Roman Thomas

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.

It identified a driver in the one lung histology that had none, and it defined a mechanism, ligand presentation, that requires an antibody against the receptor pair rather than a kinase inhibitor.

It was the first therapeutically tractable alteration found in squamous lung cancer, and in the decade since it has become the standard example of amplification not equalling dependence, because copy number alone has selected patients poorly in trials.