{"entity":{"id":"sclc","kind":"indication","name":"Small-cell lung cancer","aka":[],"tldr":"A fast-growing lung cancer that responds to chemotherapy then relapses quickly. After 30 years without progress, T-cell engagers and ADCs are finally moving the needle.","summary":"Small-cell lung cancer is a high-grade neuroendocrine carcinoma, almost always caused by smoking, defined by near-universal loss of TP53 and RB1 and by explosive growth. It presents as extensive-stage disease in two thirds of patients, responds to chemotherapy in most, and relapses in almost all. For three decades the treatment was platinum-etoposide, thoracic radiotherapy for limited-stage disease, prophylactic cranial irradiation, and topotecan at relapse.\n\nThe field moved in three steps. First-line chemo-immunotherapy (IMpower133 2018, CASPIAN 2019, ASTRUM-005 2022) added two to five months of median survival and a small tail of long-term survivors. Consolidation durvalumab after chemoradiotherapy for limited-stage disease (ADRIATIC, approved December 2024) was the first curative-intent advance in 30 years, lifting median survival to nearly five years. In relapsed disease, tarlatamab, the DLL3 T-cell engager, became the first drug to beat chemotherapy on overall survival (DeLLphi-304; full FDA approval November 2025), and lurbinectedin plus atezolizumab became the first approved first-line maintenance regimen (IMforte, October 2025).\n\nWhat is next: maintenance intensification with tarlatamab (DeLLphi-305), the B7-H3 ADC ifinatamab deruxtecan in second line (IDeate-Lung02), alpha-emitting SSTR radioligands (RYZ101), subtype-directed therapy (ASCL1, NEUROD1, POU2F3, inflamed), bispecific and trispecific DLL3 engagers, and the settled question of whether MRI surveillance can replace prophylactic cranial irradiation. Screening remains limited to low-dose CT in smokers, which detects few small-cell cancers early.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Small-cell_carcinoma","links":[{"label":"NCI PDQ: small cell lung cancer treatment","url":"https://www.cancer.gov/types/lung/hp/small-cell-lung-treatment-pdq"},{"label":"IASLC: tarlatamab first-line maintenance data","url":"https://www.iaslc.org/iaslc-news/press-release/tarlatamab-anti-pd-l1-first-line-maintenance-after-chemo-immunotherapy-es"}],"tags":["lung"],"related":[],"indications":[],"sections":[],"technologies":["targeted-alpha-therapy"],"targets":["dll3","b7h3","sstr2","parp"],"drugs":[],"companies":["astrazeneca","merck","bms"],"institutions":["mskcc","md-anderson","dana-farber"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"Small-cell lung cancer makes up about 15% of lung cancers, roughly 250,000 cases a year worldwide, almost entirely in current or former smokers. Limited-stage disease is treated with curative intent and now with durvalumab consolidation. Median survival is nearly five years in limited-stage and about one year in extensive-stage disease.","subtypes":["Limited-stage (one hemithorax, ~30%)","Extensive-stage (~70%)","SCLC-A (ASCL1-driven, DLL3-high; ~50%)","SCLC-N (NEUROD1)","SCLC-P (POU2F3, tuft-cell-like)","SCLC-I (inflamed, IO-responsive)","Transformed SCLC (from EGFR-mutant NSCLC under TKI)","Combined small-cell / non-small-cell histology"],"biomarkers":["DLL3 (not required for tarlatamab)","B7-H3","SCLC-A/N/P/I subtypes (research)","Stage (limited vs extensive) is the dominant decision","B7-H3 (I-DXd trials)","SSTR2 (RYZ101)","Transcription-factor subtype (ASCL1/NEUROD1/POU2F3/YAP1, research)","PD-L1 and TMB (not predictive in SCLC)","SLFN11 (chemotherapy/PARP sensitivity, research)","ctDNA (research)"],"standardOfCare":[{"setting":"Limited stage","approach":"Chemoradiation → durvalumab; prophylactic cranial irradiation or MRI surveillance.","refs":["durvalumab"],"guideline":{"version":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"Extensive stage","approach":"Platinum-etoposide + atezolizumab/durvalumab; lurbinectedin + atezolizumab maintenance.","refs":["durvalumab"],"guideline":{"version":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"Relapsed","approach":"Tarlatamab (preferred), lurbinectedin, topotecan; I-DXd in trials.","refs":[],"guideline":{"version":"NCCN Guidelines: Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462"}},{"setting":"Screening and diagnosis","approach":"Low-dose CT screening in heavy smokers finds some SCLC but stage shift is limited; diagnosis by bronchoscopic or CT-guided biopsy; staging with PET/CT and brain MRI.","refs":["ct","pet-ct"],"guideline":{"nccn":"SCLC guideline, staging workup","version":"NCCN SCLC v2.2026"}},{"setting":"Very limited stage (T1-2 N0, ~5%)","approach":"Lobectomy with mediastinal node dissection or SBRT, followed by adjuvant platinum-etoposide; PCI or MRI surveillance.","refs":[],"guideline":{"nccn":"2A"}},{"setting":"Limited stage","approach":"Concurrent cisplatin-etoposide with thoracic radiotherapy (45 Gy twice daily or 60-70 Gy once daily), then durvalumab consolidation up to 2 years (ADRIATIC); PCI or MRI surveillance.","refs":["durvalumab"],"guideline":{"nccn":"1 (durvalumab consolidation, category 1)","esmoMcbs":"A","version":"NCCN SCLC v2.2026"}},{"setting":"Extensive stage, first line","approach":"Carboplatin-etoposide plus atezolizumab or durvalumab (4 cycles), then maintenance immunotherapy; lurbinectedin added to atezolizumab maintenance since 2025 (IMforte). Serplulimab-chemotherapy where approved. Consolidative thoracic radiotherapy for residual thoracic disease in good responders.","refs":["durvalumab"],"guideline":{"nccn":"1 (chemo-IO); 2A (lurbinectedin maintenance)","esmoMcbs":"3"}},{"setting":"Relapsed, platinum-sensitive (≥90 days)","approach":"Tarlatamab (preferred, OS benefit); platinum-etoposide rechallenge; lurbinectedin; topotecan.","refs":[],"guideline":{"nccn":"1 (tarlatamab)","esmoMcbs":"4"}},{"setting":"Relapsed, platinum-resistant (<90 days)","approach":"Tarlatamab; lurbinectedin; topotecan; clinical trials (I-DXd, RYZ101, DLL3 bispecifics).","refs":["ryz101"],"guideline":{"nccn":"1 (tarlatamab)"}},{"setting":"Brain metastases","approach":"Whole-brain radiotherapy or, increasingly, stereotactic radiosurgery for limited numbers of lesions; PCI decisions individualised.","refs":[]},{"setting":"Transformed SCLC (from EGFR-mutant NSCLC)","approach":"Platinum-etoposide, often with continued EGFR TKI; immunotherapy benefit uncertain; trials.","refs":[]}],"stateOfArt":["Tarlatamab: first OS improvement in relapsed SCLC in decades.","Immunotherapy consolidation in limited stage.","Limited-stage: chemoradiation followed by durvalumab consolidation (ADRIATIC), median OS approaching five years.","Extensive-stage first line: chemo-immunotherapy, now with lurbinectedin-atezolizumab maintenance (IMforte, 2025).","Relapse: tarlatamab (DLL3×CD3) improved OS over chemotherapy (DeLLphi-304) and received full approval in November 2025.","B7-H3 ADC ifinatamab deruxtecan and alpha-emitting SSTR radioligand RYZ101 are in phase 3.","MRI surveillance is displacing prophylactic cranial irradiation while the definitive trial (SWOG S1827) reads out.","Molecular subtypes (A/N/P/I) explain heterogeneity and are moving toward prospective use."],"history":[{"year":1973,"title":"VA Lung Study Group defines limited vs extensive stage","refs":[]},{"year":1980,"title":"Platinum-etoposide becomes standard","refs":[]},{"year":1985,"title":"Platinum-etoposide becomes the standard regimen","refs":[]},{"year":1992,"title":"Meta-analysis: thoracic radiotherapy improves survival in limited-stage disease","refs":[]},{"year":1996,"title":"Topotecan approved for relapsed disease","refs":[]},{"year":1999,"title":"Prophylactic cranial irradiation improves survival in complete responders","refs":[]},{"year":1999,"title":"Twice-daily 45 Gy (Turrisi) sets the limited-stage radiotherapy standard","refs":[]},{"year":2017,"title":"CONVERT: once-daily 66 Gy not superior to twice-daily 45 Gy","refs":[]},{"year":2017,"title":"Japanese trial: PCI gives no survival benefit in extensive-stage disease with MRI surveillance","refs":[]},{"year":2018,"title":"IMpower133: first immunotherapy OS benefit","refs":[]},{"year":2018,"title":"IMpower133: first survival gain in decades with atezolizumab","refs":[]},{"year":2019,"title":"Rovalpituzumab tesirine (first DLL3 ADC) fails","refs":[]},{"year":2019,"title":"Rovalpituzumab tesirine (first DLL3 ADC) fails","refs":["dll3"]},{"year":2019,"title":"CASPIAN confirms chemo-immunotherapy with durvalumab","refs":["durvalumab"]},{"year":2020,"title":"Lurbinectedin accelerated approval in relapsed SCLC","refs":[]},{"year":2021,"title":"SCLC molecular subtypes (A, N, P, I) proposed","refs":[]},{"year":2024,"title":"Tarlatamab approved","refs":[]},{"year":2024,"title":"Tarlatamab accelerated approval; ADRIATIC changes limited-stage care","refs":[]},{"year":2025,"title":"DeLLphi-304 OS benefit and full approval of tarlatamab; IMforte maintenance approved","refs":[]},{"year":2026,"title":"Phase 3 readouts pending for I-DXd and tarlatamab maintenance","refs":[]}],"pipeline":["ryz101","targeted-alpha-therapy"],"openProblems":["Rapid chemoresistance.","Brain metastases.","No screening beyond CT for smokers.","Extensive-stage disease almost always relapses after first-line therapy, so maintenance (lurbinectedin-atezolizumab, tarlatamab) is the current lever; median survival is still barely over a year.","No validated predictive biomarker for immunotherapy benefit; PD-L1 and TMB do not work in SCLC.","Sequencing of tarlatamab, I-DXd, lurbinectedin, and platinum rechallenge is untested.","Cytokine release syndrome and neurotoxicity of T-cell engagers require inpatient step-up dosing that many community centres cannot provide.","Prophylactic cranial irradiation versus MRI surveillance remains unresolved until SWOG S1827 reads out.","Transformed SCLC arising from EGFR-mutant NSCLC has no dedicated evidence base.","Screening rarely catches SCLC early; prevention is tobacco control.","Trials rarely enrol patients with poor performance status, who are common in this disease."]},"route":"/indications/sclc/","neighbours":{"technology":[{"id":"ct","kind":"technology","name":"CT (computed tomography)","route":"/technologies/ct/"},{"id":"pet-ct","kind":"technology","name":"PET/CT","route":"/technologies/pet-ct/"},{"id":"sstr-pet","kind":"technology","name":"Somatostatin receptor PET (68Ga/64Cu-DOTATATE)","route":"/technologies/sstr-pet/"},{"id":"targeted-alpha-therapy","kind":"technology","name":"Targeted alpha therapy","route":"/technologies/targeted-alpha-therapy/"}],"target":[{"id":"b7h3","kind":"target","name":"B7-H3","route":"/targets/b7h3/"},{"id":"cck2-receptor","kind":"target","name":"CCK2 receptor (gastrin receptor)","route":"/targets/cck2-receptor/"},{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/"},{"id":"sstr2","kind":"target","name":"Somatostatin receptor 2","route":"/targets/sstr2/"}],"company":[{"id":"abdera-therapeutics","kind":"company","name":"Abdera Therapeutics","route":"/companies/abdera-therapeutics/"},{"id":"aktis-oncology","kind":"company","name":"Aktis Oncology","route":"/companies/aktis-oncology/"},{"id":"ariceum-therapeutics","kind":"company","name":"Ariceum Therapeutics","route":"/companies/ariceum-therapeutics/"},{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"},{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"},{"id":"evergreen-theragnostics","kind":"company","name":"Evergreen Theragnostics","route":"/companies/evergreen-theragnostics/"},{"id":"mariana-oncology","kind":"company","name":"Mariana Oncology","route":"/companies/mariana-oncology/"},{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"},{"id":"molecular-targeting-technologies","kind":"company","name":"Molecular Targeting Technologies","route":"/companies/molecular-targeting-technologies/"},{"id":"telix","kind":"company","name":"Telix Pharmaceuticals","route":"/companies/telix/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"md-anderson","kind":"institution","name":"MD Anderson Cancer Center","route":"/institutions/md-anderson/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"},{"id":"shandong-cancer-hospital","kind":"institution","name":"Shandong Cancer Hospital and Institute","route":"/institutions/shandong-cancer-hospital/"}],"drug":[{"id":"ryz101","kind":"drug","name":"Actinium-225 DOTATATE","route":"/drugs/ryz101/"},{"id":"durvalumab","kind":"drug","name":"Durvalumab","route":"/drugs/durvalumab/"}],"indication":[{"id":"prostate-nepc","kind":"indication","name":"Neuroendocrine and small-cell prostate cancer","route":"/indications/prostate-nepc/"},{"id":"nsclc","kind":"indication","name":"Non-small cell lung cancer","route":"/indications/nsclc/"}],"pathway":[{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"}],"term":[{"id":"net-grade-ki67","kind":"term","name":"Neuroendocrine tumour grade (Ki-67) and WHO classification","route":"/terms/net-grade-ki67/"}],"trial":[{"id":"nct05142696","kind":"trial","name":"A Study of [177Lu]Lu-DOTA-TATE in Newly Diagnosed ES-SCLC Patients in Combination With Carboplatin, Etoposide and Atezolizumab","route":"/trials/nct05142696/"},{"id":"nct07278479","kind":"trial","name":"Study of [212Pb]Pb-DOTAM-MAM279 ([212Pb]Pb-MP0712) in Patients With Small Cell Lung Cancer and Other DLL3 Expressing Solid Tumors","route":"/trials/nct07278479/"}],"opportunity":[{"id":"opp-dll3-imaging-sclc","kind":"opportunity","name":"DLL3 imaging for small-cell lung cancer","route":"/opportunities/opp-dll3-imaging-sclc/"}]}}