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Example clinical scenario

A 47-year-old man who has never smoked is diagnosed with metastatic lung cancer (non-small cell). Somatic (tumour) testing via a multi-target massively parallel sequencing (sometimes called next-generation sequencing) panel reveals a ROS1 fusion to the CD74 gene.

Impact of the genomic result

The ROS1 gene

  • ROS1 fusions occur in 1%–2% of lung cancer (non-small cell). The most common fusion partner is CD74.
  • Fusions result in constitutive activation and persistent downstream signalling via several oncogenic pathways.
  • ROS1 is phylogenetically related to ALK. This may explain the co-inhibition of both ALK and ROS1 by various tyrosine kinase inhibitors (TKIs) – see below.

Clinical characteristics

What do you need to do?

Management of the current cancer

  • Several TKIs, including crizotinib, entrectinib, lorlatinib and repotrectinib, have shown activity against ROS1-rearranged cancers.
  • Crizotinib and entrectinib are currently funded for routine use in the UK.

Following progression on first-line therapy

  • Several secondary mutations conferring resistance to first-line ROS1-targeting therapy (such as crizotinib) have been identified. These include the G2023R, D2033N and L2026M variants.
  • Lorlatinib and repotrectinib have shown activity against tumours harbouring certain secondary (resistance) ROS1 mutations, but are not recommended by NICE for this indication at present.
  • Patients may be eligible for clinical trials of these and other agents following progression on first-line ROS1 targeting therapy.

For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.

Resources

For clinicians

References:

For patients

  • Lung Cancer Foundation of America: ROS1
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  • Last reviewed: 03/11/2023
  • Next review due: 03/11/2024
  • Authors: Dr Amit Samani
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh, Dr Amal Singh