellphi-304/)
- people: [Byoung Chul Cho](https://onco.cc/people/cho-byoung-chul/), [Enriqueta Felip](https://onco.cc/people/enriqueta-felip/), [Fiona Blackhall](https://onco.cc/people/fiona-blackhall/), [Jürgen Wolf](https://onco.cc/people/juergen-wolf/), [Luis Paz-Ares](https://onco.cc/people/luis-paz-ares/), [Myung-Ju Ahn](https://onco.cc/people/ahn-myung-ju/)
- bottlenecks: [Fragmented care and guideline gaps](https://onco.cc/bottlenecks/b-care-fragmentation/), [Manufacturing cost and time for living and radioactive medicines](https://onco.cc/bottlenecks/b-manufacturing-cell-therapy/), [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- ideas: [Run small-cell lung cancer as one platform with shared controls and subtype stratification](https://onco.cc/ideas/idea-lung-small-cell-platform-with-shared-controls-and-subtypes/), [Subtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed)](https://onco.cc/ideas/idea-sclc-subtype-directed/)
- roadmaps: [Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/)

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