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Example clinical scenario

A 42-year-old male who has never smoked is diagnosed with metastatic lung cancer (non-small cell). Somatic testing via a multi-target next-generation sequencing (NGS) panel reveals an EML4-ALK fusion gene.

ALK-rearranged lung cancer

The ALK gene

  • Rearrangements of ALK are found in around 5% of lung adenocarcinomas.
  • The most common fusion partner is EML4.
  • Rearrangements can be detected by fluorescent in situ hybridisation (FISH), immunohistochemistry (if appropriately validated) or NGS.
  • ALK rearrangements sensitise tumours to ALK tyrosine kinase inhibitors (TKIs).

Clinical characteristics of ALK-rearranged lung cancer

  • On average, patients are younger than those with wild-type ALK and are more likely to be never, light or ex-smokers.
  • There is no strong association with gender or ethnicity.
  • The vast majority of cases are adenocarcinoma, often containing signet ring cells.
  • ALK-rearranged tumours have a higher propensity for central nervous system metastases than wild-type tumours.

What do you need to do?

Management of the current cancer

  • The presence of an ALK fusion gene makes patients eligible for ALK TKI therapy, potentially for both first- and second-line treatment.
  • Different ‘generations’ of ALK TKI exist with different receptor specificities, binding affinities (to the ALK protein), CNS penetration and clinical efficacy.
  • Several agents are licensed and routinely funded in the UK (such as alectinib, brigatinib, ceritinib) for both first- and second-line treatment.

Following progression on first- or second-line therapy

  • Resistance to ALK TKIs may result from secondary ALK mutations.
  • Research is ongoing to explore the sensitivity of different ALK resistance mutations to different TKIs.
  • Clinical trials may be available for patients who have progressed on ALK TKIs. Some stratify according to molecular testing for secondary ALK mutations.


For clinicians

For patients

Cancer Research UK: About targeted cancer drugs – see section on crizotinib, ceritinib, alectinib and brigatinib

Tagged: Lung cancer

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  • Last reviewed: 04/05/2022
  • Next review due: 04/05/2023
  • Authors: Dr Amit Samani
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh