{"entity":{"id":"idea-sclc-subtype-directed","kind":"idea","name":"Subtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed)","aka":[],"tldr":"Small-cell lung cancer is at least four diseases under the microscope's uniform appearance. Treat each by its transcription-factor subtype.","summary":"Small-cell lung cancer looks uniform under the microscope, but the Rudin and Gay classification splits it into transcription-factor subtypes: ASCL1-driven SCLC-A, which is DLL3-high and BCL-2 dependent, NEUROD1-driven SCLC-N, POU2F3-driven SCLC-P and the inflamed SCLC-I. The idea is to assign subtype prospectively by RNA or immunohistochemistry and treat each accordingly: tarlatamab for SCLC-A, immunotherapy for SCLC-I, Aurora kinase inhibitors for SCLC-N and PARP or ATR inhibitors for SCLC-P. The rationale is that these dependencies are reproducible in cell lines and xenografts, and a retrospective IMpower133 analysis suggested SCLC-I gained most from atezolizumab. The proposed test is a subtype-stratified umbrella trial in relapsed patients, and the evidence so far is preclinical.","asOf":"2026-09-07","links":[{"label":"DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer (New England Journal of Medicine 2023)","url":"https://doi.org/10.1056/NEJMoa2307980"},{"label":"ClinicalTrials.gov NCT05740566: DeLLphi-304","url":"https://clinicaltrials.gov/study/NCT05740566"}],"tags":[],"related":["lung-cancer-evidence-roadmap","idea-lung-small-cell-platform-with-shared-controls-and-subtypes"],"cancers":["sclc"],"sections":[],"technologies":[],"targets":["dll3","bcl2","atr","parp"],"drugs":["tarlatamab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-dellphi-301-nejm-2023","paper-dll3-sclc-clin-cancer-res-2019","paper-tarlatamab-sclc-n-engl-j-med-2025"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Prospective subtype assignment (RNA or IHC) will predict benefit: DLL3 engagers in SCLC-A, immunotherapy in SCLC-I, Aurora kinase inhibitors in SCLC-N, and PARP/ATR inhibitors in SCLC-P.","rationale":"Subtype-specific dependencies are reproducible in cell lines and PDX; DLL3 expression tracks ASCL1.","test":"Biomarker-stratified umbrella trial assigning relapsed patients by IHC subtype to tarlatamab, ATR inhibitor, Aurora A inhibitor, or chemo-immunotherapy.","maturity":"preclinical-evidence"},"route":"/ideas/idea-sclc-subtype-directed/","neighbours":{"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/"}],"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/"}],"cancer":[{"id":"extensive-stage-sclc","kind":"cancer","name":"Extensive-stage small-cell lung cancer","route":"/cancers/extensive-stage-sclc/"},{"id":"limited-stage-sclc","kind":"cancer","name":"Limited-stage small-cell lung cancer","route":"/cancers/limited-stage-sclc/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"target":[{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/"}],"drug":[{"id":"tarlatamab","kind":"drug","name":"Tarlatamab","route":"/drugs/tarlatamab/"}],"paper":[{"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","route":"/key-papers/paper-dellphi-301-nejm-2023/"},{"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/"}]}}