First Frameshift Mutation of ALK in Non-Small Cell Lung Cancer Remaining Sensitive to Alectinib: Case Report

Abstract

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  Nonrearrangement ALK alterations are rare in NSCLC. As most guidelines focuses on ALK fusions, these variants are often underestimated in routine practice.
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  Frameshift mutations alone can activate the ALK kinase domain without a canonical fusion. In this case, an exon 19 deletion caused strong Ventana ALK immunoreactivity and a durable response to alectinib.
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  Comprehensive genomic profiling (NGS-based DNA or RNA) should be considered in any NSCLC patient—especially mixed histology or rapidly progressing disease—when standard fusion assays are negative.
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  Strong, diffuse Ventana ALK staining predicted alectinib benefit even without an EML4-ALK fusion, supporting its use when sequencing is limited.
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  The optimal dosing for uncommon ALK variants is undefined. This patient’s tolerance of standard-dose alectinib for over 19 months suggests conventional dosing is appropriate pending further data.
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  Multidisciplinary discussion is critical. Pathologists, molecular biologists, and oncologists should jointly review discordant results (eg, ALK-IHC+ / FISH-) to avoid missing rare targetable mutations.