Alice T. Shaw

The current first choice for ALK-positive lung cancer in most guidelines, and the strongest evidence in solid tumour oncology that a drug can be designed to work inside the brain. Five-year follow-up has since shown the majority of patients still progression-free.

It turned the laboratory prediction into a clinical rule: after a second-generation ALK inhibitor, genotype the tumour, and treat the absence of an ALK mutation as evidence that the cancer has stopped depending on ALK.

First-line ALK treatment moved to a drug designed for the brain, and brain metastasis prevention became an explicit design goal rather than a hoped-for side effect. ALK-positive lung cancer is now among the longest-surviving metastatic solid tumours.

It is the cleanest demonstration in oncology that resistance is a property of a particular drug bound to a particular protein rather than a property of the tumour, and that genotyping at every progression can reopen an option that looked closed.

ROS1 testing became standard in lung adenocarcinoma; crizotinib was the first approved ROS1 inhibitor and remains an option, though entrectinib, repotrectinib and taletrectinib now offer brain penetration and resistance coverage.

It defined a class of lung cancer by a rearrangement and a clinical phenotype at the same time, and it is the reason ROS1 testing is recommended for every patient with adenocarcinoma rather than only for those with an obvious risk profile.

The trial that made ALK testing worth doing. It is also the clearest case in oncology of a drug finding its disease after the fact: crizotinib entered the clinic as a MET inhibitor and became an ALK drug because somebody checked.