ALK-Positive Lung Cancer: — Drugs, Response and What Comes Next

Crizotinib was the first ALK inhibitor and proved the principle that targeting the ALK mutation works. Later clinical evidence showed that alectinib produces longer periods of disease control and crosses the blood-brain barrier more effectively — which matters because ALK-positive cancers frequently spread to the brain. NCCN and ESMO updated their guidance accordingly. Crizotinib remains available but is no longer the standard starting point for most patients.

Lorlatinib is a third-generation ALK inhibitor, more potent than second-generation drugs and designed to overcome the resistance mutations that develop after alectinib or brigatinib. It has strong central nervous system penetration. NCCN includes it as both a first-line option for select patients and as a standard later-line option after progression on earlier drugs. It has a distinct side-effect profile — changes in cholesterol and, in some people, mood or cognitive effects — which your team will monitor closely.

Yes, and the newer ALK inhibitors were designed with this in mind. Alectinib, brigatinib and lorlatinib all cross the blood-brain barrier more effectively than crizotinib and have demonstrated activity against brain metastases in trials cited by NCCN and ESMO. For most patients with ALK-positive disease and brain involvement, an appropriate ALK inhibitor — rather than upfront whole-brain radiation — is now the preferred first approach. Your team will decide based on the number, size and symptoms from the metastases.

Common side effects across the class include fatigue, swelling in the legs, nausea and raised liver enzyme levels. Each drug has a somewhat different profile. Brigatinib can cause early pulmonary symptoms in the first days of treatment that your team will monitor for. Lorlatinib can affect cholesterol levels and, in some people, mood or memory. Alectinib is generally well tolerated, with photosensitivity and muscle aches among the effects to watch for. None of these are reasons to stop without calling your team — many are manageable with dose adjustment or supportive treatment.

Not as first-line treatment. ALK-positive tumours often show low expression of PD-L1, the marker that predicts response to checkpoint inhibitor immunotherapy, and the evidence base for immunotherapy in this group is limited. NCCN guidance places ALK inhibitors, not immunotherapy, as the standard first-line treatment for ALK-positive disease. There is also evidence that using a checkpoint inhibitor before an ALK inhibitor may increase the risk of certain inflammatory reactions. If immunotherapy is being discussed for you, ask your oncologist specifically how it fits with your ALK-positive status.

ALK rearrangement is detected by fluorescence in situ hybridisation (FISH), immunohistochemistry (IHC), or next-generation sequencing (NGS) of tumour tissue. NGS has the advantage of detecting the ALK rearrangement alongside other actionable mutations in a single test. The initial result does not change. At the point of progression — when a drug stops working — a repeat biopsy or liquid biopsy is useful to identify the specific resistance mutation, which guides which drug to use next.