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Small-cell lung cancer has had two real advances in twenty-five years. It is probably four diseases being tested as one, in separate small trials that each need their own control group.
Rudin and eighteen colleagues proposed that small-cell lung cancer comprises subtypes defined by ASCL1, NeuroD1, YAP1 and POU2F3 expression, with different therapeutic vulnerabilities. George's genomes explain why conventional targeting failed: the disease is defined by biallelic loss of TP53 and RB1, and losses cannot be inhibited. Progress since has come from elsewhere, from DLL3 as a surface target and from immunotherapy given at lower tumour burden.
The disease is uncommon enough, and deteriorates fast enough, that individual randomised trials are slow and underpowered, and every one of them spends half its patients on a control arm that is the same in all of them. A platform trial with a shared control, subtype stratification at entry and the ability to drop and add arms is the design the situation calls for, and Lung-MAP has already shown it is operable in squamous non-small-cell disease.
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.
The organising framework for every small-cell lung cancer trial designed since. It is also why the slow progress in the disease is now attributed to treating four diseases as one rather than to the biology being intractable.
Immunotherapy is now part of first-line treatment for extensive-stage small-cell lung cancer everywhere, on the strength of a gain measured in weeks. The size of that gain is the reason small-cell lung cancer remains the clearest unmet need in thoracic oncology.
Why small-cell lung cancer has no targeted therapy in the conventional sense: it is built from the loss of TP53 and RB1, and the drugs that transformed non-small-cell disease inhibit gains rather than restore losses. The NOTCH result pointed at DLL3 and, eventually, at tarlatamab.
Shares Limited-stage small-cell lung cancer, 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, Extensive-stage small-cell lung cancer, Small-cell lung cancer and the tag lung-evidence.
Shares Limited-stage small-cell lung cancer, 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, Small-cell lung cancer, Lung cancer (all types) and the tag lung-evidence.
Shares Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data, RB1, 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, TP53 and the tag lung-evidence.
Shares 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, The undruggable drivers, Immunohistochemistry (IHC), Lung cancer (all types) and the tag lung-evidence.
Shares 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, Immunohistochemistry (IHC), Trial design, endpoints and cost, Lung cancer (all types) and the tag lung-evidence.
Shares 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, Trial design, endpoints and cost, Lung cancer (all types) and the tag lung-evidence.
Shares 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, Trial design, endpoints and cost, Small-cell lung cancer, Lung cancer (all types) and the tag lung-evidence.
Shares 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, Trial design, endpoints and cost, Lung cancer (all types) and the tag lung-evidence.