Results: Patient with lung cancer (non-small cell) and a somatic (tumour) ROS1 rearrangement

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.

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.

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.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

For clinicians

• NHS England: National Genomic Test Directory
• NICE: Guidance relevant to lung cancer
• NICE: Crizotinib for treating ROS1-positive advanced non-small-cell lung cancer
• NICE: Entrectinib for treating ROS1-positive advanced non-small-cell lung cancer
• NICE: Pathways for lung cancer (see advanced non-squamous (stages IIIB and IV) lung cancer: ROS1-positive)

References:

• Drilon A, Siena S, Dziadziuszko R and others. ‘Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: Integrated analysis of three phase 1-2 trials‘. The Lancet Oncology 2020: volume 21, issue 2, pages 261–270. DOI: 10.1016/S1470-2045(19)30690-4
• Hendriks LE, Kerr KM, Menis J and others. ‘Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up‘. Annals of Oncology 2023: issue 34, volume 4, pages 339–357. DOI: 10.1016/j.annonc.2022.12.009
• Ou SI and Zhu VW. ‘CNS metastasis in ROS1+ NSCLC: An urgent call to action, to understand, and to overcome‘. Lung Cancer 2019: volume 130, pages 201–207. DOI: 10.1016/j.lungcan.2019.02.025
• Shaw AT, Solomon BJ, Chiari R and others. ‘Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: A multicentre, open-label, single-arm, phase 1-2 trial‘. The Lancet Oncology 2019: volume 20, issue 12, pages 1,691–1,701. DOI: 10.1016/S1470-2045(19)30655-2

For patients

• Lung Cancer Foundation of America: ROS1
• Macmillan Cancer Support: Crizotinib targeted therapy – treatment and side effects
• Macmillan Cancer Support: Entrectinib (Rozlytrek®)
• Macmillan Cancer Support: Targeted therapies for lung cancer