{"entity":{"id":"opp-dll3-imaging-sclc","kind":"opportunity","name":"DLL3 imaging for small-cell lung cancer","aka":["DLL3 PET","delta-like ligand 3 imaging"],"tldr":"A drug that attacks small-cell lung cancer through a protein called DLL3 is already approved, but there is no approved scan that shows whether a patient's tumours still carry that protein. Doctors decide from a single biopsy taken from one place, which cannot show what the rest of the disease is doing.","summary":"Tarlatamab, a DLL3-directed bispecific T-cell engager, received accelerated FDA approval on 16 May 2024 and traditional approval on 19 November 2025, and DLL3-directed antibody-drug conjugates, CAR-T cells and a second T-cell engager (obrixtamig) are in trials. Patient selection rests on tissue immunohistochemistry from one archival or fresh biopsy. DLL3 is expressed in 85% of small-cell lung cancers at a 25% cut-off in the largest real-world series (895 of 1,050 patients), so most patients qualify on a single sample, but nothing in routine practice shows whether every metastatic site still expresses the target.\n\nOne imaging agent has human data. The zirconium-89-labelled anti-DLL3 antibody 89Zr-DFO-SC16.56, run investigator-initiated at Memorial Sloan Kettering under NCT04199741, was reported in Lancet Oncology in 2024: 18 patients, DLL3-avid tumours delineated on a single scan in 12 of 15 patients in the expansion cohort, uptake congruent with DLL3 immunohistochemistry in 15 of 16 patients with evaluable tissue, mean effective dose 0.49 mSv/MBq, one grade 1 allergic reaction and no grade 2 or worse adverse events. The trial is still recruiting with an estimated 105 patients. A gallium-68 DLL3 tracer opened in China in May 2026 (NCT07677787, 20 patients planned) and has not reported. A next-generation MSK construct, 89Zr-DFO-TDI-Y-010, with a lutetium-177 therapeutic pair, is preclinical.\n\nThe gap is therefore not biological plausibility, which a published 94% concordance with immunohistochemistry supports, but the absence of any industry-sponsored development path: the only clinical agent is an academic antibody with multi-day imaging kinetics, and no DLL3 imaging agent has been filed with any regulator.","asOf":"2026-09-23","links":[{"label":"First-in-human DLL3 immuno-PET, Lancet Oncology 2024","url":"https://pubmed.ncbi.nlm.nih.gov/38950555/"},{"label":"NCT04199741: 89Zr-DFO-SC16.56 immuno-PET of neuroendocrine tumours","url":"https://clinicaltrials.gov/study/NCT04199741"},{"label":"NCT07677787: DLL3-targeted PET/CT in small-cell lung cancer (gallium-68)","url":"https://clinicaltrials.gov/study/NCT07677787"},{"label":"DLL3 expression in 1,050 patients, Lung Cancer 2020","url":"https://pubmed.ncbi.nlm.nih.gov/32745892/"},{"label":"FDA: accelerated approval of tarlatamab, May 2024","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-extensive-stage-small-cell-lung-cancer"}],"tags":["theranostic gap","companion diagnostic","lung","neuroendocrine"],"related":["zr-89","ga-68","lu-177"],"indications":["sclc"],"sections":[],"technologies":["immuno-pet","pet-ct"],"targets":["dll3"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"lens":"theranostic-gap","unmetNeed":"Before starting a DLL3-directed T-cell engager, no test shows whether every metastatic site in a patient with small-cell lung cancer still expresses DLL3, or whether some lesions have lost it; the decision rests on one biopsy from one place.","useCase":"A medical oncologist or nuclear medicine physician would scan a patient with extensive-stage small-cell lung cancer, or a patient with suspected neuroendocrine transformation of a lung or prostate adenocarcinoma, before committing to a DLL3-directed therapy. A whole-body map of DLL3-avid and DLL3-negative disease would either confirm the target or redirect the patient to another line, and would give a baseline for judging loss of target at progression.","hypothesis":"A same-day DLL3 imaging agent, built on a small molecule, peptide or antibody fragment rather than a full antibody, would agree with tissue immunohistochemistry at least as well as the published antibody tracer while capturing between-lesion heterogeneity that a single biopsy misses, and would identify the minority of patients whose disease has lost DLL3 before they are exposed to a T-cell engager.","rationale":"The published first-in-human antibody data already show target-specific uptake that tracks immunohistochemistry in 15 of 16 evaluable patients, so the target is reachable in vivo. DLL3 is expressed in the large majority of small-cell lung cancers but not uniformly, and DLL3-directed therapy carries a cytokine-release and neurotoxicity burden that makes treating a target-negative patient costly. The limitation of the existing agent is pharmacokinetic rather than biological: a zirconium-89 antibody requires imaging three to six days after injection, which no routine oncology service can absorb at scale.","test":"A prospective study of a same-day DLL3 tracer in patients starting a DLL3-directed T-cell engager, powered on the agreement between scan-positive and immunohistochemistry-positive disease on a per-lesion basis with biopsy as the truth standard in accessible lesions, and reporting how often the scan finds a target-negative lesion in a patient whose biopsy was target-positive. The response rate of scan-positive against scan-negative patients would be the secondary endpoint that decides whether the scan should gate treatment.","maturity":"early-clinical","verdict":"companion-only","mostAdvanced":"89Zr-DFO-SC16.56, an academic anti-DLL3 antibody tracer at Memorial Sloan Kettering, phase 1/2 and still recruiting under NCT04199741, with 18 patients published in Lancet Oncology in 2024.","dueDiligence":[{"domain":"target-biology","state":"strong","why":"DLL3 is expressed in 895 of 1,050 small-cell lung cancers (85%) at a 25% tumour-cell cut-off, and in 68% at a 75% cut-off, in the largest international real-world immunohistochemistry series.","source":"Rojo et al., Lung Cancer 2020;147:237-243","url":"https://pubmed.ncbi.nlm.nih.gov/32745892/","weighted":true},{"domain":"clinical-evidence","state":"thin","why":"One published first-in-human cohort of 18 patients with an antibody tracer; the trial continues to an estimated 105 patients. No second agent has reported human data.","source":"Tendler et al., Lancet Oncology 2024;25:1015-1024","url":"https://pubmed.ncbi.nlm.nih.gov/38950555/"},{"domain":"diagnostic-performance","state":"moderate","why":"A single scan delineated DLL3-avid tumour in 12 of 15 patients, and uptake agreed with tissue immunohistochemistry in 15 of 16 patients with evaluable tissue. No study yet relates scan findings to response on DLL3-directed therapy.","source":"Tendler et al., Lancet Oncology 2024","url":"https://pubmed.ncbi.nlm.nih.gov/38950555/","weighted":true},{"domain":"safety-dosimetry","state":"moderate","why":"Mean effective dose 0.49 mSv/MBq with the highest absorbed organ dose in liver at 1.83 mGy/MBq; one grade 1 allergic reaction in 18 patients and no grade 2 or worse events.","source":"Tendler et al., Lancet Oncology 2024","url":"https://pubmed.ncbi.nlm.nih.gov/38950555/"},{"domain":"regulatory-path","state":"thin","why":"No DLL3 imaging agent has been filed anywhere. The nearest precedent for a receptor-status tracer is 68Ga-DOTATATE, approved in 2016 on localisation performance against a reference standard rather than an outcome endpoint.","source":"NETSPOT FDA label","url":"https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208547lbl.pdf"}],"flags":[{"category":"technical","flag":"amber","why":"The only clinical agent is a full antibody needing imaging three to six days after injection, which does not fit a routine service. A same-day construct exists only preclinically."},{"category":"unmet-need","flag":"amber","why":"Real but narrow: because DLL3 is expressed in most small-cell lung cancers, a scan changes management mainly in the minority with heterogeneous or lost expression, and that fraction has not been measured prospectively."},{"category":"ip","flag":"amber","why":"The lead antibody and its next-generation successor are institutionally owned at Memorial Sloan Kettering; freedom to operate for an independent construct is unexamined in public sources."},{"category":"commercial","flag":"red","why":"Sales would depend on the DLL3 therapy market, and small-cell lung cancer is a small, short-lived population with no standalone diagnostic question of its own."},{"category":"isotope","flag":"green","why":"Any of gallium-68, fluorine-18 or copper-64 would suit a small-molecule or fragment construct; the published antibody uses zirconium-89, which is cyclotron-made but established."},{"category":"competition","flag":"green","why":"Only one academic agent has human data and one Chinese tracer has just opened; no company has a disclosed clinical DLL3 imaging programme."}],"competition":[{"name":"Memorial Sloan Kettering Cancer Center","what":"89Zr-DFO-SC16.56, the only DLL3 tracer with published human data, and a preclinical successor pair 89Zr-DFO-TDI-Y-010 with 177Lu therapy.","stage":"phase 1/2 recruiting","url":"https://clinicaltrials.gov/study/NCT04199741"},{"name":"First Affiliated Hospital of Xiamen University","what":"A gallium-68 DLL3-targeted PET tracer; 20 patients planned, opened May 2026, no results published.","stage":"recruiting","url":"https://clinicaltrials.gov/study/NCT07677787"},{"name":"Amgen","what":"Tarlatamab, the approved DLL3 T-cell engager that creates the demand; selection is by tissue immunohistochemistry, not imaging.","stage":"approved","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-extensive-stage-small-cell-lung-cancer"},{"name":"Boehringer Ingelheim","what":"Obrixtamig, a second DLL3 T-cell engager in DLL3-positive small-cell lung cancer and other neuroendocrine tumours.","stage":"active, not recruiting","url":"https://clinicaltrials.gov/study/NCT04429087"}],"differentiation":"The competing test is DLL3 immunohistochemistry on tissue, which is already used to enrol patients in trials. No blood or ctDNA test for DLL3 status exists. Imaging would add whole-body coverage and repeatability rather than a new biological readout, which is exactly why its value depends on how often lesions within one patient disagree.","metrics":[{"label":"Small-cell lung cancers expressing DLL3 in at least 25% of tumour cells","value":"85%","source":"Rojo et al., Lung Cancer 2020 (895 of 1,050)","url":"https://pubmed.ncbi.nlm.nih.gov/32745892/"},{"label":"Patients in whom one scan delineated DLL3-avid tumour","value":"12 of 15","source":"Tendler et al., Lancet Oncology 2024","url":"https://pubmed.ncbi.nlm.nih.gov/38950555/"},{"label":"Agreement between tracer uptake and tissue immunohistochemistry","value":"15 of 16","source":"Tendler et al., Lancet Oncology 2024","url":"https://pubmed.ncbi.nlm.nih.gov/38950555/"}],"risks":["If almost every patient is DLL3-positive on biopsy, a scan that confirms it adds cost without changing management; the case rests on heterogeneity that has not been quantified prospectively.","The market is tied to one therapy class in one small indication, so a companion-only agent carries the therapy's commercial risk without any standalone use to fall back on.","A full antibody cannot be delivered at service scale; whoever wants this needs a same-day construct, and the published work does not provide one."],"watch":["Readout of the expansion cohort of NCT04199741, which would take the published series from 18 to a larger number of patients.","First results from the gallium-68 DLL3 tracer at Xiamen (NCT07677787), the first non-antibody agent in humans.","Any registered trial of the MSK next-generation 89Zr-DFO-TDI-Y-010 or its lutetium-177 pair, which would signal the field moving to a theranostic construct."]},"route":"/opportunities/opp-dll3-imaging-sclc/","neighbours":{"isotope":[{"id":"ga-68","kind":"isotope","name":"Gallium-68","route":"/isotopes/ga-68/"},{"id":"lu-177","kind":"isotope","name":"Lutetium-177","route":"/isotopes/lu-177/"},{"id":"zr-89","kind":"isotope","name":"Zirconium-89","route":"/isotopes/zr-89/"}],"indication":[{"id":"sclc","kind":"indication","name":"Small-cell lung cancer","route":"/indications/sclc/"}],"technology":[{"id":"immuno-pet","kind":"technology","name":"Immuno-PET","route":"/technologies/immuno-pet/"},{"id":"pet-ct","kind":"technology","name":"PET/CT","route":"/technologies/pet-ct/"}],"target":[{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"}]}}