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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 testing via a multi-target next-generation sequencing (NGS) panel reveals a ROS1 fusion to the CD74 gene.

ROS1-rearranged lung cancer

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

  • Compared with ROS1 wild-type patients, patients with ROS1 fusions are younger and more likely to be ex, light or never-smokers.
  • Like ALK-rearranged lung cancer (non-small cell), some data suggest that brain metastases in patients with ROS1 fusions are not uncommon (Ou and Zhu, 2019).

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 clinicians


For patients

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