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

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.

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).

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

• ESMO: Consensus guidelines for treatment of advanced lung cancer (2020) – includes recommendations for molecular testing and treatment (PDF, 71 pages)
• NHS England: National Genomic Test Directory and eligibility criteria
• NICE: Guidance relevant to lung cancer – many guidelines related to treatments following somatic (tumour) molecular testing
• 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: What is ROS1-positive lung cancer and how is it treated?