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

A 42-year-old male 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 an EML4-ALK fusion gene.

The ALK gene

• Rearrangements of ALK are found in around 5% of lung adenocarcinomas.
• The most common fusion partner is EML4.
• Rearrangements can be detected by fluorescent in situ hybridisation (FISH), immunohistochemistry (if appropriately validated) or NGS.
• ALK rearrangements sensitise tumours to ALK tyrosine kinase inhibitors (TKIs).

Clinical characteristics of ALK-rearranged lung cancer

• On average, patients are younger than those with wild-type ALK and are more likely to be never, light or ex-smokers.
• There is no strong association with gender or ethnicity.
• The vast majority of cases are adenocarcinoma, often containing signet ring cells.
• ALK-rearranged tumours have a higher propensity for central nervous system metastases than wild-type tumours.

Management of the current cancer

• The presence of an ALK fusion gene makes patients eligible for ALK TKI therapy, potentially for both first- and second-line treatment.
• Different ‘generations’ of ALK TKI exist with different receptor specificities, binding affinities (to the ALK protein), CNS penetration and clinical efficacy.
• Several agents are licensed and routinely funded in the UK (such as alectinib, brigatinib, ceritinib) for both first- and second-line treatment.

Following progression on first- or second-line therapy

• Resistance to ALK TKIs may result from secondary ALK mutations.
• Research is ongoing to explore the sensitivity of different ALK resistance mutations to different TKIs.
• Clinical trials may be available for patients who have progressed on ALK TKIs. Some stratify according to molecular testing for secondary ALK mutations.

For clinicians

• ESMO: Consensus guidelines for treatment of advanced lung cancer (2020) – includes recommendations for molecular testing and treatment
• IASLC: Atlas of ALK and ROS1 testing in lung cancer
• 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: ALK-positive

For patients

Cancer Research UK: About targeted cancer drugs – see section on crizotinib, ceritinib, alectinib and brigatinib