EvidenceALK-positive non-small-cell lung cancer

Adjuvant treatment for lung cancer is now chosen by genotype. A resected ALK-positive tumour is treated with two years of a tablet instead of four cycles of platinum, which is a different life as well as a different outcome.

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.

For ALK-positive advanced lung cancer, lorlatinib as the first drug offers the possibility of many years without progression and strong protection against brain metastases. Alectinib and brigatinib remain alternatives with a gentler side-effect profile; the choice weighs lorlatinib's cognitive, metabolic and weight effects against its unmatched duration of control.

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.

This is the trial behind brigatinib's first approval, after crizotinib, and it set the 180 mg dose with a 90 mg lead-in that the label uses. For a patient it shows a drug with strong activity in the brain and an unusual early lung side effect that the lead-in week was designed to soften.

ASCEND-4 gave ceritinib its 2017 US first-line approval and showed that a second-generation ALK inhibitor beats chemotherapy in untreated disease. In practice alectinib, brigatinib and lorlatinib, tested against crizotinib rather than chemotherapy, became the usual first-line choices, partly because ceritinib's gut side effects at 750 mg fasted were hard to live with.

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.

The second driver in lung cancer, and the one that proved the first was not a special case. It also established mutual exclusivity as a working assumption: a tumour usually has one driver, so finding it tells you what to give.