ALK Inhibitor Generations Compared: Crizotinib to Lorlatinib
ALK rearrangements produce a constantly active fusion kinase that drives a subset of non-small-cell lung cancers. Several ALK inhibitors are approved, grouped into generations that differ in potency against ALK, penetration of the central nervous system, and the range of resistance mutations they can still inhibit.
Quick Answer
ALK rearrangements produce a constantly active fusion kinase that drives a subset of non-small-cell lung cancers. Several ALK inhibitors are approved, grouped into generations that differ in potency against ALK, penetration of the central nervous system, and the range of resistance mutations they can still inhibit.
Side-by-side comparison
ALK inhibitors by generation: relative central-nervous-system penetration, coverage of the G1202R resistance mutation, and the toxicities that most shape monitoring.
| Drug | Generation | CNS penetration | Covers G1202R | Notable toxicity |
|---|---|---|---|---|
| Crizotinib | First | Low | No | Vision changes, oedema, nausea |
| Ceritinib | Second | Moderate | No | Gastrointestinal toxicity; taking with food helps |
| Alectinib | Second | High | No | Myalgia, raised CK and bilirubin, photosensitivity |
| Brigatinib | Second | High | Partial | Early pulmonary events; hypertension |
| Lorlatinib | Third | High | Yes | Hyperlipidaemia, weight gain, oedema, mood and cognitive changes |
First Generation: Crizotinib
Crizotinib was developed as a MET inhibitor and also inhibits ALK and ROS1. It binds the ATP pocket of the ALK kinase and blocks signalling from the fusion protein. It outperformed chemotherapy in ALK-positive lung cancer but has modest central nervous system exposure, so brain relapse is common.
Resistance mutations in the ALK kinase domain, and bypass signalling, typically emerge within a year.
Second Generation: More Potent, Better CNS
Alectinib, brigatinib and ceritinib are more potent against ALK and against many crizotinib-resistance mutations, and they achieve higher drug concentrations in the brain. In first-line trials (for example ALEX), alectinib produced longer progression-free survival and fewer CNS progressions than crizotinib.
Each second-generation drug still has gaps: certain resistance mutations, notably ALK G1202R, reduce their activity.
Third Generation: Lorlatinib
Lorlatinib is a compact macrocycle designed to inhibit ALK broadly, including G1202R and compound mutations, and it penetrates the central nervous system well. In first-line use (CROWN) it produced the longest progression-free survival reported for an ALK inhibitor.
Its broad activity comes with distinctive side effects — hyperlipidaemia, weight gain, oedema, and neurocognitive or mood changes — that require monitoring and dose adjustment.
Choosing and Sequencing
A second- or third-generation inhibitor is now the usual first choice. After progression, the resistance mutation profile — obtained from tissue or circulating tumour DNA — guides whether another ALK inhibitor is likely to help, since specific mutations are sensitive or resistant to specific drugs.
Compound (multiple) ALK mutations and bypass mechanisms limit how many lines of ALK inhibition are useful.
Toxicity by Drug and Practical Monitoring
Alectinib is generally the best tolerated of the potent options; the main monitoring is liver enzymes, bilirubin, creatine kinase and, less often, a slow heart rate. Brigatinib carries a small risk of early breathing problems in the first week, so it is started low and stepped up. Lorlatinib's metabolic and neuropsychiatric effects call for lipid panels, weight and blood-pressure checks and a direct conversation about mood and concentration, with dose reduction if they emerge.
Because these drugs are taken for years, the tolerability differences compound. Selecting and sequencing them balances expected disease control against a side-effect profile the person can live with, informed at progression by the specific resistance mutation found.
Key Takeaways
- ·All ALK inhibitors block the fusion kinase's ATP pocket; generations differ in potency and CNS reach.
- ·Second-generation alectinib and brigatinib beat crizotinib first line, especially for brain disease.
- ·Lorlatinib covers the broadest resistance-mutation range, including G1202R, with a distinct toxicity profile.
Put these genes in pathway context
Frequently asked questions
Is crizotinib still a first choice for ALK-positive lung cancer?
Generally no. Second- and third-generation inhibitors produce longer progression-free survival and far fewer central-nervous-system relapses, so they are preferred first line.
What makes lorlatinib different?
It inhibits the broadest range of ALK resistance mutations, including G1202R and some compound mutations, and penetrates the brain well, at the cost of a distinct toxicity profile including hyperlipidaemia, weight gain and neurocognitive effects.
How is the next ALK inhibitor chosen after progression?
By the resistance-mutation profile from tissue or circulating tumour DNA, because individual ALK mutations are sensitive or resistant to specific drugs.
References
Continue Reading
ALK Rearrangements in Lung Cancer: Fusions and Their Inhibitors
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Gene Fusion Testing: FISH, Immunohistochemistry, DNA and RNA Sequencing
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NTRK Fusions Explained: A Tumour-Agnostic Target
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ROS1 Rearrangements in Lung Cancer: A Rare but Targetable Driver
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How Larotrectinib and Entrectinib Work: TRK Fusion Inhibitors
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How Selective RET Inhibitors Work: Selpercatinib and Pralsetinib
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