{"entity":{"id":"paper-dellphi-301-nejm-2023","kind":"paper","name":"DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer","aka":[],"tldr":"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.\n\nAt 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).","asOf":"2026-09-08","links":[{"label":"NEJM 2023","url":"https://doi.org/10.1056/NEJMoa2307980"},{"label":"ClinicalTrials.gov NCT05060016","url":"https://clinicaltrials.gov/study/NCT05060016"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37861218/"}],"tags":[],"related":["paper-tarlatamab-sclc-n-engl-j-med-2025","paper-dll3-sclc-clin-cancer-res-2019","paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019"],"cancers":["sclc","lung-cancer","extensive-stage-sclc"],"sections":["immunotherapy","drug-discovery"],"technologies":["t-cell-engager","bispecific-antibody"],"targets":["dll3","cd3"],"drugs":["tarlatamab"],"companies":["amgen"],"institutions":["samsung-medical-center"],"pathways":[],"terms":["orr","crs","icans","accelerated-approval","resistance"],"trials":["dellphi-304"],"people":["ahn-myung-ju","cho-byoung-chul","enriqueta-felip","juergen-wolf","fiona-blackhall","luis-paz-ares"],"bottlenecks":["b-undruggable-targets","b-dose-optimisation","b-toxicity-qol","b-rare-cancers","b-manufacturing-cell-therapy","b-care-fragmentation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/NEJMoa2307980","pmid":"37861218","authors":"Ahn MJ, Cho BC, Felip E, et al.","paperType":"rct","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."],"whatItMeans":"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."],"changedPractice":true,"participants":220},"route":"/key-papers/paper-dellphi-301-nejm-2023/","neighbours":{"paper":[{"id":"paper-george-sclc-genomic-profiles-nature-2015","kind":"paper","name":"Comprehensive genomic profiles of small cell lung cancer","route":"/key-papers/paper-george-sclc-genomic-profiles-nature-2015/"},{"id":"paper-paz-ares-caspian-durvalumab-es-sclc-lancet-2019","kind":"paper","name":"Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN)","route":"/key-papers/paper-paz-ares-caspian-durvalumab-es-sclc-lancet-2019/"},{"id":"paper-dll3-sclc-clin-cancer-res-2019","kind":"paper","name":"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","route":"/key-papers/paper-dll3-sclc-clin-cancer-res-2019/"},{"id":"paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","kind":"paper","name":"Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data","route":"/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/"},{"id":"paper-tarlatamab-sclc-n-engl-j-med-2025","kind":"paper","name":"Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy","route":"/key-papers/paper-tarlatamab-sclc-n-engl-j-med-2025/"}],"cancer":[{"id":"extensive-stage-sclc","kind":"cancer","name":"Extensive-stage small-cell lung cancer","route":"/cancers/extensive-stage-sclc/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"section":[{"id":"drug-discovery","kind":"section","name":"Drug Discovery Platforms","route":"/fronts/drug-discovery/"},{"id":"immunotherapy","kind":"section","name":"Immunotherapy","route":"/fronts/immunotherapy/"}],"technology":[{"id":"bispecific-antibody","kind":"technology","name":"Bispecific antibodies","route":"/technologies/bispecific-antibody/"},{"id":"t-cell-engager","kind":"technology","name":"T-cell engagers (bispecific)","route":"/technologies/t-cell-engager/"}],"target":[{"id":"cd3","kind":"target","name":"CD3","route":"/targets/cd3/"},{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"}],"drug":[{"id":"tarlatamab","kind":"drug","name":"Tarlatamab","route":"/drugs/tarlatamab/"}],"company":[{"id":"amgen","kind":"company","name":"Amgen","route":"/companies/amgen/"}],"institution":[{"id":"samsung-medical-center","kind":"institution","name":"Samsung Medical Center","route":"/institutions/samsung-medical-center/"}],"term":[{"id":"accelerated-approval","kind":"term","name":"Accelerated approval","route":"/terms/accelerated-approval/"},{"id":"crs","kind":"term","name":"Cytokine release syndrome (CRS)","route":"/terms/crs/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"icans","kind":"term","name":"ICANS (neurotoxicity)","route":"/terms/icans/"},{"id":"orr","kind":"term","name":"Objective response rate (ORR)","route":"/terms/orr/"}],"trial":[{"id":"nct05060016","kind":"trial","name":"A Phase 2 Study of Tarlatamab in Patients With Small Cell Lung Cancer (SCLC)","route":"/trials/nct05060016/"},{"id":"dellphi-304","kind":"trial","name":"DeLLphi-304","route":"/trials/dellphi-304/"}],"person":[{"id":"cho-byoung-chul","kind":"person","name":"Byoung Chul Cho","route":"/people/cho-byoung-chul/"},{"id":"enriqueta-felip","kind":"person","name":"Enriqueta Felip","route":"/people/enriqueta-felip/"},{"id":"fiona-blackhall","kind":"person","name":"Fiona Blackhall","route":"/people/fiona-blackhall/"},{"id":"juergen-wolf","kind":"person","name":"Jürgen Wolf","route":"/people/juergen-wolf/"},{"id":"luis-paz-ares","kind":"person","name":"Luis Paz-Ares","route":"/people/luis-paz-ares/"},{"id":"ahn-myung-ju","kind":"person","name":"Myung-Ju Ahn","route":"/people/ahn-myung-ju/"}],"bottleneck":[{"id":"b-care-fragmentation","kind":"bottleneck","name":"Fragmented care and guideline gaps","route":"/bottlenecks/b-care-fragmentation/"},{"id":"b-manufacturing-cell-therapy","kind":"bottleneck","name":"Manufacturing cost and time for living and radioactive medicines","route":"/bottlenecks/b-manufacturing-cell-therapy/"},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"idea":[{"id":"idea-lung-small-cell-platform-with-shared-controls-and-subtypes","kind":"idea","name":"Run small-cell lung cancer as one platform with shared controls and subtype stratification","route":"/ideas/idea-lung-small-cell-platform-with-shared-controls-and-subtypes/"},{"id":"idea-sclc-subtype-directed","kind":"idea","name":"Subtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed)","route":"/ideas/idea-sclc-subtype-directed/"}],"roadmap":[{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"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","route":"/roadmaps/lung-cancer-evidence-roadmap/"}]}}