A novel intergenic region ALK fusion is targetable by alectinib in a non-small cell lung cancer patient with brain metastasis

ALK rearrangement defines a unique non-small cell lung cancer (NSCLC) molecular subtype, of which the patients could potentially benefit from anti- ALK therapies. So far, the outcomes of the canonical EML-ALK patients subjected to ALK inhibitors are well established. However, given the increasing complexity of ALK fusion partners, as detected by high-throughput sequencing, the responses of those with rare ALK fusion events remain to be explored. Here, we report a lung adenocarcinoma patient with brain metastasis harboring an ARHGAP5 downstream intergenic region (IGR) ALK fusion, as detected by using DNA-based next-generation sequencing (NGS), who experienced a partial response to alectinib treatment. While whole transcriptome RNA sequencing (RNA-seq) failed to identify potential ALK fusion transcripts, subsequent targeted deep RNA-seq revealed the expression of EML4-ALK transcripts in the tumor tissue. Given the increasingly application of the ALK-TKIs, it is extremely crucial to define the patients who could be suitable for this treatment in clinic. The present case has provided supporting evidence that non-canonical ALK rearrangements on the genomic level are often functionally relevant and targetable by ALK-TKI, particularly in cases with sub-optimal quantity and quality for RNA validation.