Teaching pack: Small-cell lung cancer

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.

The 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).

• 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.

1. 1973VA Lung Study Group defines limited vs extensive stage
2. 1980Platinum-etoposide becomes standard
3. 1985Platinum-etoposide becomes the standard regimen
4. 1992Meta-analysis: thoracic radiotherapy improves survival in limited-stage disease
5. 1996Topotecan approved for relapsed disease
6. 1999Prophylactic cranial irradiation improves survival in complete responders
7. 1999Twice-daily 45 Gy (Turrisi) sets the limited-stage radiotherapy standard
8. 2017CONVERT: once-daily 66 Gy not superior to twice-daily 45 Gy
9. 2017Japanese trial: PCI gives no survival benefit in extensive-stage disease with MRI surveillance
10. 2018IMpower133: first immunotherapy OS benefit

• Ifinatamab deruxtecan (product)
• Actinium-225 DOTATATE (product)
• Tarlatamab (product)
• DeLLphi-305 (trial)
• IDeate-Lung02 (trial)
• Serplulimab (product)
• Lurbinectedin (product)
• Subtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed) (idea)
• MRI surveillance replaces prophylactic cranial irradiation in SCLC (idea)
• Prophylactic cranial irradiation vs MRI surveillance (technology)
• Sequencing DLL3 engager and B7-H3 ADC in relapsed SCLC (pairing)
• Chemo-immunotherapy induction → maintenance intensification (SCLC) (pairing)

• CASPIAN (phase 3, n=805): Overall survival: 13 months vs 10.3 months, HR 0.73
• ASTRUM-005 (phase 3, n=585): Overall survival: 15.4 months vs 10.9 months, HR 0.63
• DeLLphi-304 (phase 3, n=509): Overall survival: 13.6 months vs 8.3 months, HR 0.6
• IMpower133 (phase 3, n=403): Overall survival: 12.3 months vs 10.3 months, HR 0.7
• ADRIATIC (phase 3, n=730): Overall survival: 55.9 months vs 33.4 months, HR 0.73
• IMforte (phase 3, n=483): Overall survival: 13.2 months vs 10.6 months, HR 0.73

• Rapid chemoresistance.
• Brain metastases.
• No screening beyond CT for smokers.
• Near-universal relapse after first-line therapy in extensive-stage disease; median survival 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.

1. What is the first T-cell engager to improve survival in a common solid tumour?
   Answer

   Tarlatamab (Imdelltra), DLL3×CD3, in second-line small-cell lung cancer: OS 13.6 vs 8.3 months in DeLLphi-304.
2. What is the standard adjuvant treatment after resection of EGFR-mutant lung cancer and what did it do to survival?
   Answer

   Three years of osimertinib (ADAURA): DFS HR 0.20 in stage II-IIIA and OS HR 0.49, five-year OS 88% vs 78%.
3. Why might an alpha-emitting PSMA drug work after lutetium PSMA has stopped working?
   Answer

   Alpha particles (actinium-225) deposit far more energy over 50-100 µm, causing clustered double-strand breaks independent of oxygen and cell cycle, so beta-resistant, hypoxic, or small-volume disease can still be killed; retrospective series show PSA responses in about half after 177Lu failure. Supply of Ac-225 and salivary toxicity are the limits.
4. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.
5. What is the difference between a CT scan and a PET scan?
   Answer

   CT is a fast 3D X-ray showing size and shape; PET shows biology by tracking where a radioactive tracer accumulates (for example glucose uptake with FDG or a specific protein such as PSMA). PET/CT combines both.
6. What is the difference between lutetium-177 and actinium-225 as therapeutic isotopes?
   Answer

   177Lu emits beta particles (range 1-10 mm, crossfire helps bulky heterogeneous tumours, marrow toxicity, 6.7-day half-life); 225Ac emits alpha particles (range 50-100 µm, very high energy, oxygen-independent clustered DNA damage, good for micrometastases, daughter redistribution and supply constraints).

• NCI PDQ: small cell lung cancer treatment: https://www.cancer.gov/types/lung/hp/small-cell-lung-treatment-pdq
• IASLC: tarlatamab first-line maintenance data: https://www.iaslc.org/iaslc-news/press-release/tarlatamab-anti-pd-l1-first-line-maintenance-after-chemo-immunotherapy-es
• Wikipedia: https://en.wikipedia.org/wiki/Small-cell_carcinoma
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462