Background: ALK  fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK  rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK  variants that may predict sensitivity to multiple approved ALK inhibitors.
Methods: Comprehensive genomic profiling (CGP) of DNA isolated from formalin‐fixed paraffin‐embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians.
Results: We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK  rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK  internal inversions, RNA testing identified an EML4-ALK  fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an ALK  internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that ALK  internal deletions removing a portion of the N-terminus are drivers themselves and do not result in ALK  fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events.
Conclusion: Rare internal inversions of ALK  appear to be indicative of ALK  fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, ALK  internal deletions are not associated with ALK  fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.
Keywords: ALK rearrangement, inversion, deletion, genomic profiling, targeted therapy