Results: Patient with lung cancer (non-small cell) and a somatic (tumour) ROS1 rearrangement
The identification of somatic (tumour) ROS1 rearrangement in a patient with lung cancer has implications for the clinical management of the current cancer, eligibility for clinical trials and, possibly, prognosis.
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
- 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.
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
- European Society for Medical Oncology: Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow up (PDF, 71 pages)
- NHS England: National Genomic Test Directory
- NICE: Guidance relevant to 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
- Ou SI, 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